Population Genetics

Question 1

Population Genetics

Answer 1

• the study of the distribution of genes in populations, of the factors that maintain or change the frequency of genes and genotypes from generation to generation
• used primarily in: genetic counseling, planning genetic screening programs, explains why we can assume people with autosomal dominant disorders are heterozygous and why both parents of children with autosomal recessive disorders are usually carriers

Question 2

Population screening requirements

Answer 2

• cost effective- frequency of genetic disease, cost of screening versus treatment
• intervention/treatment- need to be able to take some action
• population compliance- perception of the disease

Question 3

Population

Answer 3

• in a genetic sense is a breeding group or gene pool
• most human populations are composed of subgroups which were originally relatively separate (isolates)
• in modern times there groups are being mixed, especially in US “Melting Pot”

Question 4

Gene frequencies

Answer 4

• the genetic constitution of a population, referring to the gene it carries, is described by the array of gene frequencies
• the frequencies of all alleles at any one locus must add up to unity- p+q=1

Question 5

Genotypes

Answer 5

-the genotypes must also add up to unity
P + H + Q = 1
-where, P= homozygotes for one allele
-Q= homozygotes for the other allele and H is heterozygotes
-we observe the phenotype, but sometimes we can derive the genotypes assuming H-W is true and thus the allele frequencies

Question 6

Hardy-Weinberg Law

Answer 6

-consider a single autosomal locus with two alleles A and a with frequencies p and q (p+q=1)
-with random mating, i.e. random mixing of sperm and eggs then the expected genotype frequencies in the progeny are:
p^2 +2pq +q^2

Question 7

Hardy-Weinberg Proportions

Answer 7

• if a population is in Hardy-Weinberg equilibrium then genotype frequencies can be derived from gene frequencies
• usually 2pq»_space;q^2
• derive heterozygous frequency from the homozygous recessive frequency

Question 8

Ratio of carriers to autosomal recessive affected individuals

Answer 8

• the ratio of carriers to affected individuals increases as the frequency of the disease decreases
• the rarer the disease (the smaller q) the greater the ratio of carriers to affected individuals so harder to remove disease alleles

Question 9

Recessives appear sporatic

Answer 9

Parents of autosomal recessive are both carriers

-for one of the parents to not be a carrier requires a new mutation, >99% of CF children born to carrier parents

Question 10

Dominants are heterozygotes

Answer 10

• 2pq>q^2
• for dominant disorder to be homozygous require both parents to be affected or a new mutation (unlikely)
• in reality homozygotes are usually more severe, even lethal or undocumemted

Question 11

X-linked recessive traits

Answer 11

-diseased male is equal to q,
-carrier female- 2pq
-affected female q^2
ratio of carrier females to affected males 2:1
ratio of affected males to females 5000 :1

Question 12

H-W assumptions

Answer 12

1) the population is large, and matings are random with respect to the locus in questions
2) Allele frequencies remain constant over time because:
a) there is no appreciable rate of mutation
b) individuals with all genotypes are equally capable of mating and passing on their genes i.e. there is no selection against any particular genotype
c) There has been no significant immigration of individuals from a population with allele frequencies very different from the endogenous population

Question 13

Random mating

Answer 13

• random mating (panmixia) is when individual has an equal chance of mating with any other individual in the population
• exceptions to random mating:
• assortative mating
• usually positive, generally increase the proportion of homozygotes
• stratification into subgroups e.g. race, ethnic groups, congenitally deaf, religious
• negative assortative mating (increases the proportion of heterozygotes)
• little long term consequence to the population

Question 14

Consanguinity (inbreeding)

Answer 14

• relationship by descent from a common ancestor
• found proportionally more often in rare recessive disease
• the absolute risk of abnormal offspring in first cousin marriages is less than double the population risk; consanguity at the level of third cousin or less is not considered significant
• we each carry on average more than 10 detrimental recessive genes
• results in increased frequency of autosomal recessive disorders compared to H-W expected incidence
  ex. Tay-Sachs

Question 15

Population Size

Answer 15

• large population size (100s rather than 10s)
• world population recently exceeded 7 billion but was less than a million through late Paleolithic. Effective population size was ~10,000 for most of our history
• no random fluctuations leading to sample variation
• inbreeding is inversely proportional to population size
• small population size: founder effect- bottlenecks, island populations
• Random genetic drift

Question 16

Genetic Drift and Migration

Answer 16

• efficiency of selection greater in Isolates
• drift was possibly more important in prehistoric times when our species was broken up into hunting camps, tribes and clans
• 10,000-100,000 years ago drift was more important than now because population was smaller
• migration can reverse the effects of Drift on the ratio of Hom/Het

Question 17

Migration

Answer 17

-no migration; a population’s gene frequencies will be altered if there is immigration from another population with different gene frequencies; will increase frequency of Heterozygotes

Question 18

Races

Answer 18

• race-is a geographically or culturally more-or-less isolated division whose gene pool differs from that of similar isolates
• African non-African split occured about 140,000 years ago
• causcasian asian split occured about 70,000 years ago
• at the simplest level, each of us carries a set of genes that affects the color of his or her skin (often a surrogate for race). The exact number of genes isn’t known, but they represent only a small fraction of the estimated 20,000+ total genes in our genomes

Question 19

Genetic background

Answer 19

• variation within race (85%) is greater than between races (6-10%)
• two randomly chosen individuals are expected to differ at ~15,000,000 bases (of the 3,000,000,000)
• CNV means that we differ from each other on average in copy number at 73-87 genes
• we are 99.5% the same
• the degree of diversity in humans is less than what typically exists among other species, due to a recent bottleneck

Question 20

Ethnic background

Answer 20

• 3-30 races
• ~700 ethnic groups
• it can be useful to know a families’ racial/ethnic background, particularly in the multicultural US so as to give more accurate estimates of disease incidence, carrier frequencies, mutation frequencies

Question 21

Selection and Fitness

Answer 21

• assume no selection, all genotypes equally viable i.e. no effects on fertility and viability leads to unequal contribution to the next generation
• natural selection is the operation of forces that determine the relative fitness of the genotype in the population, thus affecting the frequency of the gene concerned

-s=coefficient of selection
f= genetic fitness (1-s)
-fitness (f) is the probability of transmitting genes to the next generation and of the survival in that generation to be passed on to the next, in relation to the average probability for the population

Question 22

Selection

Answer 22

• dominant alleles are expressed in carriers i.e. are openly exposed; the consequences of selection are more obvious so they tend to be milder than recessives e.g. dominant lethals are removed straight away
• selection against X-linked recessive versus autosomal recessive alleles is more efficient due to “exposure” in hemizygous males
• selection against polygenic characters is less effective- new equilibrium will be established only gradually.

Question 23

MOI and exposure to selection

Answer 23

• selection can remove dominants easier
• AD- most exposed, only some non-penetrant
• XLR- females 2/3 invisible since they are carriers, males 1/3
• AR- q is exposed, 1-q is no exposed

Question 24

Heterozygous advantage

Answer 24

• sickle cell anemia/plasmodium
• Tay-Sachs heterzygotes maybe more resistant to TB
• certain toxins produced in bacterial diarrhea cause oversecretion of chlorid; give CF heterozygotes an advantage in resistance to cholera
• NOTE if heterozygous advantage of a particular genotype is present but unrecognized the mutation rate of the gene may be grossly overestimated. A relatively small selective advantage can outweigh a large disadvantage in the homozygote

Question 25

Mutation

Answer 25

mutation rate will alter allele frequencies very slowly- to change the frequency of an allele from 1.0 to 0.5 with u= 10^-5 would require 70,000 generations (1.4 million years) -mutation rate- the rate of mutation per locus per generation or the rate per locus per gamete -mutation is the only course of genetic variability but acting alone it has minimal effect on allele frequencies ~1 in 100 million base pairs per generation Mutation rate higher on Y chromosome and on mitochondria

Question 26

New mutation rate

Answer 26

u= n/2N - where n=number of affected patients born to unaffected parents and N= total number of births. But difficulties in determining prevalence figures if variation in expression, penetrance, age-of-onse (die before manifesting e.g. HD) locus heterogeneity - asumes 100% penetrance and ascertainment

Question 27

Balance between mutation rate and selection

Answer 27

- at equilibrium new mutations replace lost (removed by selection) disadvantageous alleles - for most autosomal recessive genes q=0.02 to 0.003, 2pq= 1/25 to 1/167 - typical mean mutation rates u= 10^-6 to 10^-4 - ~10% of individuals carry a new detrimental mutation - at equilibrium selection and mutant allele frequency at H-W

Question 28

Hemophilia- an example of change in selection with time

Answer 28

- in early 1960s fitness was up due to transfusion - in late 1960s fitness was down due to hepatitis B contamination of blood supply - fitness was up due to Hep B vaccination - fitness down again due to Hep C - 1978 to 1983 fitness way down due to HIV and 30-90% of hemophilicas were HIV infected - fitness up due to screening and blood product treatment