Codominant Inheritance: HLA

• Each allele is capable of producing an

additive effect
• Many alleles for each gene
• Many Haplotypes
 What is the probability that if a patient has just a
single sibling that the two will be HLA matched?

The probability for a match with one sibling is about 1/4

Probability of HLA Matching Any Given Sibling = 1/4

Therefore, if one has 4 siblings, then the probability

of having an HLA match is 4 x ¼ = 1, right ???
 Wrong!

Better to ask, “What is the probability of not

achieving an HLA match when having 4
opportunities to do so?”

Probability of a particular sib not being matched = 1-

1/4= ¾

Thus, probability of not matching any of 4 sibs =

(¾)4 = 32%.

So, the probability of matching HLA matching at

least one of 4 sibs is 100% – 32% = 68%
 Recombination

A A 2 1 28 9
B B 7 16 15 13

2 9 2 9 2 9 28 1 28 1
result of 16 13 7 13 7 13 15 16 15 16
chromosome 6 2 1
homologs
7 16

1% x ¼= 1/400
 Characteristics of Sex-Linked
Recessive Inheritance

 Males are more commonly affected than females.

 The gene responsible is transmitted from an affected man

through his daughters, who are seldom affected. Each daughter is
an obligatory heterozygous carrier. Each of the carrier daughter's
sons has a 50% chance of inheriting it

 No male to male transmission occurs

 The affected males in a pedigree are usually related through

females

 Heterozygous female carriers are usually unaffected, but some

may express the condition with variable severity (“Lyonization”)
X-Linked
Example: hemophilia A
What is the probablity
that she is a carrier after
having 3 unaffected boys

P Predict possible fetal outcomes

 Punnett Square

maternal
X x 1
paternal

4 female carriers
1
X XX Xx 2 female 1
4
female non-carriers
1 1
Y XY xY 2 male 4 male affected
1
male unaffected
4
Example: hemophilia A
What is the probablity
that she is a carrier after
having 3 unaffected boys

P Predict possible fetal outcomes

 Posterior Probability
non-
probability carrier carrier
prior 1 1
2 2
1 3 1
conditional (
2
) =
8 1
1 1 1 1 1
joint X =
2 8 16 2
X 1 =
2

posterior 1
probability 16
=
1 ~
~ 11%
that she's a carrier 1 1 9
+
16 2
after having 3
unaffected boys
Bayes’ theorem: Branching diagram
 Fourth pregnancy outcome
• The likelihood that her fourth child would
be a boy with hemophilia would be 1/9 ??????
X
• 1/2 (the probability that she would
segregate the mutant factor VIII allele to the
egg during oogenesis)
X
• 1/2 (the probability of the egg being
fertilized by a sperm containing a Y
chromosome)
• = 1/36.
 Lyonization
• A term used for the random inactivation of
one X chromosome in each cell of a female
and is named after Mary Lyon, who
discovered X inactivation

• The word usually means a "skewed" or

"unfavorable" pattern of X chromosome
inactivation, such that the female is at least
partly affected for an X-linked recessive
disorder
Lyonization = skewed X inactivation

XX-distribution of active X
 Unusual Forms of Inheritance & Complex Inheritance
• Unusual Inheritance
– Mitochodrial
– Imprinting
– Uniparental Disomy
– Germline Mosaicism
– Sex-linked Dominant
– Y Chromosome Inheritance
– Pseudoautosomal Inheritance
• Mutation
– New mutation, fitness, manifestations, Heterozygote
selection
• Dynamic Mutation
– Trinucleotide repeats
• Complex Inheritance
 1-Mitochondrial inheritance

• Mitochondrial DNA
– 2 to 100 mitochondria/cell
– 5 to 10 chromosomes/mitochondrion
– 16.5 kb mt DNA
– 37 genes
• Mitochondrial inheritance
– Maternal
– Heteroplasmy
Example : mitochondrial inheritance

Example: mitochondrial inheritance

 Mitochondrial Disease
• Myoclonus epilepsy with ragged red fibers
(MERRF)
• Mitochondrial myopathy, encephalopathy,
lactic-acidosis, and stroke-like episodes
(MELAS)
– Mutations in mitochondrial tRNA molecules
 Mitochondrial Disease
• Kearns-Sayre syndrome
• Progressive external ophthalmoplegia
– weakness of the orbit muscles coordinating eye
movement
• Leber Hereditary Optic Neuropathy (LHON)
• Result from large-scale mitochondrial
deletions
– Occur sporadically
– Arise “de novo”
Heteroplasmy
Children of an affected mother
can escape inheriting a
mitochondrial disorder,
or be affected to variable
degrees, depending on how the
mutation is distributed within the
population of hundreds of
mitochondria inherited from the
oocyte. Similarly, an unaffected
mother could conceivably
have affected children.
It offers an explanation for
incomplete penetrance
in a mitochondrial disorder.
 MERRF Pedigree
(myoclonus epilepsy with ragged red fibers)
 2-Imprinting

• Inheritance occurs only from one parent

– Expression from one parent’s allele
• Chosen allele is constant over generations
• Only the sex of the parent determines disease
• Imprinting Centers that control maternal vs
paternal patterns switches

AS Maternal

PWS Paternal
 Imprinting
Imprinting

maternally
Paternal mutant gene inherited
expressed paternally
Maternal inherited
mutant gene expressed
alleleallele
Maternal is not
notexpressed
expressed allele isallele
Paternal not expressed
not expressed
Prader-Willi
???
& Angelman Syndromes
Inactive M. Chr.

Inactive P. Chr.
Microdeletion P Microdeletion M
Maternal Disomy Paternal Disomy
 3-Uniparental Disomy
• Occurs when both copies are inherited
from just one parent
• Uniparental disomy of imprinted genes
cause:
– Prader-Willi syndrome
• Mild to moderate MR, hypotonia, notorious
appetite
– Beckwith-Wiedemann syndrome
• 11p15 (IGF2)
• large, hypoglycemic, and are predisposed to
develop Wilms’ tumor of the kidney
• Discovered with CFTR Chr.7 disomy
 Origins of uniparental Disomy (UPD)

Maternal non- Normal paternal

disjunction of disjunction of
Chromosome 15 Chromosome 15

Trisomy 15 in
zygote
Trisomic rescue

Maternal UPD Bi-paternal inheritance

 4-Germline Mosaicism

• Mutation arises post-zygotically

• Germ line cells contain the mutation
• The body does not produce a
recognizable phenotype
Germline Mosaicism

Embryo
Osteogenesis Imperfecta
 5-Autosomal Dominant Non-Viable
• Only seen in mosaic
state
• McCune-Allbright
syndrome
– Multiple endocrine
tumors Autosomal Embryo
dominant
• Virtually never inherited Non-viable

• Mutations in the
stimulatory G protein
– Intracellular signaling
 6-Sex-linked Dominant

• Mosaic pattern of
expression severe
enough to produce
phenotype
• Lethal in males
• Almost never
inherited
• Rett syndrome
– Severe MR
 7-Y-Chromosome Inheritance
• SRY, a DNA binding protein
• Master switch for embryonic male sex
development
– Deletion or point mutation within SRY causes
sex reversal
– XY phenotypic female lacking gonads
• Small deletions of the Y chromosome also
cause azoospermia and have been
recognized as a common cause of male
infertility
8-Pseudoautosomal Dominance
Pseudoautosomal Regions (PAR)
Of Human X and Y chromosomes
 Leri-Weill Dyschondrosteosis
And Madelung deformity

Indistinguishable from autosomal inheritance

Mutation in the SHOX homeobox TF

 Mutation
Whenever a child with a highly
penetrant autosomal dominant
disease is born to two unaffected
parents, then the possibility of new
mutation or non-paternity should be
considered (in that order). When a
second affected child is born to the
same couple, then germline mosaicism
also becomes a possibility.
 A. New mutation
Example : anchondroplasia (FGFR3)
Spontaneous deamination of
methylcytosine residues

Every child has about 100

new DNA sequence changes

GGG to AGG
Gly to Arg
Increased Frequency With Age

Sperm have relatively

large amounts of
methylcytosine residues
 For serious autosomal dominant
illness new mutations account for
100%
Why should it be so high?
 B. Fitness

• The relative reproductive success of a particular

phenotype
• Between 0 and 100%
• It may be reduced by decreased survival to the
age of reproduction, diminished fertility, or less
attractiveness
 Haldane’s Rule

Since the incidence of a disease remains

constant over time, then the mutant alleles
lost because of reduced fitness must be
balanced by alleles arising from new
mutation.

Males: XY Females: XX

For a sex-linked recessive disorder with zero

fitness, such as Duchenne muscular
dystrophy, 1/3 of disease alleles are in males
and are lost with each generation. Thus, 1/3
of disease alleles must be replaced with a
new mutation in each generation
 Hutchinson-Gilford Progeria

LMNA Chr.19

Autosomal Dominant, Zero Fitness

Always the Result of a New Mutation
 C. Mutations & Manifestations

MUTATION - A change in DNA sequence

usually conferring a deleterious effect

POLYMORPHISM - DNA sequence difference

usually of no pathologic significance
 1. Allelic Heterogeneity
• Occurs when multiple types of mutations in a given
gene can account for the inheritance of the same
disorder in different families
 2. Allelic Disorders

• Different mutations in the same gene can

cause divergent phenotypes

• Two different diseases caused by the same

gene
 The RET gene

Hirschsprung Megacolon MEN2B

-No formation of the myenteric -Medullary thyroid carcinoma,
plexus -Parathyroid adenoma
- Adynamic colon
 3.Locus Heterogeneity

• When the same disease is caused

by mutations in more than one
gene

• Polycystic kidney disease, tuberous

sclerosis, or spinal cerebellar ataxia
 D. Heterozygote Selection

New mutation is not a consideration for AR diseases

 Heterozygote selection

• The heterozygote advantage results from

the fact that 2pq >> q2 , from the Hardy-
Weinberg law
• Explains the high carrier frequency for
certain autosomal recessive disease alleles
that confer disease resistance in a
heterozygote state