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” (12 th 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 allele Mutation vs Polymorphism Genotype vs. Phenotype Genotype frequency, phenotype frequency, allelic frequency Homozygote, heterozygote (compound & double heterozygote), hemizygote

Anatomy of a pedigree Dizygotic & monozygotic twin Heterozygote Spontaneous abortion Pregnancy Multiple union Still birth Miscarriage No offspring

A vertical pattern of inheritance indicates a rare dominant trait Huntington’s disease: A rare dominant trait Assign the genotypes by working backward through the pedigree

Autosomal Dominant Disorders Manifested in the heterozygote or homozygote state Vertical inheritance: at least one parent of the index case is usually affected Equal 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 capability 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 affected does not skip generations affected individuals are homozygous dominant or heterozygous affects 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 disease Siblings 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 chromosomes parents are carriers or are affected affected individuals are homozygous recessive affects males & females Albinism, Cystic fibrosis, Phenylketonuria, Sickle cell disease

X-linked Disorders Affected male (hemizygous for X-liked genes)  no sons are affected Carrier 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 heterozygote 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