Molecular Single Gene Initiation

Front 1

Modes of Mendelian Inheritance

Back 1

Autonomic dominant

Autosomal recessive

Sex-linked
X-linked recessive
X-linked dominant
Y-linked

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What is an Autosomal Dominant (AD) Inheritance

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-Heterozygotes are affected
i.e only one allele is enough to give rise the disease phenotype
-people who are homozygous for the allele do not survive!
-e.g. Huntington’s disease, Osteogenesis imperfecta

Front 3

Pedigree characteristics of an
Autosomal Dominant (AD) Inheritance

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Pedigree characteristics:
vertical pattern of inheritance
recurrence risk is 50% if an affected marries an unaffected
both sexes equally affected and equally likely to pass on mutant allele
complications abound

Front 4

Variable expressivity

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-in part due to the effect of modifying loci
-e.g cystic fibrosis

Front 5

Complications of AD inheritance

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Variable expressivity
-Non-penetrance or incomplete penetrance
-Anticipation
- Imprinting
-Mosaicism

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Imprinting

Back 6

refers to the fact that although certain genetic disease genes can be transmitted by parents of either sex, the disease is phenotypicially evident only when the mutations is transmitted from a particular parent.eg Prader syndrome and Angelman syndrome

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Mosaicism

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presence of mutant allele in select tissues only

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Anticipation

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Anticipation: tendency of some dominant conditions to become more severe in successive generations e.g. Huntington’s disease

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Age-related Penetrance(akaNon-penetrance or incomplete penetrance )

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probability that an
individual carrying the disease gene will have developed symptoms by a
given age.

Front 10

Germline mosaicism

Back 10

mutation in the gene which is only visible in DNA from his sperm but not in
blood DNA ;the coming generations may be affected

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Autosomal Recessive (AR) Inheritance

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-Homozygotes are affected
-parents of affected children are often asymptomatic carriers

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Autosomal Recessive (AR) Inheritance pedigree characteristics

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horizontal pattern of inheritance
frequently seen in consanguineous unions
-both sexes equally affected
-if both parents are carriers, 1 in 4 risk of an affected child

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X-linked recessive disorders pedigree features

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males affected
disease is transmitted by carrier women who are asymptomatic
disease can affect women if a carrier female mates with an affected male (very rare situation)

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X-linked dominant Inheritance

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-Very rare; affects either sex

-Child of an affected female, regardless of gender, has a 50% chance of being affected

-Inheritance pattern looks like AD, except that all daughters of affected males are affected

Front 15

Candidate Gene Analysis

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Screen/sequence candidate genes
Compare to unaffected controls
Confirm that all affected family members have observed mutation

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Genetic Linkage Analysis

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used when there is no obvious candidate gene
uses polymorphic markers to tract disease

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Polymorphic markers

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Polymorphic markers:

simple sequence variations
occur in all populations
are inherited in a Mendelian fashion
have precise chromosomal locations

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Linkage analysis with polymorphic markers generates lod scores

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Significant linkage is lod score > 3 (greater than 1000:1 odds that a given marker is linked (that is, lies at or near) to the disease gene

Suggestive linkage is lod score between 1 and 3

lod scores <1 indicate an absence of linkage

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Functional Consequences of Gene Mutations

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Haploinsufficienc
Dominant negative

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Haploinsufficienc

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One-half normal product:
phenotype is a consequence of
decreased amount of product

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Dominant negative

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Abnormal product (from mutant allele)
interacts with normal product (from normal
allele) to make <50% good product; seen
in multimeric proteins