Download 슬라이드 1 - Korea University

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 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
Sickle Cell Anemia
Hg synthesis
Physiology
Clinical level
Hb A/Hb A
-----------------Normal Hb
Normal
Hb A/Hb S
-------------------------------Normal & mutant Hb
 Codominant
Mild anemia
 Incomplete dominant
 A recessive trait
Hb S/Hb S
-----------------Mutant Hb
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
Locus Heterozygosity
Double heterozygote
Allelic Heterozygosity
Factors Affecting Pedigree Patterns
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
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