Phenotypes, genotypes Populations genetics RNDr Z.Polívková RNDr Z.Polívková Lecture No Lecture No course : Heredity

Population genetics distribution of genes in populations No of individuals with trait Frequency of trait = ( allele, genotype) No of all individuals in population frequency 1/2500, 1 : 2500, Human population – 3 races – Caucasians, Blacks, Asians genetically different (in allele frequencies) also ethnic groups are genetically different The basis of genetic differences: mutations selection, degree of reproductive isolation

Examples of differences albinism in some Indians sickle cell anemia in Blacks in Africa β-thalasemia – regions around Mediterranean sea cystic fibrosis in Caucasians – high frequency low in Finland, in Asian and African population Finland : XR choroideremia - rare X-linked eye disease only 400 cases in the world – 1/3 in Finland high frequency of 20 disorders – rare elsewhere in the world low frequency of CF (cystic fibrosis) and PKU (phenylketonuria) South Africa – high frequency of Huntington disease, porphyria variegata (AD defect of hemoglobin) in white population of South Africa

Thompson & Thompson: Genetics in medicine, 7th ed., 2007

Passarge: Color Atlas of Genetics, 1995

Calculations of alleles and genotypes frequencies from frequency of disorder: The Hardy – Weinberg low f(A) = p, f(a) = q - 1 locus with 2 alleles p + q = 1 - alleles frequencies gametes A p a q A pAA p 2 Aa pq a qAa pq aa q 2 p 2 + 2pq + q 2 = 1 – genotypes frequencies (p + q) 2 = 1

Genotypes AA p 2 Aa 2pqaa q 2 AA p 2 p4p4 2p 3 qp2q2p2q2 Aa 2pq2p 3 q4 p 2 q 2 2pq 3 aa q 2 p2q2p2q2 2pq 3 q4q4 Each of three paternal genotypes may mate with each of three maternal genotypes

mating typesFrequency of matings AAAaaa 1.AA x AA p4p4 p4p AA x Aa 4p 3 q2p 3 q - 3.AA x aa 2p 2 q Aa x Aa 4p 2 q 2 p2q2p2q2 2p 2 q 2 p2q2p2q2 5.Aa x aa 4pq 3 -2pq 3 6.aa x aa q4q4 --q4q4 genotypes of offspring

Offspring: AA : p 4 + 2p 3 q + p 2 q 2 = p 2 (p 2 + 2pq + q 2 ) = p 2 Aa: 2p 3 q + 2p 2 q p 2 q 2 + 2pq 3 = 2pq(p 2 + 2pq + q 2 ) = 2pq aa : p 2 q 2 + 2pq 3 + q 4 = q 2 (p 2 + 2pq + q 2 ) = q 2 p 2 + 2pq + q 2 = 1 Genotypes are distributed in proportions to the frequencies of individual alleles in a population and these proportions remain constant from generation to generation

Frequency of autosomal recessive disorder = q 2 Frequency of autosomal dominant disorder = p 2 + 2pq

3 alleles – frequencies - p, q, r p + q + r = 1 (p + q + r ) 2 = 1 Ex.:Frequency of alleles A,B,0 in AB0 blood groups: p,q,r Frequency of genotypes: AA + A0 = p 2 + 2pr BB + B0= q 2 + 2qr AB = 2pq 0 = r 2 X-linked genes ♂ p + q = 1 ♀ p 2 + 2pq + q 2 = 1 Frequency of mutant allele = frequency of affected males Frequency of normal allele = frequency of normal males

Condition of HW equilibrium: random mating balance between mutation and selection no migration large population

Disturbance of gene frequencies in population: 1.Non random mating - stratification – population subgroups mating in restricted - assortative mating – choise of a mate - consanquinity – risk of AR diseases → increase in proportion of homozygotes, decrease in proportion of heterozygotes

2. Mutation and selection lethal mutation = is not transmitted to the next generation = Selection against AD mutations - against homozygotes and heterozygotes - effective in a single generation Deleterious mutation, but not lethal Coefficient of selection s Fitness (ability to reproduce) f = 1 – s Example: achondroplasia (dwarfism) f = 0.2 (only 20% of affected people have children) s = 0.8 = 80% are new mutations = constant frequency of disease

Selection against AR mutations - less effective – mutation are maintained in heterozygotes Selection against XR mutations Example: DMD (Duchenne muscular dystrophy) 1/3 of alleles lost in each generation 1/3 of cases = new mutation Selection against heterozygotes in Rh maternal – fetal incompatibility = haemolytic disease in Rh+ newborns (Rh- mother)

Heterozygote advantage Example: sickle cell anemia (AR) - highest frequency in West Africa in regions with endemic malaria - lower frequency in Blacks in U.S. Heterozygotes – resistence to malarian parasite low fitness: homozygotes AA – suffer from malaria homozygotes aa – suffer from sickle cell anemia

Passarge: Color Atlas of Genetics, 1995

3. Small populations – genetic drift = change in gene frequency Founder effect = one of the original founders of a new population carries a rare allele allele may become fixed in a new population or can disappear from population it depends on a chance in case of fixation of allele = relatively high frequency in small breeding population in relatively short time

Example: The Afrikaners (South Africa) in 1652 settlers from Holland 1 was carrier of Huntington disease (AD) 1 was carrier of variagate porphyria (AD) All current carriers are direct descendents of this original carriers High frequency of these diseases in this country (rare elsewhere) Each population is characterised by its own molecular mutations

4. Migration - gene flow = slow diffusion of genes across barriers (geografical, racial…) gradual changes in large populations Mechanism = migration Example: B allele (AB blood groups) declines from Asia (f = 0.3) to Europe ( f = 0.06) Spreading of mutation in agreement with migration of some populations Example: Celtic mutation in cystic fibrosis, phenyketonuria

5. Eugenics Positive - selective breeding (plants, animals) Negative – elimination of some genotypes (genetic counselling, prenatal diagnosis) Medical treatment – reduces selection, maintains mutant alleles in population, enables transfer of mutant alleles to the next generation Genetic counselling prenatal diagnosis – reduction of incidency of some disorders, but it retains healthy heterozygotes

Thompson &Thompson: Genetics in medicine,7th ed. Chapter 9: Genetic variation in individuals and population: Mutation and polymorphism (from page 192) + informations from presentation