Mendelian inheritance in humans

• Most traits in humans are due to the interaction of multiple genes and do not show a simple Mendelian pattern of inheritance.

• A few traits represent single-genes. Examples include sickle-cell anemia, cystic fibrosis, Tay-Sachs disease, and Huntington’s disease

• Because we can not do breeding experiments on humans.

Three main categories of genetic disorders (1) Single-gene disorders (2) Chromosomal disorders (3) Complex disorders (multifactorial or polygenic) : hypertension, Diabetes mellitus

Types of Single-Gene Disorders (Mendelian Disorders) (1) Autosomal Dominant Disorders (2) Autosomal Recessive Disorders (3) X-linked Disorders

Single-Gene Disorders ( > 9,000 disorders recognized) (1) Victor A. McKusick’s “Mendelian Inheritance in Man” (12th edition, 1998) (2) Online version : Mendelian Inheritance in Man (OMIM) : continually updated. (3) >1,400 gene loci : mutations are associated with a clinically significant disorders (4) >90%: pediatric age range, <10%: after puberty, <1%: after the end of the reproductive period (5) 0.36% of live birth, 6-8% of hospitalized children (6) Every individual is a carrier of 4-8 deleterious genes (mostly recessive) 80-85% : familial, 15-20% : new mutations acquired de novo

Terminology

Wild-type allele vs. Mutant type alleleMutation vs Polymorphism Genotype vs. PhenotypeGenotype frequency, phenotype frequency, allelic frequencyHomozygote, heterozygote (compound & double heterozygote), hemizygote

Anatomy of a pedigree

Dizygotic & monozygotic twinHeterozygoteSpontaneous abortionPregnancy

Multiple unionStill birthMiscarriageNo offspring

A vertical pattern of inheritance indicates a rare dominant trait

Huntington’s disease: A rare dominant traitAssign the genotypes by working backward through the pedigree

Autosomal Dominant Disorders

Manifested in the heterozygote or homozygote stateVertical inheritance: at least one parent of the index case is usually affectedEqual probability: both male and female can transmit the condition Siblings have 50% chance for the recurrence

*New mutations in germ cells of parents normal parents but affected child Transmission of new mutations depends on their effect on reproductive capabili

ty

Ex) Achondroplasia (short-limbed dwarfism) : reduced reproductive fitness Thus, nearly all achondroplasias occurs by new mutations

------------------------------------------------------------------------------------------------------------located on non-sex chromosomes

at least one parent is affecteddoes not skip generationsaffected individuals are homozygous dominant or heterozygousaffects males & females Achondroplasia, Huntington’s disease, Lactose intolerance, Polydactyly

Autosomal Recessive Disorders

Manifested in the homozygote state (both alleles are mutants)Horizontal inheritance: patrents are normal, but siblings show the diseaseSiblings have 25% chance for the recurrence Consanguineous marriage has a high recurrence risk for a rare disease

A certain mutant gene is common in population Cystic fibrosis: White Tay-Sacchs disease: Ashkenazi Jews or Central East Europe Sickle cell anemia: Black *Quasi-dominance: carrier X affected marriage: 50% offspring affected

-------------------------------------------------------------------------------------------------------------located on non-sex chromosomesparents are carriers or are affectedaffected individuals are homozygous recessiveaffects males & females

Albinism, Cystic fibrosis, Phenylketonuria, Sickle cell disease

X-linked Disorders

Affected male (hemizygous for X-liked genes) no sons are affectedCarrier female 50% of sons are affected “No father to son transmission” is a hallmark of X-linked inheritance

Hemophilia A (clotting factort VIII) Duchenne muscular dystrophy G6PD deficiency: red cell hemolysis in patients receiving certain drugs (Primaquine) If normal allele is inactivated in marrow cells drug-induced hemolysis X-linked disorder in female Random inactivation of X chromosome: Lyonization: Barr body If normal allele is inactivated in most cells full expression If normal allele is inactivated in only some of the cells partial expression

Dominance is not always complete

Incomplete dominance : Phenotype severity is intermediate between homozygote and heteroz

ygote Neither allele is dominant or recessive to the other Phenotypic ratios are same as genotypic ratios

Codominance : F1 hybrids express phenotype of both parents equally Phenotypic ratios are same as genotypic ratios

Histocompatibility, Blood group antigens

Codominance Incomplete dominance

Codominant blood group alleles

Hb A/Hb A Hb A/Hb S Hb S/Hb S ------------------ -------------------------------- ------------------Hg synthesis Normal Hb Normal & mutant Hb Mutant Hb Codominant Physiology Normal Mild anemia Anemia Incomplete dominant

Clinical level A recessive trait

Sickle Cell Anemia

Factors Affecting Pedigree Patterns

1. Delayed Onset Not all genetic disorders are congenital (congenital: “born with”) Not all congenital disorders have a genetic basis Huntington disease : average age of onest 35 years old Familial adenomatous plyposis coli (FAP)

Factors Affecting Pedigree Patterns

2. Genetic Heterogeneity A number of phenotypes that are similar but are actually determined by different genotypes. Locus Heterozygosity: Similar disease phenotype caused by different genes Retinitis pigmentosa 3 X-linked, 12 autosomal dominant, & 5 autosomal recessive forms

Ehlers-Danlos syndrome >10 different loci (X-linked, autosomal dominant or recessive) Childhood deafness

Allelic heterozygosity: Different clinical phenotypes by different mutations at the same locus Different mutations in the RET gene Hirsch-sprung disease (defective colonic motility constipation) Multiple endocrine neoplasia type IIa and IIb

Double heterozygote

Locus Heterozygosity Allelic Heterozygosity

3. Pleiotrophism Single mutant gene may lead to many end effects : Sickle cell anemia

4. Codominance Histocompatibility, Blood group antigens

5. Reduced Penetrance “all or none” (% penetrance) normal persons can transmit the disease

6. Variable Expressivity expressed differentially Neurofibromatosis: brownish spots (café au lait spot) skin cancer

Factors Affecting Pedigree Patterns

Four different situations in which one normal copy of the genes does not prevent disease

1. Haploinsufficiency Normal physiology requires more than 50% of fully active gene product

2. Dominant negative effect Abnormal protein causes an abnormal phenotype by interfering with normal protein function

3. Gain of function effect Mutant protein is enhanced or acquires a novel function through mutation

4. Predisposition to inherited cancers An inherited dysfunction of one allele results in pedigrees with inherited cancers