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Chance and the Distribution.
                                                   of Families.




     In genetic experiments with plants and other animals, the most direct inferences as
     to method of inheritance come from a count of the progeny. For example, if one'
     were to make a cross betwee~ two pure lines. intercross the FJ,and from the inter-.
    cross obtaip approximately three-fourths ofone parental type and one-fourth of the
     other in thl! F z, a simple Mendelian model. one locus witbJ»'P...".aJJeJes...!'lnd-c1Qmi.".
,-llilllc.e-~oJJiJ1..b.elI1kII.~~ This conclusion would be reinforced if the backcross of
     an Fr hybrid (to the pure-line parental type that had not appeared in the F 1) pro.:
     duced progeny of which approximately one-half resembled the. aforementioned;
     parental ty)X's and one-hctlf the Fr hybrid.
          In man, the number of progeny from any single family is usually so ;m~ll that.
    these conclusions would not be warranted. A mating of two .heterozygotes for a.
    recessive defect can produce 4:0, 2:2, I :3, and 0:4 ratios, as ,well as the expected
    J: I, in families offour children. Similarly, the mating A/a X a/a having two chil­
    dren, can produce 2:0 and 0:2 ratios as well as the expected 1:1.
          A bit ofreflection will convince the reader that this is not surprising. Consider., .
    for example, the couple with genotypes A/a and a/a, respectively, having two chil­
    dren. Genetic theory expects them to have one A/a child and one a/a child because
    the A/a parent is expected to produce 1/2 A gemetes and 1/2 a gametes. ffthe A/a.
    parent is the male, this ratio will usually be realized among the sperm. Is there,'
    however, any guarantee that these"sperm will take turns, so to. speak, in fertilizing
    the egg'! Obviously not. The sperm involved in producing the two children could.
    well be A sperm in both cases or a sperm in both. If the A/a parent is the female,                       ,
    there is not even a guarantee that the gametic ratio will be 1/2 A and 1/2 a, since                      !
    each meiosis ordinarily produces only one gamete and the various meioses are
    independent events: what happens in one meiosis does not influence what is to
   happerl the next or any subsequent one. Hence, it could happen easily that the two'
   children of this A/a X a/a mating are both A/a or both a/a.
         Clearly the prediction of genetic results is fraught with uncertainties, events
   over which no one has control. Such uncertainty is generally referred to as'
   "chance." One author has recognized the large element of chance involved byenti.
   t1ing his book <?n genetics The Dice ofDestiny. The reader may well ask: how can .
                                                                                          171            !
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                                                                                                    I

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..'1 ~
     I
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                                                                                       S    I
                                                                                            J
                                                                                            :

                                Chance and (he Distribution
                                                bf Families                                       ..




  In genetic experiments with plants and other animals, the most direct inferences as 

  to method of inheritance come from a count of the progeny. For example, if one 

  were to make a cross between two pure lines, intercross the Flo :and from the inter-; 

  cross oblaip approximately three-fourths of one parental type a~d one-fourth of the, 

  other in lh. F 2• a simple Mendelian model. one locus with tw~ alleles and domi-I 

  nance. wouid be inferred. This conclusion would be reinforced if the backcross of· 

  an F,hybrid (to the pure-line parental type that had not appeared in the F,) pro- i 

 duced progeny of which approximately one-half resembled the aforementioned I 

  parental tyIXs and one-half the F, hybrid.                            :                    '

       In man, the number of progeny from any single family is usually so small that..
 these conclusions would not be warranted. A mating of two heterozygotes for a I
 recessive defect can produce 4:0, 2:2, I: 3, and 0:4 ratios, as ..Jell as the expected :
 3: I, in families of four children. Similarly, the mating A/a X a/a having two chil- I
 dren, can produce 2:0 and 0:2 ratios as well as the expected I: Ii.                         i

       A bit of reflection will convince the reader that this is not s'u·rprising. Consider, '
 for example, the couple with genotypes A/a and a/a, respectively, having two chil­
 dren. Genetic theory expects them to have one A/a child and one a/a child because
 the A/a parent is expected to produce 1/2 A gemetesand 1/2 a gametes. If the A/a
 parent is the male, this ratio will usually be realized among the sperm. Is there,
 however, any guarantee that these sperm will take turns, so to speak, in fertilizing
 the egg'! Obviously not. The.sperm involved in producing the two children could
well be A sperm in both c:;ases or a sperm in both. If the A/a parent is the female,
there is not even a guarantee that the gametic ratio will be 1/2 ~ and 1/2 a, since
each meiosis ordinarily produces only one gamete and the various meioses are
independent events: what happens in one· meiosis does not influence what is to
happed the next or any subsequent one. Hence, it could happen basily that the two
children of this A/a X a/a mating are both A/a or both a/a.
      Clearly the prediction of genetic results is fraught with uncertainties, events I
                                                                          I
over which no one has control. Such uncertainty is generally referred to as
"chance." One author has recognized the large element.ofchance..involved byenti­
tling his book on genetics The Dice ofDestiny. The reader may rell ask: how can
                                                                                      177
J
....-=----~ ~-­



      Ii

                                                                                    /




                   (a)




                  (e)                                       (d)




                  (e)                                       (f)

                  Figure 3.10 Examples of some simple Mendelian traits in hJmans that are relatively bommon: (a)common ba!dness, (b)
                  chin fissure, (c) ear pits, (d) Darwin tubercle, (e) congenital ptosis, (f)epicanthus, (g)camptodactyly, and (h) mid-digital
                  hair. See Table 3.1 for descriptions and modes of inheritance.,
I',
SIMPLE MENDELIAN INHERITANCE                                                             11




   c




                                                                                               Ii
                                                                                               ,
                                                                                                f
Fig. 1-'4 A-C Nail defects in the nail-patella syndrome (anonycho-osteo-dysplasia). In
A they are most severe on the index fingers and (not shown) the thumbs. The little
fingers appear normal. B. Dystrophy of thumbnails in an affected brother. The lunulae
are abnormally large. C. Complete absence of thumbnails in a daughter of the patient
in A and in her eight-year old son. O-G. Some of the bone defects encountered in the
nail-patella syndrome. O. Absence of the patella in the eight-year old boy whose nail
defects are shown in C. (The epiphyseal centers of his femur and tibia have not yet fused
to the shafts.) The boy's mother has a patella (E) but suffers greater difficulties in walk­
ing because the patella-and the associated extensor tendon-is displaced laterally. In
other affected the patella may be in normal position but hypoplastic. F and G: Typical
elbow defects. In F the head of the right radius. somewhat abnormally shaped, is dis­
placed fdrward; in G the left radius, similarly abnormal, is displaced backward. In other
cases the capitulum of the humerus is poorly developed, compounding the problem.
Note also, in F, the exostosis of the coronoid process of the ulna. (A-D courtesy of L. S.
Wildervanck. E-G from Wildervanck, 1950b; courtesy of L. S. Wildervanck and Acta
Radioiogica. )
(a)




(e)                                       (d)



                                                                                    (h)




                                                       ~~~f
(e)                                       (i)                  I
Figure 3.10      Examples of some simple Mendelian traits in humans that are relatively common: (a)common ba!dness, (b)
chin fissure, (c) ear pits, (d) Darwin tubercle, (e) congenital ptosis, (f)epicanthus. (g)camptodactyly, and (h) mid-digital
hair. See Table 3.1 for descriptions and modes of inheritance.'
SIMPLE MENDELIAN INHERITANCE                                                             11




Fig. 1-'4 A-C Nail defects in the nail-patella syndrome (anonycho-osteo-dysplasia). In
A they are most severe on the index fingers and (not shown) the thumbs. The little
fingers appear normal. B. Dystrophy of thumbnails in an affected brother. The lunulae
are abnormally large. C. Complete absence of thumbnails in a daughter of the patient
in A and in her eight-year old son. D-G. Some of the bone defects encountered in the
nail-patella syndrome. D. Absence of the patella in the eight-year old boy whose nail
defects are shown in C. (The epiphyseal centers of his femur and tibia have not yet fused
to the shafts.) The boy's mother has a patella (E) but suffers greater difficulties in walk­
ing because the patella-and the associated extensor tendon-is displaced laterally. In
other affected the patella may be in normal position but hypoplastic. F and G: Typical
elbow defects. In F the head of the right radius, somewhat abnormally shaped, is dis­
placed forward; in G the left radius, similarly abnormal, is displaced backward. In other
cases the capitulum of the humerus is poorly developed, compounding the problem.
Note also, in F, the exostosis of the coronoid process of the ulna. (A-D courtesy of L. S.
Wildervanck. E-G from Wildervanck, 1950b; courtesy of L. S. Wildervanck and Acta
Radiologica. )
1-6. Anonycho-osteo-dysplasia, better known as the nail-pateJla syndrome (Fig. 1­
  4), is one of the traits listed in Table 1-3. <!:all it the np locus. A man and his sister
  both have the trait, and both marry persons who lack it. The man's son, who lacks
  it, marries the sister's daughter, his cousin( who does have it. (a) What is the out­
  look for their children? (b) If their first ctlild is normal with respect to this trait,
  what is the outlook for their next child?
  1-7. Suppose you examine the widowed mother of the man add his sister of exer­
  cise 1-6 and you find that she lacks the nail-patella syndrome. What would you
  conclude about the phenotype and genotype of her late husband (their father)? If
  more than one answer is possible, which islthe more likely, and why?



Table 1-3 Progeny from testcrosses for several dominant traits (For references see
Table 5-1 of Levitan and Montagu, 1977)                           ,
                                            Num~r of Test
                     Trait                  Cross Sibships    Normal     Affected   Total
Anonychia with ectrodactyly (Fig. 1-9)            139         57            66       123
ElliptocytosIS (ovalocytosis). both loci          '65        113            99       212
  (Fig. 13-2)
Epidermolysis bullosa, all dominant forms         50          80            62       142
                                                  i
  (Fig. 1-3)
Nail-pate~la   syndrome (Fig. 1-4)               157         268           288       556
TOlal                                            31         518           515      1033
Ratio                                                          1.006 :
3.29. 	 Infantile amaurotic idiocy (Tay-Sachs disease) is a recessive hereditary abnormality causing death within
        the first few years of life only when homozygous (ii), The dominant condition at this locus produces a
        normal phenotype (/-), Abnormally shortened fingers (brachyphalangy) is thought to bidue't~- a 'genoi"ype
        heterozygous for a lethal gene (BB L ), the hom~~ygote (Sii) being~riormal, and the-9th~rfi(;;;;~Jyg9.!~JBLBL)
        be~r:tgJetha.L What are the phenotypic expectations among teenage children from parents_who ,are both
        brachyphalangic and heterozygous(or''nfantileamaurotic idiocy?
              .               '-~'      '.~    ..--"" '-"--_'_- ..
                                                            -   ,   ,   .


3.30. 	 In addition to the gene governing mfantile amaurotic idiocy in the above problem, the recessive genotype
        of another locus (jj ) results in death before age 18 due to a condition called "juvenile amaurotic idiocy."
        Only individuals of genotype /-J- will survive to adulthood, (a) What proportion of the children from parents
        of genotype liJj would probably nol survive to adulthood? (b) What proportion of the adult survivors in
        part (a) would not be carriers of either hereditary abnormality?
..                                     "




   Table 1-3 Progeny (rom testcrosses (~r several domina,nt                              tr~its (For refer~nces see
   Table 5-1 of Levitan and Montagu, 1977)              i
                                                           Number of Test
                                                           Cross Sibships                Normal         ' Affected        Total
                         Trait
   Anonychia with ectrodactyly (Fig. 1-9)                         39                      57                 66            123
                                                                  65                     113                 99            212
  . Elliptocytosis (ovalocytosis), both loci                                   .j
                                                                           ~    r    1
      (Fig. 13-2)
                                                                  50            .    ~    80                 62            142
    Epidermolysis buJlosa, all dominant forms
                                                                                                         ,
      (Fig. 1-3)
                                                                 157                     268                 288        556
    Nail.patella syndrome (Fig. 1-4)
                                                                 311                     518                 515      I 033
   Total
   Ratio                                                                                   1.006 :




Table 1-4 Offspring in 416 marriages b¢tween various M·N blood types. Data (rom
Wiener et aJ. (1963).
                                                 Progeny                                Total                 Number of
Father            Mother             M             M:N              N               ! • Offspring             Families

   M                M                 71              1"             0                         72                   42
   N                N                  0             0             29                       29                      20
   M                N                  0            43'             0                       43                      23
   N                M                  0            24              0                       24                       i3
       All M X N                       0   ~
                                                    67           ,­ 0                       67                      36
 M          MN                       67             46              0                      113                      63
 MN         M                        60             55              0                      115                      59
   All M X MN                       127            IOIj             0                      228                     122
 N          MN                         0            31             44                       75                      39
 MN         N                          0            40,            27                                               35
   All N X MN                          0            71)            71                      142                      74
 MN                MN                61            118             53                    '232       <              122
         Totals                     259            358 '          153                     770                      416
                                                      , ,
                                                        I
3This apparent contradiction to the laws of heredity is believed to be owing t~ ,illegitimacy. but it may represent
a new mutation, a change in the genetic material of one of the parents.       '
5i




     o
             o
     o




         "
--.~-
                                                        --~~       ..         .~.




./it




           1-6. Anonycho-osteo-dysplasia, better known as the nail-patella syndrome (Fig. 1­
           4), is one of the traits listed in Table 1-3. Call it the np locus. A man and his sister
                                                        1      •                '
           both have the trait, and both marry persons who'lack it. The'man's son, who lacks
           it, marries the sister's daughter, his cousin, who does have it. (a) What ,is the out ­
           look for their children? (b) If their first ehild is normal witt{ respect to this trait,
           what is the outlook for their next child?                          '
           1-7. Suppose y6u examine the widowed ,mother of the man and his sister of exer­
           cise 1-6 and you find that she lacks the nail-patella syndrome. What would you
           conclude about the phenotype and genotype of her late husband (their father)? If
                                                    ,                   1
           more than one answer is possible, which is the more likely, and why?



         Table 1-3 Progeny from testcrosses for several dominant traits (F'or references see
         Table 5-1 of Levitan and Montagu, 1977)    .
                                                                                    i'   

                                                     Number of Test                 !
                             Trait                   CrosslSibships      Normal          Affected   Total 

         Anonychia with ectrodactyly (Fig. 1-9)              39          57                   66     123
         ElliptocytosIS (ovalocytosis). both loci           i 65        113                   99     212
           (Fig. 13-2)
         Epidermolysis bullosa, all dominant forms           50          80                   62     142
           (Fig. 1-3)
         Nail-patella syndrome (Fig. 1-4)                   157         268                  288     556
         Total                                              311         518                  515    1033
         Ratio                                                            1.006 :
3.29. 	 Infantile amaurotic idiocy (Tay-Sachs disease) is a recessive hereditary abnormality causing death within
        the first few years of life only when homozygous (ii). The dominant condition at this locus produces a
        normal phenotype (/-). Abnormally shortened fingers (brachyphalangy) is thought to be due to a genotype
        heteroz.ygous for a lethal gene (881..), the homozygote (88) being normal. and the other homozygote (8 L8 L )
        being lethal. What are the phenotypic expectations among teenage children from parents who are both
        brachyphaJangic and heterozygous for infantile amaurotic idiocy?

3.30. 	 In addition to the gene governing infantile amaurotic idiocy in the above problem. the recessive genotype
        of another locus (jj ) results in death before age 18 due to a condition called "juvenile amaurotic idiocy."
        Only individuals of genotype /.). will survive to adulthood. (u) What proportion of the children from parents
        of genotype IUj would probably not survive to adulthood'! (b) What proportion of the adult survivors in
        part (a) would not be carriers of either hereditary abnormality? .
Table 1-3 Progeny from testcrosses for several domin~nt traits (For'references see
    Table 5-1 of Levitan and Montagu, 1977)
                                                            Number of Test
                          Trait                             Cross Sibships t       Normal        Affected         Total

    Anonychia with ectrodactyly (Fig. 1-9)                           39            57                 66           123
    Elliptocytosis (ovalocytosis), both loci                         65           113                 99           212
      (Fig. 13-2)
    Epidermolysis bullosa. all dominant forms,I                      50            80                 62           142
      (Fig. 1-3)                              ,
    Nail~patella syndrome (Fig. 1-4)                              157             268               288            556
                                                                  311             518               515          I 033
    Total
    Ratio                                                                           1.006 :




  Table 1-4 Offspring in 416 marriages between various M-N blood types. Data from
                                        ,               I
  Wiener et al. (1963).
                                                 . Progeny                        lotal                Number of
  Father           Mother             M             MN                N           Offspring            Families
    M                M                  71             I"              0                72                   42
    N                N                   0            0               29              29                     20
    M                N                   0           43                0              43                     23
    N                M                 ~             24                0              24                     13           .-4

       All M X N                        0            67                0              67                     36
    M            MN                    67            46                0             113                     63
   MN            M                     60            5$
                                                     -,              ~               115                     59
      All M X MN                      127           101'               0             228                    122
                                       ..~.
    N            MN·.t                                              144              75                     39
                 N                      0            4gt                              67
   MNt                                                           ~                                          35
      All N X MN                        0            71               71             142                    74
   MN            MN                    61           118               53             232                   122
          Totals                      259          .358'             153             770                   416
  "This apparent contradiction to the laws of heredity is believed to be owing to illegitimacy, but it may represent
. a new mutation, a change in the genetic material of one of the parents.                   .
,
         Table 8-1 Expected progeny in a random sample of four-children families vhere one
               is A/a and the other a/a, locus A being autosomal
                                                                                              Expected Progeny
                                                                                                           As Proportions
                                                                                                           of Next
                                                                                 In    Numbers~            Generation
         Kind of                                          Number of
         Family                   ProbabililY~            FamiJies b            A/a            a/a             A/a            a/a

         4 A/a                         1/16                     100              400                       1/16
         3 A/a, 1 a/a                  4/16                     400             1200           400         3/16               1/16
         2 A/a, 2 a/a                  6/16                     600             1200          1200         3/16               3/16
         I A/a, 3 a/a                  4/16                     400              400          1200         1/16               3/16
                4 a/ans               ---'1.L.§                 100                            400                            !L!..Q
            Tolal                     16/16                    1600             3200          3200         8/16               8/16
                                                                                                            1/2                 1/2
         'Calculated in the text. 

         bCalculated on the basis of 1600 families. 





      Table 8-2 Expected progeny in a random sample of four-children families where the
      parents are heterozygous for a recessive gene a
                                                                                       Expected Progeny
                                                                                                  As Proportions of
                                                                         In Numbersb              Next Generation
      Kind of                                     Number of
      Family                Probability'          Families b           A/-c            a/a        A/-<                a/a

      4,1/­81/256                                       2025            8100                         81/256
      3.1/-,1 a/a             108/256                   2700            8100           2700          81/256           27/256
      2,1/-,2 a/a              54/256                   1375            2700           2700          27/256           27/256
      I ,1/-,3 a/a             12/256                    300             300            900           3/256            9/256
              4 a/a             1/256                     25                            100                            1/256
        Total                 256/256                   6400           19200           6400          192/256          64/256
                                                                                                         3/4              1/4

      'Calculated in the text. 

      bCalculated on the basis of 6400 families. 

      <.4/- means that the genotype is either A/d or A/a. 





    Table 8-3 Expected progeny in truncate sample of four-children families of which
    the parents are both heterozygous for a recessive gene a
                                                                                                 Progeny in the
       Kind of             Proportions of all                  Proportions of the                Observed Sample
       Family              A/a X A/a Families'                 Observed Families                A/­                   a/a
    3.4/-, I a/a                   108/256                            108/175                   81/175               27/175
    2A/-,2a/a                       54/256                             54/175                   27/175               27/175
    I A/a, 3 a/a                    12/256                             12/175                    3/175                9/175
            4 a/a                    1/256                              1/175                                        ~
      Total                        175/256                            175/175                  111/175               64/175
                                                                                                63.4%                 36.6%
    ·See Table 8-2.
r




    r
                                                                                                                               /
            Table 8-4 Analysis of the data in Table 8-3 by the direct $ib method (Weinberg's
            general proband method)                                    .
                                                                                      Total Sibs of        Corrected
                     Expected        "Observed"                    Sibs/Proband       Probands             Progeny
            Affected Proportion"     Proportion     Probands       Affected: Normal   Affected: Normal     Affected: Normal
                 0           81             0           0               0:0                  0:0                          0:0
                 I          108           108            I              0:3                  0:3                          0:324
                 2           54            54           2               1:2                  2:4                        108:216
               3             12            12           3               2: I                 6:3                         72;36
               4                                        4               3:0                 12:0 •                       12:0
                                                                                                               Total    192: 576
                                                                                                               Ratio      1:3
            'Per 256 four-children families of A/a x A/a marriages in the population.



                                                                                                .,




              Table 8-5 Suggested calculation of the~ gib Fl'IcrilOct:"'1l1ustration is for a
              theoretical truncate distribution of four-child families from ~/a X A/a

                            Number of                Number of                 Number of             Corrected Progeny
             Family         Unaffected/Family        Affected/Family           Families        Normal              Affected
             Type                  (U)                     (A)                    (N)          UAN                 A(A - I)N
             3: I                   3                          I                  108                    324              0
             2:2                    2                         2                    54                    216            108
             1:3                    I                         3                    12                     36              72
             0:4                    0                         4                     I                                    12
                                                                                               Total 576                192




        Table 8-6       Direct sib correction in six families of spongy type polycystic kidneys of
                 onset. (Data from Lundin and Olow, 1         )
                      Unaffected        Affected
        Family        Per Family        Per Family           Number of
        Type          (U)               (A)                  Familie.s (N)                 UAN                 'A(A -   I)N
        A                    I                  I                      3                             3               0
        B                   2                   2                      2                             8               4
        C                   2                   l                     ' I                                            2
        Totals              8                   5                      6                           21                6
                                                                        Ratio                   0.778            0.222
                                                                ExPected ratio                   0.75             0.25
                                                             Expected numbers                   20.25             6.75
                                                                                        x 2 : . 0.106
                                                                                           P;> 0.70
........ 





             .I
~8
        ·.~ .. - ':---.=.-.~




                                                            Chance and the Distribution
                                                                            of Families




                               In genetic experiments with plants and other animals, the most direct inferences as
                               to method of inheritance come from a count of the progeny. For example. if one
                               were to make a cross between two pure lines, intercross the F" and from the inter­
                               cross obtain approximately three-fourths ofone parental type and one-fourth of the
                               other in the F2• a simple Mendelian model, one locus with two alleles and domi­
                               nance, would be inferred. This conclusion would be reinforced if the backcross of
                               an F, hybrid (to the pure-line parental type that had not appeared in the F,) pro~
                               duced progeny of which approximately one-half resembled the aforementioned
                               parental types and one-half the F, hybrid.
                                     In man, the number of progeny from any single family is usually so small that
                               these conclusions would not be warranted. A mating of two heterozygotes for a
                               rece!>sive defect can produce 4:0, 2:2, I :3, and 0:4 ratios, as well as the expected
                               3: I, in families offour children. Similarly, the mating A/a X a/a having two chil­
                               dren, can produce 2:0 and 0:2 ratios as well as the expected I: I.
                                     A bit ofreflection will convince the reader that this is not surprising. Consider,
                               for example, the couple with genotypes A/a and a/a. respectively, having two chil­
,

    .                 _~,Il
                               dren. Genetic theory expects them to have one A/a child and one a/a child because
                               the A/a parent is expected to produce 1/2 A gemetes and 1/2 a gametes. If the A/a
                               parent is the male, this ratio will usually be realized among the sperm. Is there,
                               however, any guarantee that these sperm will take turns, so to speak, in fertilizing
                               the egg? Obviously not. The sperm involved in producing the two children could
                               well be A sperm in both cases or a sperm in both. If the A/a parent is the female,
                               there is not even a guarantee that the gametic ratio will be 1/2 A and 1/2 a, since
                               each meiosis ordinarily produces only one gamete and the various meioses are
                               independent events: what happens in one meiosis does not influence what is to
                               happen the next or any subsequent one. Hence. it could happen easily that the two
                               children of this A/a X a/a mating are both A/a or both a/a.
                                     Oearly the prediction of genetic results is fraught with uncertainties. events
                               over which no one has control. Such uncertainty is generally referred to as
                               "chance." One author has recognized the large element ofchance involved by enti­
                                tling his book on genetics The Dice ofDestiny. The reader may well ask: how can
    ~                                                                                                              177
         ~.
                               -elY.i
/  ',.
       178
                  '.
c                                                          TEXTBOOK OF HUMAN GENETICS                      CHANCE AND THE DISTRIBUTION OF FAMILlES                                                      179
       genetics pretend to be a science if it cannot really predict the results of a given                   failure. The chance of tossing a coin heads, for example, is I: I. one chance of suc­
       mating? Or. to put it more concretely, since chance plays such a large part in genetic                cess to one chance of failure; similarly the odds of obtaining a five in the toss of a
       transmission. of what value are the stated Mendelian ratios? The question becomes                     die are I :5. one chanee of success to five chances of failure. For arithmetic
       especially pertinent. we shall discover below, when the family size becomes greater
                                                                                                             ulation, however, the best way to state the probability is the way it is often instinc­
       than two: 1110.1'1 families then will /lol yield the stated ratios of offspring.
                                                                                                             tively given for the coin example: a~~aJ.1iQt1,..¥"hQs~dc:,Mminator is the nl!.T ber
            Before answering this question it is necessary to understand that genetics in
                                                                                                          ...oLeg.l1,alLy_likely-e..f.ents-flossible-in-th@-osi-tuat,ion,..llJld,er discussion and whosc
       being beset with uncertainties is not singular among the sciences. Every scientist
                                                                                                           _n!l.menl1o~is..the.JlUll1,q~J_qlt.he~e_that~Qnsli!uJe the event whoscfik"ClTil'O'OO is in
      knows that in the real world absolute certainty does not exist: there arc only relative              _q_ue~tion.,.                                                                           ­
      degrees ofuncertainty. To pick a rather absurd example, one could ask the follow.
                                                                                                                  Example: Suppose an urn contains five balls of identical size and shape. Two
      ing two questions of a meteorologist: (I) will the sun rise tomorrow'? and (2) will
                                                                                                             arc black, marked B I and B2, and three arc white, marked WI, W2, and WJ.
      tomorrow be a sunny day? He cannot answer either question with absolute ccr.
                                                                                                             respectively. We reach in to take out one ball. (I) What is the probability of obtain­
              but it is clear that he can answer the first with much more confidence than                    ing the ball marked W2; and (2) what is the probability of obtaining a white ball')
      the sl'cond.
              A great stride in the progress of a science is mad~: when it can ascertain or                                              "I'                                                  I
       measure these relative degrees of uncertainty. The mc:eorologist feels a sense of                                  ( I) P ro b ab 1 Jty 0 f W2   = ___
                                                                                                                                                            n_um_be_r_o_f_W_2_b_al_ls__
                                                                                                                                                          total number of balls present       5
       achievement when he can improve his forecast from "it may rain" or even '"it will
       probahly rain" to "there is a 90 percent chance ofrain:'... JJ'cpmeasurement or quan.
                                                                          1                                                                                   number of white balls           3
       ti.l;lti.Ql}"Qf~uncc:natnt~iS"eallt'a..f~t:61t)alJiJUJ;"                                       ­                (2) Probability of white         = total number of balls present      -
                                                                                                                                                                                              5
     ,._' " Usually the positive aspect of probability is emphasized. We arc more inter.
      ested in the degree we have moved toward certainty than in the amount of uncer­                      Mathematically. these statements would be written:
      tainty left. Hence we think of probability as the likclihoGd ofa desired event rather
      than as the degree to which we fall short of certainty in attaining it.
                                                                                                                                                     P (W2)    = 1/5:
             Let us examine some of the basic properties of probability. Perhaps we should
                                                                                                                                                   P (white)   = 3/5.
      hegin with a well-known example. If a coin were to be tossed and we were asked                       P represents the phrase "probability of' the item in parentheses.
      the probability of its turning up "heads" the immediate answer would be some                         •. How large or now small may probabilities be? Thc....maximum probability
      'ariant of "tinY-fifty:' "one to one" or "one-hal(" If we asked why we gave this                    would be reached if we were satisfied with obtaining any ball present. wfictliCr"'ii
     answer the reply would be roughly: why. it stands to reason; there are two ways the                   was white or black. Thus,
     coin may fall and one of these is heads, so the chance is I out of 2. one-halfor one
     10 one. If we had an evenly weighted die and wished to know the probability of its                                                    P (white or black)    =   5/5   =   I.
     upright face showing five dots when thrown, it does not seem difficult to extend the
     logic of this answer: since any of the six sides of the cube could turn up and the                    Similarly, the mlfllmum probability would come from wishing to obtain so 111 t'
     l:lCe with five dots is only one of these, there is one chance out of six of obtaining                other color than white or black from this urn:
    the "Ii'e." Clearly. the proba 1 ility of success, that is. the likelihood that a desired
    l'Cnt will happen, depends on the number of alternative events that could happen                                                /' (neither white nor black) = 0/5             = O.
    and on the number of these that spell "success."
                                                                                                           This indicates that probabilit~ is a positive number between 0 and I.
            Merely saying "the number of alternative events" C:.tll be misleading. however.
                                                                                                                The sophisticated reader will suggest that probabilities of I and 0 repn:sl'nt
    heca lISC one could argue that in throwing the die on a gi ven throw there arc only
                                                                                                           "certainty," certainty of success and certainty of failure. rl'spectively, This is cor­
    two alternatives. success or failure, obtaining a five or not obtaining a five. and this
                                                                                                           rect. Certainty is possible in a mathematical sense, since a mathematical system
               lead to the belief that the probability of SUCcess was one of two. Obviously
                                                                                                           assumes that only the conditions postulated will occur. In a few simple real situa­
    this is not true: for every chance of obtaining a five there arc five chances of obtain­
                                                                                                           tions this degree of simplicity may be approximated-but there is never a guaran­
    il'g something else. We must modify our statement. therefore, to state that the
                                                                                                           tee that the postulated condition will prevail. Thus we may feci secure that there
    lllJ.l.bah.il~t..j;.,Qf success depends on the number of eqll(/I/J;,.lwn/Jahil' (or equally likely.
                                                                                                           are two black and three white balls in the urn, and this usually docs approximall'
    :1~1b,(ll1alicians-sa.Y;)..Go;€'nts"'fl0ssihlG-and_Lh~!lumber of these""'1IUi'l'Spell
    ~~l;CS,"-                                                                                    _         a mathematical system. but we really cannot guarantee absolutely, for example.
                                                                                                           that one or another of the balls did not disintegrate after wc placed it in the urn. III
          The probabilities discussed above may be stated "one chance out of two" and
                                                                                                           practice, tl},elikelihoQd.of.su~c,~af,l~ull~lI,.pec.te_d.e,y,glltjs_oO,cn so small that we ignore
    " lilt'cham'!' out of six." They could also be phrased as relative odds of success and
                                                                                                           it and we do speak of probabilities of I or 0 even for living things. Thus we have
"
     "-"""J.-______

                                                                                                                    8
                      ,,!   .:.

                                                                                '

0­                                                                                   "
-

a
M
a                                                              Chance andthe Distribution
CT                                                                             of Families
o



                                                                                                         "

                                  In genetic experiments with plants and other animals, the most direct inferences as
                                  to meJhQd, of inheri!anfe~come from a count of tQ~_l'-rogeJ:lY. For example;-if one
                                  were to make a cross between t"'QPureljJle.s, inten::ross tl!e. Fh and from the inter­
                                  cross obtain approximately three-fourths ofone parental type and one-fourth ofthe
                                  other in the F2, a simple Mendelian m~del, onc;Jp~l!s with two allel~~ ;~d do~i­
                                  nance, would be interred. This conclusion would be reinforce<rifthe backcross of
                                  an-F,hybrid (to the pure-line parental type~thai had-not appeared in ti!e F,) pro­
                                  ducedpr()geny~f which appro~imately ol,le-6a-lf resembled ·the' a'forementioned
                                  parental types and one-half the F, hybri4.
                                          In man, the number of progeny from any single family is usually so small that
                                  these conclusions  woui<f     noi'be" ~arr;.~ted Amating-of t~o heterozygotes for a
                                  ~<:e.~si~e_d~fectca'!.PIo_<!uce 4:0,2:2, 1:3. and 0:4 ratio.s. as wella's the expected
                                  .3: I., in families of four children. SimilarlY. the mating A/a X a/a having two chil­
                                  dren, 'can produce '2:0 and 0:2 ratios as well-as the' expected I : I. .       ".  "
                                   . - . A bit of reflection wiUoonvince the reader that this is not surprising. Consider,
                                  for example, the couple with genotypes A/a and a/a, respectively. having two chil­
                                  dren. Genetic theory expects them to have one A/a child and one a/a child because
                                  the A/a parent is expected to produce 1/2 A gemetes and 1/2 a gametes. If the A/a
                                  parent is the male, this ratio will usually be realized among the sperm. Is there,
                                  however, any guarantee that these sperm will take turns. so to speak, in fertilizing
                                  the egg? Obviously not. The sperm involved in producing the two children could
                                  well be A sperm in both cases or a sperm in both. If the A/a parent is the female,
                                  there is not even a guarantee that the gametic ratio will be 1/2 A and 1/2 a, since
                                  each meiosis ordinarily produces only one gamete and the various meioses are
                                  independent events: what happens in one meiosis does not influence what is to
                                  happen the next or any subsequent one. Hence, it could happen easily that the two
                                  children ofthis A/a X a/a mating are both A/a or both a/a.
                                          Clearly the prediction of genetic results is fraught with uncertainties, events
                                  over which no one has control. Such uncertainty is generally referred to as
                                  "chance." One author has recognized the large element ofchance involved by enti­
                                  tling his book on genetics The Dice of Destiny. The reader may well ask: how can
                                                                                                                         117
     :
;> ".      '&
    178
                                                    TEXTBOOK OF HUMAN GENETICS                  CHANCE AND THE DISTRIBUTION OF FAMILIES                                               179
    g('netics pretend to be a science if it cannot really predict the results of a given
                                                                                                failure. The chance of tossing a coin heads, for exam pic, is I: I, one chance of suc­
    mating'.' Or, to put it more concretely, since chance plays such a large part in genetic
                                                                                                cess 'to one chance of failure; similarly the odds of obtaining a fivc in the toss of a
    transmission. of what value arc the stated Mendelian ratios? The question becomes
                                                                                                die are I :5, one chance of success to five chances of failurc. For arithmetic manip­
    cspecially pertinent. we shall discover below. when the family size becomes greater
                                                                                                ulation. however. the best way to statc the probability is the way it is oftcn instinc­
    than two: most families then will flot yield the stated ratios of offspring.
                                                                                                tively given for the coin example: as a .fractioQ~,ho~cIdC'iiQiiilnatodi!£_lbe_number
         Aefore answering this question it is necessary to understand that genetics in
                                                                                                QLtqlJ.alh: likcJLe~yenJs_possjblc_in Jhc~iJ.!.Iali.OT'l_!.I.!1der discussion and who..:;e
    hcing beset with uncertainties is not singular among the sciences. Every scientist
                                                                                               in umerato~ is the n umber oLtl;le~e_thill, cQ1Jstitllle.tl1e.eveIlLwhosdi kcl.i hoodj!!jn
   knows that in the real world absolute certainty docs not exist: there arc only relative      question,.
   dcgrees of uncertainty. To pick a rather absurd example, one could ask the follow-
                                                                                                     Example: Suppose an urn contains five balls of identical size and shape. Two
        two questions of a meteorologist: (I) will the sun rise tomorrow'! and (2) will
                                                                                                arc black. marked 81 and 82, and thrcc arc white. marked WI, W2, and W1.
   tomorrow be a sunny day? He cannot answcr either question with absolute cer­
                                                                                                respectively. We reach in to take out one ball. (I) What is the probability of obtain­
   tainty. but it is clear that he can answer the first with much more confidence than
   the sccond .                                                                                 ing the ball marked W2; and (2) what is the probability of obtaining a white ball')
         .. great stride in the progress of a science is mad~: when it can ascertain or                                                         number ofW2 balls          ~
   measure thesc relative degrees of uncertainty. The mc:eorologist feels a sense of                          (1) Probability of W2 = total number of balls present          5
   achicvement when he can improve his forecast from "it may rain" or even "it will
   probably rain" to "there is a 90 percent chance of rain. " The measurement or quan­                                                         numbc·r of white balls        ~
   titation of uncertainty is called !1 rohahility.                                                         (2) Probability of white = total number of balls present         5
         Usually the positive aspect of probability is emphasized. We arc more inter­
  ested in the degrec we have moved toward certainty than in the amount ofuncer­                Mathematically. these statements would be written:
  tainty leti. Hence we think of probability as the likelihood ofa desired event rather
  than as the degree to which we fall short of certainty in attaining it.                                                              /,(W2)    =   1/5;
                                                                                                                                     P (white)       3/5.
        Let us examine some of the basic properties of probability. Perhaps we should
  hegin with a well-known example. If a coin were to be tossed and we were asked
                                                                                               @,=eprescJ)ts.th~ph(a~g"::'lrQbl'lJ:tililJ'...QC the item in pnrentheses.
  the probability of its turning up "heads" the immediate answer would be some
                                                                                                    How Inrge or how small may probabilities be? The maximum probability
  ariant of "fiftY-fifty," "one to one" or "one-half." If wc asked why we gave this
                                                                                                would be reached if we were satisfied with obtaining any ball present, whether it
 answer the reply would be roughly: why. it stands to reason: there arc two ways the            was white or black. Thus,
 coj n may fall and one of these is heads. so the chance is lout of 2, one-half or one
 to one. If'e had an evenly weighted die and wished to know the probability of its                                         P (white or black) = 5/5        =<i)
 upright fnce shOwing five dots when thrown. it docs not seem difficult to extend the
 logic of this answer: since any of the six sides of the cube could turn up and the            Similarly, thc rninimuQlJll·Q.babiJity would come from wishing to obtain some
 nll'c with fie dots is only one of these. there is one chance out of six of obtaining        other color than white or black from this urn:
 the "five." Clearly. the proba 1 ility of success, that is. the likelihood that a desired
l'Cnt vill happen. depends on the number ofalternative events that could happen                                       P (ncither white nor black)         = 0/5 =(2)
and on the number of these that spell "success."
                                                                                               This indicates that J~'=9bability is a posi!ive number betweeo!b and I)
       Tvh.'rdy saying "the number of alternative events" can be misleading. however.
                                                                                                     The sophisticated readcr will suggest that probabilities of 1 and 0 represent
because one could argue that in throwing the die on a given throw there arc only
                                                                                               "certainty," certainty of success and certainty of failure, respectively. This is cor­
two a!ternati·es. success or failure. obtaining a five or not obtaining a five. and this
                                                                                               rect. Certainty is possible in a mathematical sense. since a mathematical systelll
might lead to the belief that the probability of success was one of two. Obviously
                                                                                               assumes that only thc conditions postulated will occur. In a few simple real situa­
this is not true: for cvery chance of obtaining a five there arc five chances of obtain­
                                                                                                tions this degree of simplicity may be approximated-but there is never a gUllrnn·
II'g something else. We must modify our statement, therefore, to state that thc
                                                                                               tec that thc postulated condition will prevail. Thus we may feci secure that there
pronability ofSuccess depends on the number of ('quail)' /lrobah/c (or equally likely.
                                                                                               arc two black and thrce white balls in the urn, and this usually does approximate
as thc mnthelllaticians say) events possible and the number of thesc that spell
SUCt'l'ss.                                                                                     a mathematical system, but we really cannot guarantee absolutely. for example,
                                                                                               that onc or another of the balls did not disintegrate after we placed it in the urn. In
      The probabilities discussed above may be stated "one chance out of two" and
      chance out of six." They could nlso be phrased as relative odds of success and
"Illlt'
                                                                                               practice, the likelihood of such an unexpected event is often so smalUl}a,t weigno!:r
                                                                                               it. and we do spcak of probabilities of i or 0 even for living things. Thus we h:lVl'
.   ~
                                                                                                                                                                                                           ,.~
       l1:fO                                                          TEXTBOOK OF HUMAN GENETICS                         CHANCE AND THE DISTRIBUTION OF FAMILIES                                                                           18

       seen already that we,ignore the p-robabililY of new mutations when we predict that                                               Urn A Urn B      Urn 1 Urn B      Urn A Urn   [j       Urn 1 Urn R    Urn 1 Urn B
       the cross:                                                    p
                                                                                                                                          0)G)             CDG)             0)G) (0G)                             QG)
                                              A/A X :1/:1 - all A/A.                                                                      0)0              (00              0) 0' (00                             80
           In probability terms we arc saying
                                                                                                                                          G)G)             CDG)             8G) (0G)                              0G)
                                           P (A/A X ..1/.·1 -         A/A) = I.
       and this cross is therefore usually wntten
                                                                                                                                          0)0              (00              80 (00                                00
                                               A/A X A/A -            I A/A.
                                                                                                                                          Q. Q             CDQ              8Q 0Q                                 QQ
               Implicit in asking the probability of obtaining a Il-hill' ball from the urn is the                                        88               08               8 8 08                                08
       Idea that il docs not matter whether we obtain W I. Wi. or W3. Any of these alter­
       n:! I i Vl' e'en Is spells success. Thus.                                                                        Fig. 8-1 The 30 combinations possible when a ball is drawn from each of two urns i
                                                                                                                         the first urn contains 2 black balls and 3 white balls, the second contains 3 black Oil!'
                                         P (white) ==
                                                          I   +   I   +   I                                              and 3 white ones, and the balls are equal in size but distinguishable by numbpr.


                                                          1/5     +   1/5     + 1/5.
                                                                                                                              Thus. 

      Hut.
                                                                                                                                                                                                 x3 

                                                  P(WI)= 1/5. 
                                                                                                 P (black. black) = 5 X 6
                                                  I' (W2) = 1/5. and 
                                                                                          .;                      2 3
                                                  P (W3) = 1/5. 
                                                                                                                    ,= 5 X'f;'
      Iknec.
                                                                                                                               But. 

                                 P(white)     =    peW!)      +   P(W2)        +   P(W3).
                                                                                                                                                               '2 

            111 ot her ords.jla II erelll has S(xccqLalt~p.wtiJ;G,J'1J;w.);J!oJla.Uaj,n m.c.n.t..,Q,f a llt.                                             ~_~       = I' (black from        urn A)
     a Ill'rna I i e is considered at tai n,1l1cn.l~ofTt.h('TdesiFC&eVcrr1'!'"tht?"flf(-)/!ahilil,h.4).t,;.IlC,1:~.~
     i~1'i11'7f1TIi(' [I}'{)bahiliI ic..!i-!J£Jjw.(!_lJi/'CI;lJati-w.l•.J(J!~!1IS-J n
                                                                     com monsen.'ie terms,                                     and
      when we arc nol particular or choQsy the chances for success areincreased.                                                                               'J
           An equally interesting probability is that of a success which is composed or                                                                                P (black from urn B).
                                                                                                                                                                6
     scwral eents thaI must happen simultancously or ill succession. Clearly, this
      prohahility must be smaller than the likelihood of attaining anyone of the events                                       Thus. the probability of obtaining black balls from both urns is the product ()
     alone. How much smaller? To solve this problem let us relurn to the urn with the                                    the probabilities or obtaining a black baH from each urn.
     10 hlack halls and the three white ones and set up a second urn with three black                                       We may generalize this into a rule:.J1l£'prohahilil.1' Oro/Jlaillillg ('('rtaill sill/III
     halls. 83. 84. B5, and Ihree white ones. W4, WS. and W6. If a ball is to be removed                                 f a 11(:tJ.IIJ-(Qt-s,ucc~si~c:,I:J:l11..W.l--llJ.(;'.J1lJ.1d.IJ5;t....Q[    11U:"'IID1!i'tilri1TTif'n'JiTl/(·   (w·n I.'
     from each urn. how likely is it. for example. that both will be black? To answer this                               illl·()lJ.;(:lLJ.J&..chcck,Jbi.s~generalization. we may note that.
     c may return to our basic concept of probability and enumerate how many                                                                                                                            -
     l'qually probable events. each consisting of one bal! from urn A and one ball rrom                                                                          I ) (white. w h'
                                                                                                                                                                        .       Itc)        =   '3 X (;
                                                                                                                                                                                                 5 .1
     urn B. can happen and no Ie how many of these consist ()f a black ball from each
     urn. The equally probable events arc shown in Fig. 8-1.                                                                                                                                     9
                                                                                                                                                                                            "" 30
                There arc .10 equally probable events and 6 of these represent pulls of two black
     1.,111 .... TIm'>,
                                                                                                                         and this corresponds to the enumerated proportion.
                                       P (black. black) ;", 6/.10           = 1/5.                                          . This rule too. fits our commonsense expectations. The likelihood that both wil
                                                                                                                         happen must be smaller than the likelihood ofcither one alone. I'or each c )uJd Oftl'l
     NOlI.' Ihal Ihe 30 in the denominator is the product of the number or balls in urn
                                                                                                                         happen without the other. Since probabilities are fractions less than one, multipl~
-.   : and the number of balls in urn B: likewise, the 6 in Ihe numerator is the product
                                                                                                                         ing them has the effect of producing a still smaller fraction. tha,1 is. decreasing th,
     oflhe Ilumherofblack balls in urn A and the number of blacks in urn B.
      no    '                                                                                                            probabilitv.
•

     Jil2 	
            #
                    .J
                                                                         TEXTBOOK OF HUMAN GENETICS              CHANCE AND THE DISTRIBUTION OF FAMILIES                                                            183

.'         This "'plUltipJkatioll~r,uk;;:";s valid whether the desired events occur simulta ­
     ncously or in a particular order. Furthermore, it is applicable whether the proba­
                                                                                                                 WHA T THE GENETIC RATIOS MEAN

     hilitics of successive events arc independent or dependent. Drawing balls from the                          We may now consider the meaning of the Mendelian ratios. 

     tO urns-described above-is an example of independent probabilities. where the
     rrohability of one event does not influence the probabilty of another in the series.
                                                                                                                 1I1ealling /: A genetic ratio sta(~.Llu:..pt;abaililil,l,-:lh[q~si!Jglc:.hil:!Jl. When we state 

                                                                                                                                    ~                                                                                  .
                                                                                                                                                 A/a X a/a ...... 1/2 A/a, 1/2 a/a
     Likewise. if only one urn is used and the ball replaced between pulls. the probabil ­
     ities of successive choices are independent. To illustrate tJ!:pendeflt nro.babililies we.,                 we are saying that at any given birth from these parents the odds arc I: I that the
     may consider only the first urn and calculate, for example. !!l$..n(ob@jLit¥~oipick­                        child will be a/a. On the other hand, for the mating
     in a black ball twice iIl..-succ~ssi0n..if-t·tu;:uirst~Q.Q.e..r~mo.xedjs not seen and 110t
     replaced )efore m!.Uil'l~Q.tJt...lJ1e_sf.CQn.d_                                     )                                                 Ala   X A/a     -+   1/4 A/A. 1/2 II/a, 1/4 a/a.
      "';;;';"Forrt~ choice. as before.
                                                                                                                 the stated ratio means that at any given birth there is twice as much chance that
                                              P (l31 or 82)              = 2/5.                                  the baby will be A/a than that it will be A/A. Likewise the odds are 2: I for A/a
                                             """""'---"!""--=:;.:00Ii!'!"- ­                                     versus a/a and I: I for A/A versus a/a. If A is dominant over a, the probability is
     I f the first choice is successful. only four balls remain in the urn and only one of
                                                                                                                 3/4 that a child from the last mating will show the A phenotype. 1/4 that it will
     I hese is black. Therefore. for the second choice
                                                                                                                 show a phenotype, in other words, three times as much chance for gene A to he
                                                 P (black) = [1.4......·                                         present at least once than for its complete absence, a/a.
                                                   .:-.lI(l$).

                                                                                                                 Meaning 2:,..!.1kall,ll.,sJbsllip..+hfM'e,5uit..-suggested.lJ,v..Jl,u;...ge/l£,tic ratio has the W!.ldal
     The probability that both events happen is. then
                                                                                                                 prohabili1.I. This probability is usually /lot the probability in the Mendelian ratio.
                                        2/5 X 1/4                 = 2/20     = 1/10                            "-but must be calculated for each case.
                                                                                                                      The genetic ratio leads us to expect that the distribution of children in a family
           The student is often disturbed by dependent probabilities because it seems
                                                                                                                 will conform to this ratio. but we know it usually will not do so. For example. if
     more necessary than for independent probabilities to suppose that the first choice
                                                                                                                 the parents in the mating
     is slIccessful before calculating the probability of the second. He should keep upper­
     most in mind that we arc seeking the likelihood that both events do happen. We                                                              A/a X a/a       ->   1/2 :I/a. 1/2 a/a
     wish to...calculate the probability of success. not the probability of failure. Failure.
     not obi5ininii'he desired resuft"tndudes all the other results that could occur: the                        decide to have two children the ratio "predicts" that they will have one A/a child
     lirst choice is "right" but the second "wrong." the first wrong even if the second is                       and one a/a child. But our biological knowledge, and observation of actual fami­
     right. or both choices are wrong. Calculating the probability of failure on the same                        lies. tells'us that such families will consists of two A/a children or two a/a children
     basis used for the probability of success verifies our result:                                              as well as one A/a and one a/a. Using our rules of probability and the first meaning
                                                                                                                 for the genetic ratio, we can calculate the probability or expected relative frequency
                                  I' (black. white)               = 2/5   X 3/4 = 6/20                           of these sibships.
                                  P (white. black)                    3/5 X 2/4 = 6/20
                                  P (white. white)                =   3/5 X 2/4 = 6/20                                                 , 1'(2:1/a)   =   /'(/I/a. A/a)   =   1/2 X 1/2      =   1/4.
     Sinn' any of these alternative spells failure.                                                              Likewise.
                              P (Failure) = 6/20                  +          +          = 18/20.
     Since
                                                                      6/20       6/20
                                                                                                                                        )Jjgj£) = P(a/a. a/.£l;.             1&~2          =
                                                                                                                 For one A/a and one a/a, we should note that this may happen in two ways. the
                                                                                                                                                                                                1/4.
                                                                                                                                                                                                       ­
           /' (Success)   + 	P (Failure) =   1*                                                                      birth first or the a/a first.
                            P (Success) 	    I - P (Failure)                                                         Therefore.
                                             I - 18/20
                                             2/20 = 1/10 = the same, result obtained directly.                                                    lJd/a. a/2)      = y2      X 1/2     =   I~
                                                                                                                                                 ..£(aLq~.Jta.),~tb2~UL2 =                 1~Jl.n~L
                                                                                                                                      ,...llWL<ca.IldJ ll.IJJJ     = JL4     +   1/4   =   1/2.
     *This is a usl'ful relation 10 keep in mind. Unlike the case above. it is Qnl'n easier 10 calculate the
     prnhahility or I l i ohwining the desired result. and then subtra(:ting rrom unily. than to calculate
                                                                                                                 The previous line is unique because the probability of obtaining the "expected"
     direrllv lhe prnhahilily or the desired result.                                                             ratio is the same as a fraction in the ratio.
.,                                                                                             CHANCE AND THE DISTRIBUTION OF FAMILIES 	                                                        183'
     "1~2 	                                                   TEXTBOOK OF HUMAN GENETICS

                                                                                                                WHAT THE GENETIC RATIOS MEAN
                                                                                                                                                                                                                        'I
(.
            This "multiplication rule" is valid whether the desired events occur simulta­
      neously or in a particular order. Furthermore, it is applicable whether the proba­
      hilities of successive events are independent or dependent. Drawing balls from the                        We may now consider the meaning of the Mendelian ratios. 

      two urns-described above-is an example of independent probabilities, where the                            Meaning I:       :'~genelic rgti!Lslq}e~_lh(' [JrQhal!.W.!J~.t(U· (LsU!gle..bil:th. When we state 

      probability of one event docs not influence the probabilty of another in the series.
                                                                                                                                               .A/a X a/a .......    II1JIjJl._IJ2.~q/.a 

      Likewise. if only 011e urn is used and the ball replaced between pulls. the probabil­
      ities of successive choices are independent. To illustrate dr.11£'ndent probabilittes_,e                we are saying that at any given birth from these parents the odds are I: I that the
      may consider only the first urn and calculate, for example, the .P!9babilit.y of pi~k­                    child will be a/a. On the other hand. for the mating                 ­
      ing.a_hIHdsJ!.~IU~ice"",iJ;uuccession, if the Jirst one rem~qye_dJs_fJQLScgO_.mJLI.1()t
      I~nlacc.(lpefore pulling_o.uJ_the..se.cond.                                                                                         A/a X A/a ....... 1/4 A/A. 1/2 A/a, 1/4 a/a,

                                                                                                                                          ----------.--~-'.­
            fool' the first choice. as before.
                                                                                                                 the stated ratio means that at any given birth there is twice as much chance that
                                            P (BI or B2) = 21J.                                                  the baby will be A/a than that it will be A/A. Likewise the odds are_2..:...Lfm.,..dul
                                                                                                                _v_e[s.u~ALa and.t:J fOL!1L.:cCv.ersus~ala. IfA.is._<:!QOJi(l3tlJ..o.Y.cL(1. the probability is         I
      If the tirst choice is successful. only four balls remain in the urn and only one of
                                                                                                                 ~/~thauuAil.dJi:Q.qUb!!Jas.tmating...w.illshow-th~...A....phcnot.y.pe. J./.;l...lb.3LiJ~
      these is black. Therefore. for the second choice
                                                                                                                 sho~{L1~henotYJ!e, in other words. three times as much chance for gene :I to be
                                               J:.Jhj~c;Jsl_=_tM_                                                present at least once than for its complete absence. a/a.
                                                                                                                 Meaning 2: itl,l1fJ,ILSiqAbiv.• lhe..resuiUu&qcsf.ecLby.. tb.('"gclI.cli.(.;..raUQ.ba:s..tlu· "Iot/ql
      The probability that bOlh events happen is. then
                                                                                                                 probabili/..!:. This probability is usually not the probability in the Mendelian ratio.
                                         2/5_~_1./_4   = 2/2Q....:;.....lLLO                                     but must be calculated for each case.
                                                                                                                      The genetic ratio leads us to expect that the distribution of children in a family
            The student is often disturbed by dependent probabilities because it seems
                                                                                                                 will conformJo this ratio, but we know it usually will not do so. For exam"plc. if
      more necessary than for independent probabilities to sUJ)pose lhat the firSt choice
                                                                                                                 the parents in the mating
      is successful beforecalcutating tlieprobability of the second. He should keep upper­
      most in mind that we arc seeking the likelihood that both events do happen. We                                                            A/a X a/a ....... 1/2 A/a. 1/2 a/a 

      wish to calculal~J!l<;..probability of SIlC(!'.!S. not the probability of failure. Failure.
      not obtaining the desired result, includes all the other results that could occur: the                     decide to have two children the ratio "predicts" that they will have one il/a child
      first choice is "right" but the second "wrong." the first wrong even if the second is                      and one a/a child. But our biological knowledge. and observation of actual fami­
      right. or both choices are wrong. Calculating the probability offailure on the same                        lies. tells us that such families will ~onsists of two A/a children or twoJl/a children
      hasis used for thc probability of success verifies our result:                                             as wellas one A/a and one a/a. Using our rules of probability and the first meaning
                                                                                                                 for the genetic ratio. we can calculate the probability or expected relative frequency
                                 f> (black. white) = 2/5 X 3/4 = 6/20                                            of these sibships.
                                 P (white. black) = 3/5 X 2/4 = 6/20
                                 P (white. white) = 3/5 X 2/4 = 6/20                                                                    lX?tJLa) "" fJJ/a...::l£g) =Jj2          X 1/2 = l/.i 

      Since any of these alternative spells failure.                                                             Likewise, 

                             P (Failure) 	= 6/20       +   6/20   +   6/20     =   18/20.                                               J.j2a/q)    = eLqLQ,.J1£q)       = JJ~ X 1/2 = -1L4:
      Since
                                                                                                                  For one A/a and one a/a. we should note that this may happen in two                     Vay~,   the
        /' (Success)   +   P (Failure) = 1*                                                                       A/a birth first or the a/a first.
                           P (Success) 	= I - P (Failure)                                                              Therefore.
                                        "" I - 18/20
                                          = 2/20    = 1/0 = the same result obtained directly';                                                                 = 1i2._~~LL2-=--ljS..
                                                                                                                                                 .P'(d/.i1,-a.iJl)
                                                                                                                                                   p(f}ja. A/.Q.l    =
                                                                                                                                                                     l.a~>-U.L2 = 1/..4. and
                                                                                        ./
                                                                                                                                        L'<L:!/a   and I a/!!..~ =:..1/4 + 1/4 = t.Lb
      *This is a useful rcialion to keep in mind. Unlike the case above, it is often ('asier 10 calculale the     The previous line is unique because the probability of obtaining the "cxpceted"
      prohahility of I/O/ obtaining the dcsir('d rcsult. and Ihen subtracting from unity. than to calculatc
      dirl:l'lly tht' prnhahility of the desired result.                                                          ratio is the same as a fraction in the ratio.
l~O         '~
                                                                     TEXTBOOK OF HUMAN GENETICS                    CHANCE AND THE DISTRIBUTION OF FAMILIES                                                   1

      seen already that l::-e ignore the probability of new mutations when we predict that                                       Urn A Urn B   Urn A Urn B     UrnA Urn Il   Urn A Urn B   UrnA Urn B

      thc cross:                                                                                                               ii8 0 fl0 0                      8G)              00         GQ
                                            ~~"""'aIlA/A.                                                                      "1100~00                          00               00         80
      In rrobability terms we are saying
                                                                                                                               -ott   0 @ -.1 0                  8@               G)0        80
                                         P lJ/A X A/A ....... A{"-L::'--l. 

                                                                                                                                      80        0                80               G)0        80
      and Ihis cross is therefore usually written

                                            .1/..1   X A/A .......   J A/A. 

                                                                                                                                      88 08                      G8               G8         G8
           Implicit in asking the probability of obtaining a while ball from the urn is the                                           08 08                        8              0)         08
      idea that it docs not matter whether we obtain WI. W2. or W3. Any of Ihese alter ­                           Fig. 8-1 The 30 combinations possible when a ball is drawn from each of two urns
      natin- CTnts spells success. Thus.                                                                          the first urn contains 2 black balls and 3 white balls, the second contains 3 black onl
                                                                                                                   and 3 white ones, and the balls are equal in size but distinguishable by number.
                                       I' (white) :: I      +   I    +   I
                                                                5

                                                         1/5    +    1/5     +
                                        Thus,
      Aul. 

                                                                                                                                                                              2X3
                                               P(W!) = 1/5. 
                                                                                        P (black, black)     =	5 X 6
                                               P (W2) = 1/5. and 
                                                                                                            2        3
                                               P(W3) = 1/5. 
                                                                                                             =   5X       6'
      IicncC'.
                                                                                                                        But.
                               I'(while)        P(WI)       +   P(W'l)       +    I'(W3).
                                                                                                                                                     2
                                                                                                                                                              P (black from urn A)
             In other 'ords:..i.fall erelll has sereral allf'!1l.S!.!.i.!,t.lill!2IS and allainQl£I1J •o C'lny                                     5
      ill!l:UEltixl,~is~(~(msidcreJ:LaJtiljnmcr!t..Qf.lhc..desired>e_vcnl. the J!f'Jh(//JiliO' IJj'SIIC<'l''
                                                                                                                        and
      IS (II(' SUIIl o[lhe pro/'ahililies of'lliese allemalire Ji}f!Ul. In commonsense lerms.
      hell we arc not particular or choosy the chances for Success arc increased.
            .-n equally interesling probability is that of a success which is composed of
                                                                                                                                                     ~        P (black from urn 8).
     sewal en~nts that must happen simultaneously or in succession. Clearly. Ihis
      probahilily must be smaller than the likelihood of attaining anyone of the events                                 Thus. the probability of obtaining black balls from both urns is the product 0
     alone. How much smaller'! To sol'(' this problem let us relurn to the urn wilh Ihe                           Ihe probabilities of obtaining a black ball from cach urn.
      two hlack halls and the three white ones and set up a second urn with Ihree black                                  We may generalize this into a rule:.:rhf.•J!rohahilill' (!( ol>ta;I/;l/g cl'rtoiJl.:Ji!PU
     halls. A3. R4. R5. and three white ones. W4. W5. and W6. If a ball is to be removed                           tal/eOIlS (or suq::£l>siyc,) _('n'llls is II/(' prodl~<.!_!f Ille pmhahilifil's 0" Ihe l'r(!}fi
     From each urn. how likely is it. for example. that both will be black? To answer Ihis                         Iiimln,:d.To check this generalization. ;"'c may note that
     c may return to our basic concept of probability and enumerate how many
                                                                                                                                                           .      .) 3 	 3
     l'qually probable events. each consisting of one ball from urn A and one ball from                                                               P (whIte. whIte = 	 5 X "6
     urn H. can happen and note how many of these consiSI of a black ball from each
                                                                                                                                                                                  9
     urn. Thl' equally probable events arc shown in Fig. 8-1.
                                                                                                                                                                                  30
            There arc 30 equally probable events and 6 of these represent pulls of two black
     I Ills. Thus.
                                                                                                                   and Ihis corresponds to the enumerated proportion.
                                      I'(black. black)      =   6/30                                                    This rule too. fits our commonsense expectations. The likelihood Ihat both wil
                                                                                                                   happen must be smaller than the likelihood ofeilher one alone. for each c .wld 011L'1
      Note Ihat the )0 in the denominator is the product of the number of balls in urn                             happen without the other. Since probabilities arc fractions less than one. nlultipl)
i   ,   and the number of balls in urn R: likewise. the 6 in the numeralor is Ihe product                         ing them has the effect of producing a still smaller fraction. that is. dccreasing 1h
     (11' thl' numher of black balls in urn A and the number of hlacks in urn R.
                                                                                                                   probabilitv.                                                       .
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GENETICS

  • 1. Chance and the Distribution. of Families. In genetic experiments with plants and other animals, the most direct inferences as to method of inheritance come from a count of the progeny. For example, if one' were to make a cross betwee~ two pure lines. intercross the FJ,and from the inter-. cross obtaip approximately three-fourths ofone parental type and one-fourth of the other in thl! F z, a simple Mendelian model. one locus witbJ»'P...".aJJeJes...!'lnd-c1Qmi.". ,-llilllc.e-~oJJiJ1..b.elI1kII.~~ This conclusion would be reinforced if the backcross of an Fr hybrid (to the pure-line parental type that had not appeared in the F 1) pro.: duced progeny of which approximately one-half resembled the. aforementioned; parental ty)X's and one-hctlf the Fr hybrid. In man, the number of progeny from any single family is usually so ;m~ll that. these conclusions would not be warranted. A mating of two .heterozygotes for a. recessive defect can produce 4:0, 2:2, I :3, and 0:4 ratios, as ,well as the expected J: I, in families offour children. Similarly, the mating A/a X a/a having two chil­ dren, can produce 2:0 and 0:2 ratios as well as the expected 1:1. A bit ofreflection will convince the reader that this is not surprising. Consider., . for example, the couple with genotypes A/a and a/a, respectively, having two chil­ dren. Genetic theory expects them to have one A/a child and one a/a child because the A/a parent is expected to produce 1/2 A gemetes and 1/2 a gametes. ffthe A/a. parent is the male, this ratio will usually be realized among the sperm. Is there,' however, any guarantee that these"sperm will take turns, so to. speak, in fertilizing the egg'! Obviously not. The sperm involved in producing the two children could. well be A sperm in both cases or a sperm in both. If the A/a parent is the female, , there is not even a guarantee that the gametic ratio will be 1/2 A and 1/2 a, since ! each meiosis ordinarily produces only one gamete and the various meioses are independent events: what happens in one meiosis does not influence what is to happerl the next or any subsequent one. Hence, it could happen easily that the two' children of this A/a X a/a mating are both A/a or both a/a. Clearly the prediction of genetic results is fraught with uncertainties, events over which no one has control. Such uncertainty is generally referred to as' "chance." One author has recognized the large element of chance involved byenti. t1ing his book <?n genetics The Dice ofDestiny. The reader may well ask: how can . 171 ! .t I f
  • 2. ..'1 ~ I
  • 3. ; S I J : Chance and (he Distribution bf Families .. In genetic experiments with plants and other animals, the most direct inferences as to method of inheritance come from a count of the progeny. For example, if one were to make a cross between two pure lines, intercross the Flo :and from the inter-; cross oblaip approximately three-fourths of one parental type a~d one-fourth of the, other in lh. F 2• a simple Mendelian model. one locus with tw~ alleles and domi-I nance. wouid be inferred. This conclusion would be reinforced if the backcross of· an F,hybrid (to the pure-line parental type that had not appeared in the F,) pro- i duced progeny of which approximately one-half resembled the aforementioned I parental tyIXs and one-half the F, hybrid. : ' In man, the number of progeny from any single family is usually so small that.. these conclusions would not be warranted. A mating of two heterozygotes for a I recessive defect can produce 4:0, 2:2, I: 3, and 0:4 ratios, as ..Jell as the expected : 3: I, in families of four children. Similarly, the mating A/a X a/a having two chil- I dren, can produce 2:0 and 0:2 ratios as well as the expected I: Ii. i A bit of reflection will convince the reader that this is not s'u·rprising. Consider, ' for example, the couple with genotypes A/a and a/a, respectively, having two chil­ dren. Genetic theory expects them to have one A/a child and one a/a child because the A/a parent is expected to produce 1/2 A gemetesand 1/2 a gametes. If the A/a parent is the male, this ratio will usually be realized among the sperm. Is there, however, any guarantee that these sperm will take turns, so to speak, in fertilizing the egg'! Obviously not. The.sperm involved in producing the two children could well be A sperm in both c:;ases or a sperm in both. If the A/a parent is the female, there is not even a guarantee that the gametic ratio will be 1/2 ~ and 1/2 a, since each meiosis ordinarily produces only one gamete and the various meioses are independent events: what happens in one· meiosis does not influence what is to happed the next or any subsequent one. Hence, it could happen basily that the two children of this A/a X a/a mating are both A/a or both a/a. Clearly the prediction of genetic results is fraught with uncertainties, events I I over which no one has control. Such uncertainty is generally referred to as "chance." One author has recognized the large element.ofchance..involved byenti­ tling his book on genetics The Dice ofDestiny. The reader may rell ask: how can 177
  • 4. J
  • 5. ....-=----~ ~-­ Ii / (a) (e) (d) (e) (f) Figure 3.10 Examples of some simple Mendelian traits in hJmans that are relatively bommon: (a)common ba!dness, (b) chin fissure, (c) ear pits, (d) Darwin tubercle, (e) congenital ptosis, (f)epicanthus, (g)camptodactyly, and (h) mid-digital hair. See Table 3.1 for descriptions and modes of inheritance., I',
  • 6. SIMPLE MENDELIAN INHERITANCE 11 c Ii , f Fig. 1-'4 A-C Nail defects in the nail-patella syndrome (anonycho-osteo-dysplasia). In A they are most severe on the index fingers and (not shown) the thumbs. The little fingers appear normal. B. Dystrophy of thumbnails in an affected brother. The lunulae are abnormally large. C. Complete absence of thumbnails in a daughter of the patient in A and in her eight-year old son. O-G. Some of the bone defects encountered in the nail-patella syndrome. O. Absence of the patella in the eight-year old boy whose nail defects are shown in C. (The epiphyseal centers of his femur and tibia have not yet fused to the shafts.) The boy's mother has a patella (E) but suffers greater difficulties in walk­ ing because the patella-and the associated extensor tendon-is displaced laterally. In other affected the patella may be in normal position but hypoplastic. F and G: Typical elbow defects. In F the head of the right radius. somewhat abnormally shaped, is dis­ placed fdrward; in G the left radius, similarly abnormal, is displaced backward. In other cases the capitulum of the humerus is poorly developed, compounding the problem. Note also, in F, the exostosis of the coronoid process of the ulna. (A-D courtesy of L. S. Wildervanck. E-G from Wildervanck, 1950b; courtesy of L. S. Wildervanck and Acta Radioiogica. )
  • 7. (a) (e) (d) (h) ~~~f (e) (i) I Figure 3.10 Examples of some simple Mendelian traits in humans that are relatively common: (a)common ba!dness, (b) chin fissure, (c) ear pits, (d) Darwin tubercle, (e) congenital ptosis, (f)epicanthus. (g)camptodactyly, and (h) mid-digital hair. See Table 3.1 for descriptions and modes of inheritance.'
  • 8. SIMPLE MENDELIAN INHERITANCE 11 Fig. 1-'4 A-C Nail defects in the nail-patella syndrome (anonycho-osteo-dysplasia). In A they are most severe on the index fingers and (not shown) the thumbs. The little fingers appear normal. B. Dystrophy of thumbnails in an affected brother. The lunulae are abnormally large. C. Complete absence of thumbnails in a daughter of the patient in A and in her eight-year old son. D-G. Some of the bone defects encountered in the nail-patella syndrome. D. Absence of the patella in the eight-year old boy whose nail defects are shown in C. (The epiphyseal centers of his femur and tibia have not yet fused to the shafts.) The boy's mother has a patella (E) but suffers greater difficulties in walk­ ing because the patella-and the associated extensor tendon-is displaced laterally. In other affected the patella may be in normal position but hypoplastic. F and G: Typical elbow defects. In F the head of the right radius, somewhat abnormally shaped, is dis­ placed forward; in G the left radius, similarly abnormal, is displaced backward. In other cases the capitulum of the humerus is poorly developed, compounding the problem. Note also, in F, the exostosis of the coronoid process of the ulna. (A-D courtesy of L. S. Wildervanck. E-G from Wildervanck, 1950b; courtesy of L. S. Wildervanck and Acta Radiologica. )
  • 9. 1-6. Anonycho-osteo-dysplasia, better known as the nail-pateJla syndrome (Fig. 1­ 4), is one of the traits listed in Table 1-3. <!:all it the np locus. A man and his sister both have the trait, and both marry persons who lack it. The man's son, who lacks it, marries the sister's daughter, his cousin( who does have it. (a) What is the out­ look for their children? (b) If their first ctlild is normal with respect to this trait, what is the outlook for their next child? 1-7. Suppose you examine the widowed mother of the man add his sister of exer­ cise 1-6 and you find that she lacks the nail-patella syndrome. What would you conclude about the phenotype and genotype of her late husband (their father)? If more than one answer is possible, which islthe more likely, and why? Table 1-3 Progeny from testcrosses for several dominant traits (For references see Table 5-1 of Levitan and Montagu, 1977) , Num~r of Test Trait Cross Sibships Normal Affected Total Anonychia with ectrodactyly (Fig. 1-9) 139 57 66 123 ElliptocytosIS (ovalocytosis). both loci '65 113 99 212 (Fig. 13-2) Epidermolysis bullosa, all dominant forms 50 80 62 142 i (Fig. 1-3) Nail-pate~la syndrome (Fig. 1-4) 157 268 288 556 TOlal 31 518 515 1033 Ratio 1.006 :
  • 10. 3.29. Infantile amaurotic idiocy (Tay-Sachs disease) is a recessive hereditary abnormality causing death within the first few years of life only when homozygous (ii), The dominant condition at this locus produces a normal phenotype (/-), Abnormally shortened fingers (brachyphalangy) is thought to bidue't~- a 'genoi"ype heterozygous for a lethal gene (BB L ), the hom~~ygote (Sii) being~riormal, and the-9th~rfi(;;;;~Jyg9.!~JBLBL) be~r:tgJetha.L What are the phenotypic expectations among teenage children from parents_who ,are both brachyphalangic and heterozygous(or''nfantileamaurotic idiocy? . '-~' '.~ ..--"" '-"--_'_- .. - , , . 3.30. In addition to the gene governing mfantile amaurotic idiocy in the above problem, the recessive genotype of another locus (jj ) results in death before age 18 due to a condition called "juvenile amaurotic idiocy." Only individuals of genotype /-J- will survive to adulthood, (a) What proportion of the children from parents of genotype liJj would probably nol survive to adulthood? (b) What proportion of the adult survivors in part (a) would not be carriers of either hereditary abnormality?
  • 11. .. " Table 1-3 Progeny (rom testcrosses (~r several domina,nt tr~its (For refer~nces see Table 5-1 of Levitan and Montagu, 1977) i Number of Test Cross Sibships Normal ' Affected Total Trait Anonychia with ectrodactyly (Fig. 1-9) 39 57 66 123 65 113 99 212 . Elliptocytosis (ovalocytosis), both loci .j ~ r 1 (Fig. 13-2) 50 . ~ 80 62 142 Epidermolysis buJlosa, all dominant forms , (Fig. 1-3) 157 268 288 556 Nail.patella syndrome (Fig. 1-4) 311 518 515 I 033 Total Ratio 1.006 : Table 1-4 Offspring in 416 marriages b¢tween various M·N blood types. Data (rom Wiener et aJ. (1963). Progeny Total Number of Father Mother M M:N N ! • Offspring Families M M 71 1" 0 72 42 N N 0 0 29 29 20 M N 0 43' 0 43 23 N M 0 24 0 24 i3 All M X N 0 ~ 67 ,­ 0 67 36 M MN 67 46 0 113 63 MN M 60 55 0 115 59 All M X MN 127 IOIj 0 228 122 N MN 0 31 44 75 39 MN N 0 40, 27 35 All N X MN 0 71) 71 142 74 MN MN 61 118 53 '232 < 122 Totals 259 358 ' 153 770 416 , , I 3This apparent contradiction to the laws of heredity is believed to be owing t~ ,illegitimacy. but it may represent a new mutation, a change in the genetic material of one of the parents. '
  • 12. 5i o o o "
  • 13. --.~- --~~ .. .~. ./it 1-6. Anonycho-osteo-dysplasia, better known as the nail-patella syndrome (Fig. 1­ 4), is one of the traits listed in Table 1-3. Call it the np locus. A man and his sister 1 • ' both have the trait, and both marry persons who'lack it. The'man's son, who lacks it, marries the sister's daughter, his cousin, who does have it. (a) What ,is the out ­ look for their children? (b) If their first ehild is normal witt{ respect to this trait, what is the outlook for their next child? ' 1-7. Suppose y6u examine the widowed ,mother of the man and his sister of exer­ cise 1-6 and you find that she lacks the nail-patella syndrome. What would you conclude about the phenotype and genotype of her late husband (their father)? If , 1 more than one answer is possible, which is the more likely, and why? Table 1-3 Progeny from testcrosses for several dominant traits (F'or references see Table 5-1 of Levitan and Montagu, 1977) . i' Number of Test ! Trait CrosslSibships Normal Affected Total Anonychia with ectrodactyly (Fig. 1-9) 39 57 66 123 ElliptocytosIS (ovalocytosis). both loci i 65 113 99 212 (Fig. 13-2) Epidermolysis bullosa, all dominant forms 50 80 62 142 (Fig. 1-3) Nail-patella syndrome (Fig. 1-4) 157 268 288 556 Total 311 518 515 1033 Ratio 1.006 :
  • 14. 3.29. Infantile amaurotic idiocy (Tay-Sachs disease) is a recessive hereditary abnormality causing death within the first few years of life only when homozygous (ii). The dominant condition at this locus produces a normal phenotype (/-). Abnormally shortened fingers (brachyphalangy) is thought to be due to a genotype heteroz.ygous for a lethal gene (881..), the homozygote (88) being normal. and the other homozygote (8 L8 L ) being lethal. What are the phenotypic expectations among teenage children from parents who are both brachyphaJangic and heterozygous for infantile amaurotic idiocy? 3.30. In addition to the gene governing infantile amaurotic idiocy in the above problem. the recessive genotype of another locus (jj ) results in death before age 18 due to a condition called "juvenile amaurotic idiocy." Only individuals of genotype /.). will survive to adulthood. (u) What proportion of the children from parents of genotype IUj would probably not survive to adulthood'! (b) What proportion of the adult survivors in part (a) would not be carriers of either hereditary abnormality? .
  • 15. Table 1-3 Progeny from testcrosses for several domin~nt traits (For'references see Table 5-1 of Levitan and Montagu, 1977) Number of Test Trait Cross Sibships t Normal Affected Total Anonychia with ectrodactyly (Fig. 1-9) 39 57 66 123 Elliptocytosis (ovalocytosis), both loci 65 113 99 212 (Fig. 13-2) Epidermolysis bullosa. all dominant forms,I 50 80 62 142 (Fig. 1-3) , Nail~patella syndrome (Fig. 1-4) 157 268 288 556 311 518 515 I 033 Total Ratio 1.006 : Table 1-4 Offspring in 416 marriages between various M-N blood types. Data from , I Wiener et al. (1963). . Progeny lotal Number of Father Mother M MN N Offspring Families M M 71 I" 0 72 42 N N 0 0 29 29 20 M N 0 43 0 43 23 N M ~ 24 0 24 13 .-4 All M X N 0 67 0 67 36 M MN 67 46 0 113 63 MN M 60 5$ -, ~ 115 59 All M X MN 127 101' 0 228 122 ..~. N MN·.t 144 75 39 N 0 4gt 67 MNt ~ 35 All N X MN 0 71 71 142 74 MN MN 61 118 53 232 122 Totals 259 .358' 153 770 416 "This apparent contradiction to the laws of heredity is believed to be owing to illegitimacy, but it may represent . a new mutation, a change in the genetic material of one of the parents. .
  • 16. , Table 8-1 Expected progeny in a random sample of four-children families vhere one is A/a and the other a/a, locus A being autosomal Expected Progeny As Proportions of Next In Numbers~ Generation Kind of Number of Family ProbabililY~ FamiJies b A/a a/a A/a a/a 4 A/a 1/16 100 400 1/16 3 A/a, 1 a/a 4/16 400 1200 400 3/16 1/16 2 A/a, 2 a/a 6/16 600 1200 1200 3/16 3/16 I A/a, 3 a/a 4/16 400 400 1200 1/16 3/16 4 a/ans ---'1.L.§ 100 400 !L!..Q Tolal 16/16 1600 3200 3200 8/16 8/16 1/2 1/2 'Calculated in the text. bCalculated on the basis of 1600 families. Table 8-2 Expected progeny in a random sample of four-children families where the parents are heterozygous for a recessive gene a Expected Progeny As Proportions of In Numbersb Next Generation Kind of Number of Family Probability' Families b A/-c a/a A/-< a/a 4,1/­81/256 2025 8100 81/256 3.1/-,1 a/a 108/256 2700 8100 2700 81/256 27/256 2,1/-,2 a/a 54/256 1375 2700 2700 27/256 27/256 I ,1/-,3 a/a 12/256 300 300 900 3/256 9/256 4 a/a 1/256 25 100 1/256 Total 256/256 6400 19200 6400 192/256 64/256 3/4 1/4 'Calculated in the text. bCalculated on the basis of 6400 families. <.4/- means that the genotype is either A/d or A/a. Table 8-3 Expected progeny in truncate sample of four-children families of which the parents are both heterozygous for a recessive gene a Progeny in the Kind of Proportions of all Proportions of the Observed Sample Family A/a X A/a Families' Observed Families A/­ a/a 3.4/-, I a/a 108/256 108/175 81/175 27/175 2A/-,2a/a 54/256 54/175 27/175 27/175 I A/a, 3 a/a 12/256 12/175 3/175 9/175 4 a/a 1/256 1/175 ~ Total 175/256 175/175 111/175 64/175 63.4% 36.6% ·See Table 8-2.
  • 17. r r / Table 8-4 Analysis of the data in Table 8-3 by the direct $ib method (Weinberg's general proband method) . Total Sibs of Corrected Expected "Observed" Sibs/Proband Probands Progeny Affected Proportion" Proportion Probands Affected: Normal Affected: Normal Affected: Normal 0 81 0 0 0:0 0:0 0:0 I 108 108 I 0:3 0:3 0:324 2 54 54 2 1:2 2:4 108:216 3 12 12 3 2: I 6:3 72;36 4 4 3:0 12:0 • 12:0 Total 192: 576 Ratio 1:3 'Per 256 four-children families of A/a x A/a marriages in the population. ., Table 8-5 Suggested calculation of the~ gib Fl'IcrilOct:"'1l1ustration is for a theoretical truncate distribution of four-child families from ~/a X A/a Number of Number of Number of Corrected Progeny Family Unaffected/Family Affected/Family Families Normal Affected Type (U) (A) (N) UAN A(A - I)N 3: I 3 I 108 324 0 2:2 2 2 54 216 108 1:3 I 3 12 36 72 0:4 0 4 I 12 Total 576 192 Table 8-6 Direct sib correction in six families of spongy type polycystic kidneys of onset. (Data from Lundin and Olow, 1 ) Unaffected Affected Family Per Family Per Family Number of Type (U) (A) Familie.s (N) UAN 'A(A - I)N A I I 3 3 0 B 2 2 2 8 4 C 2 l ' I 2 Totals 8 5 6 21 6 Ratio 0.778 0.222 ExPected ratio 0.75 0.25 Expected numbers 20.25 6.75 x 2 : . 0.106 P;> 0.70
  • 18. ........ .I
  • 19. ~8 ·.~ .. - ':---.=.-.~ Chance and the Distribution of Families In genetic experiments with plants and other animals, the most direct inferences as to method of inheritance come from a count of the progeny. For example. if one were to make a cross between two pure lines, intercross the F" and from the inter­ cross obtain approximately three-fourths ofone parental type and one-fourth of the other in the F2• a simple Mendelian model, one locus with two alleles and domi­ nance, would be inferred. This conclusion would be reinforced if the backcross of an F, hybrid (to the pure-line parental type that had not appeared in the F,) pro~ duced progeny of which approximately one-half resembled the aforementioned parental types and one-half the F, hybrid. In man, the number of progeny from any single family is usually so small that these conclusions would not be warranted. A mating of two heterozygotes for a rece!>sive defect can produce 4:0, 2:2, I :3, and 0:4 ratios, as well as the expected 3: I, in families offour children. Similarly, the mating A/a X a/a having two chil­ dren, can produce 2:0 and 0:2 ratios as well as the expected I: I. A bit ofreflection will convince the reader that this is not surprising. Consider, for example, the couple with genotypes A/a and a/a. respectively, having two chil­ , . _~,Il dren. Genetic theory expects them to have one A/a child and one a/a child because the A/a parent is expected to produce 1/2 A gemetes and 1/2 a gametes. If the A/a parent is the male, this ratio will usually be realized among the sperm. Is there, however, any guarantee that these sperm will take turns, so to speak, in fertilizing the egg? Obviously not. The sperm involved in producing the two children could well be A sperm in both cases or a sperm in both. If the A/a parent is the female, there is not even a guarantee that the gametic ratio will be 1/2 A and 1/2 a, since each meiosis ordinarily produces only one gamete and the various meioses are independent events: what happens in one meiosis does not influence what is to happen the next or any subsequent one. Hence. it could happen easily that the two children of this A/a X a/a mating are both A/a or both a/a. Oearly the prediction of genetic results is fraught with uncertainties. events over which no one has control. Such uncertainty is generally referred to as "chance." One author has recognized the large element ofchance involved by enti­ tling his book on genetics The Dice ofDestiny. The reader may well ask: how can ~ 177 ~. -elY.i
  • 20. / ',. 178 '. c TEXTBOOK OF HUMAN GENETICS CHANCE AND THE DISTRIBUTION OF FAMILlES 179 genetics pretend to be a science if it cannot really predict the results of a given failure. The chance of tossing a coin heads, for example, is I: I. one chance of suc­ mating? Or. to put it more concretely, since chance plays such a large part in genetic cess to one chance of failure; similarly the odds of obtaining a five in the toss of a transmission. of what value are the stated Mendelian ratios? The question becomes die are I :5. one chanee of success to five chances of failure. For arithmetic especially pertinent. we shall discover below, when the family size becomes greater ulation, however, the best way to state the probability is the way it is often instinc­ than two: 1110.1'1 families then will /lol yield the stated ratios of offspring. tively given for the coin example: a~~aJ.1iQt1,..¥"hQs~dc:,Mminator is the nl!.T ber Before answering this question it is necessary to understand that genetics in ...oLeg.l1,alLy_likely-e..f.ents-flossible-in-th@-osi-tuat,ion,..llJld,er discussion and whosc being beset with uncertainties is not singular among the sciences. Every scientist _n!l.menl1o~is..the.JlUll1,q~J_qlt.he~e_that~Qnsli!uJe the event whoscfik"ClTil'O'OO is in knows that in the real world absolute certainty does not exist: there arc only relative _q_ue~tion.,. ­ degrees ofuncertainty. To pick a rather absurd example, one could ask the follow. Example: Suppose an urn contains five balls of identical size and shape. Two ing two questions of a meteorologist: (I) will the sun rise tomorrow'? and (2) will arc black, marked B I and B2, and three arc white, marked WI, W2, and WJ. tomorrow be a sunny day? He cannot answer either question with absolute ccr. respectively. We reach in to take out one ball. (I) What is the probability of obtain­ but it is clear that he can answer the first with much more confidence than ing the ball marked W2; and (2) what is the probability of obtaining a white ball') the sl'cond. A great stride in the progress of a science is mad~: when it can ascertain or "I' I measure these relative degrees of uncertainty. The mc:eorologist feels a sense of ( I) P ro b ab 1 Jty 0 f W2 = ___ n_um_be_r_o_f_W_2_b_al_ls__ total number of balls present 5 achievement when he can improve his forecast from "it may rain" or even '"it will probahly rain" to "there is a 90 percent chance ofrain:'... JJ'cpmeasurement or quan. 1 number of white balls 3 ti.l;lti.Ql}"Qf~uncc:natnt~iS"eallt'a..f~t:61t)alJiJUJ;" ­ (2) Probability of white = total number of balls present - 5 ,._' " Usually the positive aspect of probability is emphasized. We arc more inter. ested in the degree we have moved toward certainty than in the amount of uncer­ Mathematically. these statements would be written: tainty left. Hence we think of probability as the likclihoGd ofa desired event rather than as the degree to which we fall short of certainty in attaining it. P (W2) = 1/5: Let us examine some of the basic properties of probability. Perhaps we should P (white) = 3/5. hegin with a well-known example. If a coin were to be tossed and we were asked P represents the phrase "probability of' the item in parentheses. the probability of its turning up "heads" the immediate answer would be some •. How large or now small may probabilities be? Thc....maximum probability 'ariant of "tinY-fifty:' "one to one" or "one-hal(" If we asked why we gave this would be reached if we were satisfied with obtaining any ball present. wfictliCr"'ii answer the reply would be roughly: why. it stands to reason; there are two ways the was white or black. Thus, coin may fall and one of these is heads, so the chance is I out of 2. one-halfor one 10 one. If we had an evenly weighted die and wished to know the probability of its P (white or black) = 5/5 = I. upright face showing five dots when thrown, it does not seem difficult to extend the logic of this answer: since any of the six sides of the cube could turn up and the Similarly, the mlfllmum probability would come from wishing to obtain so 111 t' l:lCe with five dots is only one of these, there is one chance out of six of obtaining other color than white or black from this urn: the "Ii'e." Clearly. the proba 1 ility of success, that is. the likelihood that a desired l'Cnt will happen, depends on the number of alternative events that could happen /' (neither white nor black) = 0/5 = O. and on the number of these that spell "success." This indicates that probabilit~ is a positive number between 0 and I. Merely saying "the number of alternative events" C:.tll be misleading. however. The sophisticated reader will suggest that probabilities of I and 0 repn:sl'nt heca lISC one could argue that in throwing the die on a gi ven throw there arc only "certainty," certainty of success and certainty of failure. rl'spectively, This is cor­ two alternatives. success or failure, obtaining a five or not obtaining a five. and this rect. Certainty is possible in a mathematical sense, since a mathematical system lead to the belief that the probability of SUCcess was one of two. Obviously assumes that only the conditions postulated will occur. In a few simple real situa­ this is not true: for every chance of obtaining a five there arc five chances of obtain­ tions this degree of simplicity may be approximated-but there is never a guaran­ il'g something else. We must modify our statement. therefore, to state that the tee that the postulated condition will prevail. Thus we may feci secure that there lllJ.l.bah.il~t..j;.,Qf success depends on the number of eqll(/I/J;,.lwn/Jahil' (or equally likely. are two black and three white balls in the urn, and this usually docs approximall' :1~1b,(ll1alicians-sa.Y;)..Go;€'nts"'fl0ssihlG-and_Lh~!lumber of these""'1IUi'l'Spell ~~l;CS,"- _ a mathematical system. but we really cannot guarantee absolutely, for example. that one or another of the balls did not disintegrate after wc placed it in the urn. III The probabilities discussed above may be stated "one chance out of two" and practice, tl},elikelihoQd.of.su~c,~af,l~ull~lI,.pec.te_d.e,y,glltjs_oO,cn so small that we ignore " lilt'cham'!' out of six." They could also be phrased as relative odds of success and it and we do speak of probabilities of I or 0 even for living things. Thus we have
  • 21. " "-"""J.-______ 8 ,,! .:. ' 0­ " - a M a Chance andthe Distribution CT of Families o " In genetic experiments with plants and other animals, the most direct inferences as to meJhQd, of inheri!anfe~come from a count of tQ~_l'-rogeJ:lY. For example;-if one were to make a cross between t"'QPureljJle.s, inten::ross tl!e. Fh and from the inter­ cross obtain approximately three-fourths ofone parental type and one-fourth ofthe other in the F2, a simple Mendelian m~del, onc;Jp~l!s with two allel~~ ;~d do~i­ nance, would be interred. This conclusion would be reinforce<rifthe backcross of an-F,hybrid (to the pure-line parental type~thai had-not appeared in ti!e F,) pro­ ducedpr()geny~f which appro~imately ol,le-6a-lf resembled ·the' a'forementioned parental types and one-half the F, hybri4. In man, the number of progeny from any single family is usually so small that these conclusions woui<f noi'be" ~arr;.~ted Amating-of t~o heterozygotes for a ~<:e.~si~e_d~fectca'!.PIo_<!uce 4:0,2:2, 1:3. and 0:4 ratio.s. as wella's the expected .3: I., in families of four children. SimilarlY. the mating A/a X a/a having two chil­ dren, 'can produce '2:0 and 0:2 ratios as well-as the' expected I : I. . ". " . - . A bit of reflection wiUoonvince the reader that this is not surprising. Consider, for example, the couple with genotypes A/a and a/a, respectively. having two chil­ dren. Genetic theory expects them to have one A/a child and one a/a child because the A/a parent is expected to produce 1/2 A gemetes and 1/2 a gametes. If the A/a parent is the male, this ratio will usually be realized among the sperm. Is there, however, any guarantee that these sperm will take turns. so to speak, in fertilizing the egg? Obviously not. The sperm involved in producing the two children could well be A sperm in both cases or a sperm in both. If the A/a parent is the female, there is not even a guarantee that the gametic ratio will be 1/2 A and 1/2 a, since each meiosis ordinarily produces only one gamete and the various meioses are independent events: what happens in one meiosis does not influence what is to happen the next or any subsequent one. Hence, it could happen easily that the two children ofthis A/a X a/a mating are both A/a or both a/a. Clearly the prediction of genetic results is fraught with uncertainties, events over which no one has control. Such uncertainty is generally referred to as "chance." One author has recognized the large element ofchance involved by enti­ tling his book on genetics The Dice of Destiny. The reader may well ask: how can 117 :
  • 22. ;> ". '& 178 TEXTBOOK OF HUMAN GENETICS CHANCE AND THE DISTRIBUTION OF FAMILIES 179 g('netics pretend to be a science if it cannot really predict the results of a given failure. The chance of tossing a coin heads, for exam pic, is I: I, one chance of suc­ mating'.' Or, to put it more concretely, since chance plays such a large part in genetic cess 'to one chance of failure; similarly the odds of obtaining a fivc in the toss of a transmission. of what value arc the stated Mendelian ratios? The question becomes die are I :5, one chance of success to five chances of failurc. For arithmetic manip­ cspecially pertinent. we shall discover below. when the family size becomes greater ulation. however. the best way to statc the probability is the way it is oftcn instinc­ than two: most families then will flot yield the stated ratios of offspring. tively given for the coin example: as a .fractioQ~,ho~cIdC'iiQiiilnatodi!£_lbe_number Aefore answering this question it is necessary to understand that genetics in QLtqlJ.alh: likcJLe~yenJs_possjblc_in Jhc~iJ.!.Iali.OT'l_!.I.!1der discussion and who..:;e hcing beset with uncertainties is not singular among the sciences. Every scientist in umerato~ is the n umber oLtl;le~e_thill, cQ1Jstitllle.tl1e.eveIlLwhosdi kcl.i hoodj!!jn knows that in the real world absolute certainty docs not exist: there arc only relative question,. dcgrees of uncertainty. To pick a rather absurd example, one could ask the follow- Example: Suppose an urn contains five balls of identical size and shape. Two two questions of a meteorologist: (I) will the sun rise tomorrow'! and (2) will arc black. marked 81 and 82, and thrcc arc white. marked WI, W2, and W1. tomorrow be a sunny day? He cannot answcr either question with absolute cer­ respectively. We reach in to take out one ball. (I) What is the probability of obtain­ tainty. but it is clear that he can answer the first with much more confidence than the sccond . ing the ball marked W2; and (2) what is the probability of obtaining a white ball') .. great stride in the progress of a science is mad~: when it can ascertain or number ofW2 balls ~ measure thesc relative degrees of uncertainty. The mc:eorologist feels a sense of (1) Probability of W2 = total number of balls present 5 achicvement when he can improve his forecast from "it may rain" or even "it will probably rain" to "there is a 90 percent chance of rain. " The measurement or quan­ numbc·r of white balls ~ titation of uncertainty is called !1 rohahility. (2) Probability of white = total number of balls present 5 Usually the positive aspect of probability is emphasized. We arc more inter­ ested in the degrec we have moved toward certainty than in the amount ofuncer­ Mathematically. these statements would be written: tainty leti. Hence we think of probability as the likelihood ofa desired event rather than as the degree to which we fall short of certainty in attaining it. /,(W2) = 1/5; P (white) 3/5. Let us examine some of the basic properties of probability. Perhaps we should hegin with a well-known example. If a coin were to be tossed and we were asked @,=eprescJ)ts.th~ph(a~g"::'lrQbl'lJ:tililJ'...QC the item in pnrentheses. the probability of its turning up "heads" the immediate answer would be some How Inrge or how small may probabilities be? The maximum probability ariant of "fiftY-fifty," "one to one" or "one-half." If wc asked why we gave this would be reached if we were satisfied with obtaining any ball present, whether it answer the reply would be roughly: why. it stands to reason: there arc two ways the was white or black. Thus, coj n may fall and one of these is heads. so the chance is lout of 2, one-half or one to one. If'e had an evenly weighted die and wished to know the probability of its P (white or black) = 5/5 =<i) upright fnce shOwing five dots when thrown. it docs not seem difficult to extend the logic of this answer: since any of the six sides of the cube could turn up and the Similarly, thc rninimuQlJll·Q.babiJity would come from wishing to obtain some nll'c with fie dots is only one of these. there is one chance out of six of obtaining other color than white or black from this urn: the "five." Clearly. the proba 1 ility of success, that is. the likelihood that a desired l'Cnt vill happen. depends on the number ofalternative events that could happen P (ncither white nor black) = 0/5 =(2) and on the number of these that spell "success." This indicates that J~'=9bability is a posi!ive number betweeo!b and I) Tvh.'rdy saying "the number of alternative events" can be misleading. however. The sophisticated readcr will suggest that probabilities of 1 and 0 represent because one could argue that in throwing the die on a given throw there arc only "certainty," certainty of success and certainty of failure, respectively. This is cor­ two a!ternati·es. success or failure. obtaining a five or not obtaining a five. and this rect. Certainty is possible in a mathematical sense. since a mathematical systelll might lead to the belief that the probability of success was one of two. Obviously assumes that only thc conditions postulated will occur. In a few simple real situa­ this is not true: for cvery chance of obtaining a five there arc five chances of obtain­ tions this degree of simplicity may be approximated-but there is never a gUllrnn· II'g something else. We must modify our statement, therefore, to state that thc tec that thc postulated condition will prevail. Thus we may feci secure that there pronability ofSuccess depends on the number of ('quail)' /lrobah/c (or equally likely. arc two black and thrce white balls in the urn, and this usually does approximate as thc mnthelllaticians say) events possible and the number of thesc that spell SUCt'l'ss. a mathematical system, but we really cannot guarantee absolutely. for example, that onc or another of the balls did not disintegrate after we placed it in the urn. In The probabilities discussed above may be stated "one chance out of two" and chance out of six." They could nlso be phrased as relative odds of success and "Illlt' practice, the likelihood of such an unexpected event is often so smalUl}a,t weigno!:r it. and we do spcak of probabilities of i or 0 even for living things. Thus we h:lVl'
  • 23. . ~ ,.~ l1:fO TEXTBOOK OF HUMAN GENETICS CHANCE AND THE DISTRIBUTION OF FAMILIES 18 seen already that we,ignore the p-robabililY of new mutations when we predict that Urn A Urn B Urn 1 Urn B Urn A Urn [j Urn 1 Urn R Urn 1 Urn B the cross: p 0)G) CDG) 0)G) (0G) QG) A/A X :1/:1 - all A/A. 0)0 (00 0) 0' (00 80 In probability terms we arc saying G)G) CDG) 8G) (0G) 0G) P (A/A X ..1/.·1 - A/A) = I. and this cross is therefore usually wntten 0)0 (00 80 (00 00 A/A X A/A - I A/A. Q. Q CDQ 8Q 0Q QQ Implicit in asking the probability of obtaining a Il-hill' ball from the urn is the 88 08 8 8 08 08 Idea that il docs not matter whether we obtain W I. Wi. or W3. Any of these alter­ n:! I i Vl' e'en Is spells success. Thus. Fig. 8-1 The 30 combinations possible when a ball is drawn from each of two urns i the first urn contains 2 black balls and 3 white balls, the second contains 3 black Oil!' P (white) == I + I + I and 3 white ones, and the balls are equal in size but distinguishable by numbpr. 1/5 + 1/5 + 1/5. Thus. Hut. x3 P(WI)= 1/5. P (black. black) = 5 X 6 I' (W2) = 1/5. and .; 2 3 P (W3) = 1/5. ,= 5 X'f;' Iknec. But. P(white) = peW!) + P(W2) + P(W3). '2 111 ot her ords.jla II erelll has S(xccqLalt~p.wtiJ;G,J'1J;w.);J!oJla.Uaj,n m.c.n.t..,Q,f a llt. ~_~ = I' (black from urn A) a Ill'rna I i e is considered at tai n,1l1cn.l~ofTt.h('TdesiFC&eVcrr1'!'"tht?"flf(-)/!ahilil,h.4).t,;.IlC,1:~.~ i~1'i11'7f1TIi(' [I}'{)bahiliI ic..!i-!J£Jjw.(!_lJi/'CI;lJati-w.l•.J(J!~!1IS-J n com monsen.'ie terms, and when we arc nol particular or choQsy the chances for success areincreased. 'J An equally interesting probability is that of a success which is composed or P (black from urn B). 6 scwral eents thaI must happen simultancously or ill succession. Clearly, this prohahility must be smaller than the likelihood of attaining anyone of the events Thus. the probability of obtaining black balls from both urns is the product () alone. How much smaller? To solve this problem let us relurn to the urn with the the probabilities or obtaining a black baH from each urn. 10 hlack halls and the three white ones and set up a second urn with three black We may generalize this into a rule:.J1l£'prohahilil.1' Oro/Jlaillillg ('('rtaill sill/III halls. 83. 84. B5, and Ihree white ones. W4, WS. and W6. If a ball is to be removed f a 11(:tJ.IIJ-(Qt-s,ucc~si~c:,I:J:l11..W.l--llJ.(;'.J1lJ.1d.IJ5;t....Q[ 11U:"'IID1!i'tilri1TTif'n'JiTl/(· (w·n I.' from each urn. how likely is it. for example. that both will be black? To answer this illl·()lJ.;(:lLJ.J&..chcck,Jbi.s~generalization. we may note that. c may return to our basic concept of probability and enumerate how many - l'qually probable events. each consisting of one bal! from urn A and one ball rrom I ) (white. w h' . Itc) = '3 X (; 5 .1 urn B. can happen and no Ie how many of these consist ()f a black ball from each urn. The equally probable events arc shown in Fig. 8-1. 9 "" 30 There arc .10 equally probable events and 6 of these represent pulls of two black 1.,111 .... TIm'>, and this corresponds to the enumerated proportion. P (black. black) ;", 6/.10 = 1/5. . This rule too. fits our commonsense expectations. The likelihood that both wil happen must be smaller than the likelihood ofcither one alone. I'or each c )uJd Oftl'l NOlI.' Ihal Ihe 30 in the denominator is the product of the number or balls in urn happen without the other. Since probabilities are fractions less than one, multipl~ -. : and the number of balls in urn B: likewise, the 6 in Ihe numerator is the product ing them has the effect of producing a still smaller fraction. tha,1 is. decreasing th, oflhe Ilumherofblack balls in urn A and the number of blacks in urn B. no ' probabilitv.
  • 24. Jil2 # .J TEXTBOOK OF HUMAN GENETICS CHANCE AND THE DISTRIBUTION OF FAMILIES 183 .' This "'plUltipJkatioll~r,uk;;:";s valid whether the desired events occur simulta ­ ncously or in a particular order. Furthermore, it is applicable whether the proba­ WHA T THE GENETIC RATIOS MEAN hilitics of successive events arc independent or dependent. Drawing balls from the We may now consider the meaning of the Mendelian ratios. tO urns-described above-is an example of independent probabilities. where the rrohability of one event does not influence the probabilty of another in the series. 1I1ealling /: A genetic ratio sta(~.Llu:..pt;abaililil,l,-:lh[q~si!Jglc:.hil:!Jl. When we state ~ . A/a X a/a ...... 1/2 A/a, 1/2 a/a Likewise. if only one urn is used and the ball replaced between pulls. the probabil ­ ities of successive choices are independent. To illustrate tJ!:pendeflt nro.babililies we., we are saying that at any given birth from these parents the odds arc I: I that the may consider only the first urn and calculate, for example. !!l$..n(ob@jLit¥~oipick­ child will be a/a. On the other hand, for the mating in a black ball twice iIl..-succ~ssi0n..if-t·tu;:uirst~Q.Q.e..r~mo.xedjs not seen and 110t replaced )efore m!.Uil'l~Q.tJt...lJ1e_sf.CQn.d_ ) Ala X A/a -+ 1/4 A/A. 1/2 II/a, 1/4 a/a. "';;;';"Forrt~ choice. as before. the stated ratio means that at any given birth there is twice as much chance that P (l31 or 82) = 2/5. the baby will be A/a than that it will be A/A. Likewise the odds are 2: I for A/a """""'---"!""--=:;.:00Ii!'!"- ­ versus a/a and I: I for A/A versus a/a. If A is dominant over a, the probability is I f the first choice is successful. only four balls remain in the urn and only one of 3/4 that a child from the last mating will show the A phenotype. 1/4 that it will I hese is black. Therefore. for the second choice show a phenotype, in other words, three times as much chance for gene A to he P (black) = [1.4......· present at least once than for its complete absence, a/a. .:-.lI(l$). Meaning 2:,..!.1kall,ll.,sJbsllip..+hfM'e,5uit..-suggested.lJ,v..Jl,u;...ge/l£,tic ratio has the W!.ldal The probability that both events happen is. then prohabili1.I. This probability is usually /lot the probability in the Mendelian ratio. 2/5 X 1/4 = 2/20 = 1/10 "-but must be calculated for each case. The genetic ratio leads us to expect that the distribution of children in a family The student is often disturbed by dependent probabilities because it seems will conform to this ratio. but we know it usually will not do so. For example. if more necessary than for independent probabilities to suppose that the first choice the parents in the mating is slIccessful before calculating the probability of the second. He should keep upper­ most in mind that we arc seeking the likelihood that both events do happen. We A/a X a/a -> 1/2 :I/a. 1/2 a/a wish to...calculate the probability of success. not the probability of failure. Failure. not obi5ininii'he desired resuft"tndudes all the other results that could occur: the decide to have two children the ratio "predicts" that they will have one A/a child lirst choice is "right" but the second "wrong." the first wrong even if the second is and one a/a child. But our biological knowledge, and observation of actual fami­ right. or both choices are wrong. Calculating the probability of failure on the same lies. tells'us that such families will consists of two A/a children or two a/a children basis used for the probability of success verifies our result: as well as one A/a and one a/a. Using our rules of probability and the first meaning for the genetic ratio, we can calculate the probability or expected relative frequency I' (black. white) = 2/5 X 3/4 = 6/20 of these sibships. P (white. black) 3/5 X 2/4 = 6/20 P (white. white) = 3/5 X 2/4 = 6/20 , 1'(2:1/a) = /'(/I/a. A/a) = 1/2 X 1/2 = 1/4. Sinn' any of these alternative spells failure. Likewise. P (Failure) = 6/20 + + = 18/20. Since 6/20 6/20 )Jjgj£) = P(a/a. a/.£l;. 1&~2 = For one A/a and one a/a, we should note that this may happen in two ways. the 1/4. ­ /' (Success) + P (Failure) = 1* birth first or the a/a first. P (Success) I - P (Failure) Therefore. I - 18/20 2/20 = 1/10 = the same, result obtained directly. lJd/a. a/2) = y2 X 1/2 = I~ ..£(aLq~.Jta.),~tb2~UL2 = 1~Jl.n~L ,...llWL<ca.IldJ ll.IJJJ = JL4 + 1/4 = 1/2. *This is a usl'ful relation 10 keep in mind. Unlike the case above. it is Qnl'n easier 10 calculate the prnhahility or I l i ohwining the desired result. and then subtra(:ting rrom unily. than to calculate The previous line is unique because the probability of obtaining the "expected" direrllv lhe prnhahilily or the desired result. ratio is the same as a fraction in the ratio.
  • 25. ., CHANCE AND THE DISTRIBUTION OF FAMILIES 183' "1~2 TEXTBOOK OF HUMAN GENETICS WHAT THE GENETIC RATIOS MEAN 'I (. This "multiplication rule" is valid whether the desired events occur simulta­ neously or in a particular order. Furthermore, it is applicable whether the proba­ hilities of successive events are independent or dependent. Drawing balls from the We may now consider the meaning of the Mendelian ratios. two urns-described above-is an example of independent probabilities, where the Meaning I: :'~genelic rgti!Lslq}e~_lh(' [JrQhal!.W.!J~.t(U· (LsU!gle..bil:th. When we state probability of one event docs not influence the probabilty of another in the series. .A/a X a/a ....... II1JIjJl._IJ2.~q/.a Likewise. if only 011e urn is used and the ball replaced between pulls. the probabil­ ities of successive choices are independent. To illustrate dr.11£'ndent probabilittes_,e we are saying that at any given birth from these parents the odds are I: I that the may consider only the first urn and calculate, for example, the .P!9babilit.y of pi~k­ child will be a/a. On the other hand. for the mating ­ ing.a_hIHdsJ!.~IU~ice"",iJ;uuccession, if the Jirst one rem~qye_dJs_fJQLScgO_.mJLI.1()t I~nlacc.(lpefore pulling_o.uJ_the..se.cond. A/a X A/a ....... 1/4 A/A. 1/2 A/a, 1/4 a/a, ----------.--~-'.­ fool' the first choice. as before. the stated ratio means that at any given birth there is twice as much chance that P (BI or B2) = 21J. the baby will be A/a than that it will be A/A. Likewise the odds are_2..:...Lfm.,..dul _v_e[s.u~ALa and.t:J fOL!1L.:cCv.ersus~ala. IfA.is._<:!QOJi(l3tlJ..o.Y.cL(1. the probability is I If the tirst choice is successful. only four balls remain in the urn and only one of ~/~thauuAil.dJi:Q.qUb!!Jas.tmating...w.illshow-th~...A....phcnot.y.pe. J./.;l...lb.3LiJ~ these is black. Therefore. for the second choice sho~{L1~henotYJ!e, in other words. three times as much chance for gene :I to be J:.Jhj~c;Jsl_=_tM_ present at least once than for its complete absence. a/a. Meaning 2: itl,l1fJ,ILSiqAbiv.• lhe..resuiUu&qcsf.ecLby.. tb.('"gclI.cli.(.;..raUQ.ba:s..tlu· "Iot/ql The probability that bOlh events happen is. then probabili/..!:. This probability is usually not the probability in the Mendelian ratio. 2/5_~_1./_4 = 2/2Q....:;.....lLLO but must be calculated for each case. The genetic ratio leads us to expect that the distribution of children in a family The student is often disturbed by dependent probabilities because it seems will conformJo this ratio, but we know it usually will not do so. For exam"plc. if more necessary than for independent probabilities to sUJ)pose lhat the firSt choice the parents in the mating is successful beforecalcutating tlieprobability of the second. He should keep upper­ most in mind that we arc seeking the likelihood that both events do happen. We A/a X a/a ....... 1/2 A/a. 1/2 a/a wish to calculal~J!l<;..probability of SIlC(!'.!S. not the probability of failure. Failure. not obtaining the desired result, includes all the other results that could occur: the decide to have two children the ratio "predicts" that they will have one il/a child first choice is "right" but the second "wrong." the first wrong even if the second is and one a/a child. But our biological knowledge. and observation of actual fami­ right. or both choices are wrong. Calculating the probability offailure on the same lies. tells us that such families will ~onsists of two A/a children or twoJl/a children hasis used for thc probability of success verifies our result: as wellas one A/a and one a/a. Using our rules of probability and the first meaning for the genetic ratio. we can calculate the probability or expected relative frequency f> (black. white) = 2/5 X 3/4 = 6/20 of these sibships. P (white. black) = 3/5 X 2/4 = 6/20 P (white. white) = 3/5 X 2/4 = 6/20 lX?tJLa) "" fJJ/a...::l£g) =Jj2 X 1/2 = l/.i Since any of these alternative spells failure. Likewise, P (Failure) = 6/20 + 6/20 + 6/20 = 18/20. J.j2a/q) = eLqLQ,.J1£q) = JJ~ X 1/2 = -1L4: Since For one A/a and one a/a. we should note that this may happen in two Vay~, the /' (Success) + P (Failure) = 1* A/a birth first or the a/a first. P (Success) = I - P (Failure) Therefore. "" I - 18/20 = 2/20 = 1/0 = the same result obtained directly'; = 1i2._~~LL2-=--ljS.. .P'(d/.i1,-a.iJl) p(f}ja. A/.Q.l = l.a~>-U.L2 = 1/..4. and ./ L'<L:!/a and I a/!!..~ =:..1/4 + 1/4 = t.Lb *This is a useful rcialion to keep in mind. Unlike the case above, it is often ('asier 10 calculale the The previous line is unique because the probability of obtaining the "cxpceted" prohahility of I/O/ obtaining the dcsir('d rcsult. and Ihen subtracting from unity. than to calculatc dirl:l'lly tht' prnhahility of the desired result. ratio is the same as a fraction in the ratio.
  • 26. l~O '~ TEXTBOOK OF HUMAN GENETICS CHANCE AND THE DISTRIBUTION OF FAMILIES 1 seen already that l::-e ignore the probability of new mutations when we predict that Urn A Urn B Urn A Urn B UrnA Urn Il Urn A Urn B UrnA Urn B thc cross: ii8 0 fl0 0 8G) 00 GQ ~~"""'aIlA/A. "1100~00 00 00 80 In rrobability terms we are saying -ott 0 @ -.1 0 8@ G)0 80 P lJ/A X A/A ....... A{"-L::'--l. 80 0 80 G)0 80 and Ihis cross is therefore usually written .1/..1 X A/A ....... J A/A. 88 08 G8 G8 G8 Implicit in asking the probability of obtaining a while ball from the urn is the 08 08 8 0) 08 idea that it docs not matter whether we obtain WI. W2. or W3. Any of Ihese alter ­ Fig. 8-1 The 30 combinations possible when a ball is drawn from each of two urns natin- CTnts spells success. Thus. the first urn contains 2 black balls and 3 white balls, the second contains 3 black onl and 3 white ones, and the balls are equal in size but distinguishable by number. I' (white) :: I + I + I 5 1/5 + 1/5 + Thus, Aul. 2X3 P(W!) = 1/5. P (black, black) = 5 X 6 P (W2) = 1/5. and 2 3 P(W3) = 1/5. = 5X 6' IicncC'. But. I'(while) P(WI) + P(W'l) + I'(W3). 2 P (black from urn A) In other 'ords:..i.fall erelll has sereral allf'!1l.S!.!.i.!,t.lill!2IS and allainQl£I1J •o C'lny 5 ill!l:UEltixl,~is~(~(msidcreJ:LaJtiljnmcr!t..Qf.lhc..desired>e_vcnl. the J!f'Jh(//JiliO' IJj'SIIC<'l'' and IS (II(' SUIIl o[lhe pro/'ahililies of'lliese allemalire Ji}f!Ul. In commonsense lerms. hell we arc not particular or choosy the chances for Success arc increased. .-n equally interesling probability is that of a success which is composed of ~ P (black from urn 8). sewal en~nts that must happen simultaneously or in succession. Clearly. Ihis probahilily must be smaller than the likelihood of attaining anyone of the events Thus. the probability of obtaining black balls from both urns is the product 0 alone. How much smaller'! To sol'(' this problem let us relurn to the urn wilh Ihe Ihe probabilities of obtaining a black ball from cach urn. two hlack halls and the three white ones and set up a second urn with Ihree black We may generalize this into a rule:.:rhf.•J!rohahilill' (!( ol>ta;I/;l/g cl'rtoiJl.:Ji!PU halls. A3. R4. R5. and three white ones. W4. W5. and W6. If a ball is to be removed tal/eOIlS (or suq::£l>siyc,) _('n'llls is II/(' prodl~<.!_!f Ille pmhahilifil's 0" Ihe l'r(!}fi From each urn. how likely is it. for example. that both will be black? To answer Ihis Iiimln,:d.To check this generalization. ;"'c may note that c may return to our basic concept of probability and enumerate how many . .) 3 3 l'qually probable events. each consisting of one ball from urn A and one ball from P (whIte. whIte = 5 X "6 urn H. can happen and note how many of these consiSI of a black ball from each 9 urn. Thl' equally probable events arc shown in Fig. 8-1. 30 There arc 30 equally probable events and 6 of these represent pulls of two black I Ills. Thus. and Ihis corresponds to the enumerated proportion. I'(black. black) = 6/30 This rule too. fits our commonsense expectations. The likelihood Ihat both wil happen must be smaller than the likelihood ofeilher one alone. for each c .wld 011L'1 Note Ihat the )0 in the denominator is the product of the number of balls in urn happen without the other. Since probabilities arc fractions less than one. nlultipl) i , and the number of balls in urn R: likewise. the 6 in the numeralor is Ihe product ing them has the effect of producing a still smaller fraction. that is. dccreasing 1h (11' thl' numher of black balls in urn A and the number of hlacks in urn R. probabilitv. .