Mode of inheritance

1. Modes of Inheritance
Prof Mojamed R Beshir

2. • The human genome contains about 23000 genes.
• 15000 single gene disorders.
• 8000 monogenic (single gene) trait.
• 21000 genes on autosomal chromosomes.
• 1200 on X chromosome.
• 59 genes on Y chromosome.
• 65 mitochondrial genes.

3. • Mendilian traits principles:
– Dominant and recessive inheritance.
– Segregation (only one member of paired
chromosome is transmitted to offspring).
– Independent assortment (gene at different loci
transmitted independently).

4. • Phenotype : is what actually observed
clinically or physically.
• Genotype: individual genetic constitution at
loci.
– Different genotypes may have same phenoyupe
CF.
– One genotype can produce different phenotypes
in different environments PKU.

5. pedigree

6. Autosomal dominant inheitence
• AD diseases are rather rare in population with
the most common having gene frequency
1:1000.
• So, matting between 2 persons affected by
same AD disease uncommon.

8. Characteristics of AD inheritance
• The 2 sexes exhibit the trait in approximately
equal ratios.
• No skipping of generations in pedigree (vertical
transmission).
• Father to son transmission of the disease gene.
(not required to establish AD but to exclude X-
linked disorders).
• Affected heterozygous transmits the disease
causing allele to approximately half of his/her
children.

10. Autosomal recessive
• Heterzygous carriers are much more common
than affected homozygous.

11. Characteristics of AR
• AR diseases are usually observed in one or
more siblings but not in earlier generations
(horizontal).
• Males and females are affected in equal
proportion.
• ¼ of the offspring of 2 heterzygous carriers
will be diseased.
• Consanguinity is present more often in
pedigree.

13. Recurrence risk
• The recurrence risk for AD is 50% .
• Because of independence, this risk remains
constant no matter how many affected or
unaffected are born.

16. Factors that affect expression of
disease causing gene

17. 1- new mutations (de novo)
• New mutations are common cause of the
appearance of a genetic disease in person
with no previous family history of the disease.
• The recurrence risk for the person’s sibling is
very low, but the recurrence risk for person
offspring to their offspring may be
substantially increased.

18. 2- germ line mosaicism
• Mosaicism is the presence of more than one
genetically distinct cell line in the body.
• During embryonic development of one
parents, mutation occurred that affect all or
part of germ-line but few or none somatic
cells.
• OI, achondroplasia, NF I, hemophilia.

19. 3- reduced (incomplete) penetrance.
• The situation in which who have a disease
causing genotype do not develop the disease
phenotype.
• 10% of the obligate carrier of retinoblastoma
causing allele do not have the disease. So the
penetrance of disease causing genotype is 90%.
• Obligate carriers those who have an affected
parent and affected children and therfore must
themselves carry the disease causing allele.

20. Retinoblastoma
• Incidence 1 :20,000 children
• It typically initiates between 3 months after
conception and 4 years of age, when retinal
cells are actively dividing and proliferating.
• 60% due to somatic mutations that occurs in
early development.
• 40% inherited mutations (30% de novo
mutation and transmitted mainly from father,
10% inherited from obligate carriers).

21. • Individual who has inherited a disease causing
RB 1 mutation in every cell in the body.
• However, this is not sufficient to cause the
disease due to the presence of other normal
RB 1 gene.
• to initiate the tumor a second somatic event
must occur that disable the normal RB 1 gene.

22. 4- age dependent penetrance
• Although some genetic diseases are expressed
at birth or shortly after birth, many others do
not become apparent until adulthood.
• So, it is a delay in the age of onset of genetic
disease.
• Huntingnton disease is an example.

23. 5- variable expression
• Penetrance is all or none phenomenon.
• Variable expression is the degree of severity of
the disease phenotype. It can vary greatly
from mild to severe.
• NF 1, CF

24. Factors affecting the expression of
genetic disease
• Environmental factors as diet, exercise or
exposure to harmful agent (smoke), … PKU.
• Modifier genes: interaction of other genes
with the disease causing gene.
• Different types of mutations (different allels)
at the same disease locus. [allelic
heterogegencity]. B globin gene heterogencity
can cause thalassemia or sickle cell disease.

25. 6- locus heterogenecity
• Single gene phenotype can be caused by
mutations at different loci in different families.
• OI encoded by 2 genes on 2 different
chromosoms.(17,7).

26. 7- pleitropy
• Genes that have more than one desirable
effect on the body.
• Marfan syndrome: AD mutation causing
unusual stretching connective tissue.
• So, affects eye, skeletal muscles,
cardiovascular system.

27. X linked recessive
• Females have 2 copies of X chromosome,
while males have only one. So, X R diseases
are much common among males than
females.
• It is characterized by an absence of father to
son transmission, skipped generations when
gene passed through female carrier

29. X linked dominant
• They are about twice as common in females as
in males.
• Skipped generations are uncommon.
• Father to son transmission is not seen.

31. Non mendilian modes of
inheritance

32. Mitochondrial inheritance
• The mitochondria which produces ATP, have
their own unique DNA.
• Mitochondrial DNA is maternally inherited.
• It has a high mutation rate.

36. Genomic imprinting
• One of the 2 alleles is transcriptionally inactive,
depending upon the parent from whom the allele
is received.
• The allele transmitted from mother is inactive
(imprinted) and the same allele from the father
would be active.
• Imprinted allele have to be methylated, at 5 end
along with histone hypoacetylation and
condensation. So, inhibit the binding the proteins
that promote transcription.

37. Prader willi syndrome
• PWS is related to an epigenetic phenomenon
known as imprinting.
• Normally, a fetus inherits an imprinted
maternal copy of PW genes and a functional
paternal copy of PW genes.
• Due to imprinting, the maternally inherited
copies of these genes are virtually silent, and
the fetus therefore relies on the expression of
the paternal copies of the genes.

38. • In PWS, however, there is mutation/deletion of
the paternal copies of PW genes, leaving the
fetus with no functioning PW genes.
• The PW genes are the SNRPN and NDN genes,
along with clusters of snoRNAs: SNORD64,
SNORD107, SNORD108 and two copies of
SNORD109, 29 copies of SNORD116 (HBII-85) and
48 copies of SNORD115 (HBII-52). These genes
are located on chromosome 15 located in the
region 15q11-13.

39. • This so-called PWS/AS region in the paternal
chromosome 15 may be lost by one of several
genetic mechanisms, which in the majority of
instances occurs through chance mutation.
Other, less common mechanisms
include uniparental disomy,
sporadic mutations,
chromosome translocations, and gene
deletions.

40. • Region 15q11-13 is implicated in both PWS
and Angelman syndrome (AS). While PWS
results from the loss of PW genes within this
region on the paternal chromosome, loss of a
different gene (UBE3A) within the same region
on the maternal chromosome causes AS.PWS
and AS represent the first reported instances
of disorders related to imprinting in humans.

41. • The risk to siblings is <1% if the affected child
has a gene deletion or uniparental disomy,
• up to 50% if the affected child has a mutation
of the imprinting control region,
• up to 25% if a parental chromosomal
translocation is present.

49. Multifactorial inheritance:
• Mutifactorial determined disorders are the
product of multiple genetic and
environmental factors, e.g. neural tube defect,
cleft lip and cleft palate, DM and
hypertension.

50. Thank you