population genetics and multifactorial inheritance 2002 consanguinity genetic drift founder effect...

Population Geneticsand

Multifactorial Inheritance 2002

• Consanguinity• Genetic drift• Founder effect• Selection• Mutation rate• Polymorphism• Balanced

polymorphism

• Hardy-Weinberg Equilibrium

Hardy-Weinberg Equilibrium

• Explains why, In a large population with random mating:

• 1. Allele frequencies do not change from generation to generation

• 2. Genotype frequencies are determined by allele frequencies at that locus

Note error in “AA offspring” footer !

Allele frequencies in X-linked disorders

• Males are hemizygous for the X-chromosome: therefore frequency of affected males = frequency of the mutant allele, q

• For rare XLR disorders, frequency of heterozygous carrier females is twice the frequency of affected males, or 2q

• Frequency of homozygous females is very low, q²

Applications of HWE

• Determination of allele frequency and heterozygote carrier frequency in a population for which the frequency of the trait is known

Hemophilia A and Para-hemophilia

• Hemophilia A:– XLR

– Frequency 1/5000

– Female carriers 1/2500

• Parahemophilia– Rare AR

– Frequency 1/1,000,000

– Heterozygote carrier frequency 1/500

Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Coefficient of relationship

• Parent-child First ½

• Siblings First ½

• Uncle-niece Second ¼• First cousins Third 1/8

Selected Michigan Marriage Laws(Amended 1956)

SEC 3. No man shall marry his mother, grandmother, daughter, granddaughter, stepmother, grandfather’s wife, son’s wife, grandson’s wife…..or cousin of the first degree.

Genetic Drift/ Founder EffectSingle (few) founder mutations

• Finns (“located on the edge of the populated world”)

– Indo-European immigration 2000 years ago– Population of 50,000 in 12th century, 5 million today

• Ashkenazim– Migration to Rhineland in 9th century, to Eastern

Europe in 14th century– Population 10-20,000 in Poland in 16th century, 11M

worldwide today– Repeated “bottlenecks” (pogroms)

• Amish

Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Selection

• Biological fitness (f)

• Positive and negative selection

• Selection on AD, AR, XLR

Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Mutation

• Effect of gene size

• Effect of paternal age

• Balance between introduction of new mutant alleles by mutation and removal by negative selection

Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Migration and gene flow

• Tracking human migrations

• Cohanim

• Lemba

Polymorphism

• The occurrence of two or more genetically determined alternative phenotypes in a population at such a frequency that the rarest could not be maintained by recurrent mutation alone

• Practically---a genetic locus is considered polymorphic if one or more of the rare alleles has(have) a frequency of at least 0.01.

• Examples: MHC, SNPs, SSRs

Balanced polymorphism• Balance of positive and negative selection

Malaria and genetic disorders of red blood cells

Multifactorial Inheritance

Complex Common Diseases

Evidence for Genetic Factors in Common Complex Diseases

• Familial aggregation

• Twin studies

• Mendelian forms of disease

Familial Aggregation

Increased risk to relatives: λR

• λS

– IDDM 10-15– NIDDM 4

• λ1

– Schizophrenia 10– Autism ~100

MD (and MD2B): A chronic condition with significant physical, mental, emotional, and

financial consequences

• A a first degree relative (sib,parent)

• B a second degree relative (aunt,uncle, grandparent

• C More than one 1st and/or 2nd degree relative

• D No affected 1st or 2nd degree relatives

Evidence for Genetic Factors in Common Complex Diseases

• Familial aggregation

• Twin studies

• Mendelian forms of disease

Twin Studies

Twin studies in infectious disease

• Tuberculosis (USA)• Leprosy (India)• Poliomyelitis (USA)• Hepatitis B (Taiwan)

• 62% 18%• 52% 22%• 36% 6%• 35% 4%

MZ DZ

Evidence for Genetic Factors in Common Complex Diseases

• Familial aggregation

• Twin studies

• Mendelian forms of disease

Diabetes Mellitus

Maturity onset diabetes of the young (MODY)

Association and Linkage

• ASSOCIATION of a specific allele at a genetic locus with disease in a population– Candidate gene

• LINKAGE. Co-segregation in families of a marker locus, regardless of specific allele, with disease.

Implications

• Identification of genetic markers of liability to common complex disease.

• Environmental triggers have greatest impact on genetically predisposed.

• Identification of susceptible individuals aids identification of environmental triggers.

• Medical intervention can be focused on those at greatest risk.

Threshold Model

Predictions from Threshold Model

• Recurrence risks are average

• Risk increases with # of affected relatives

• Risk increases with severity of malformation

• Differential risk increases as frequency decreases

• Sex differences

Affected Sib Pair