L52: Population Genetics

Question 1

In a recessive disease with an incidence of 1/10000, how high is the allele frequency in the gene pool? How high is the carrier frequency?

Answer 1

• f(a)^2 = 1/10000, then f(a) = 1/100 = 0.01 - f(A) = 1-f(a) = 99/100 = 0.99 - Since the disease is so rare, assume f(A) = 1, then frequency of heterozygote = 2f(a)f(A) = 0.02

Question 2

Discuss genetic polymorphisms in human populations and genetic variation between different ethnic groups

Answer 2

• When an allele is present in more than 1% of the population, it is called polymorphic - Some genes have high degree (HLA haplotypes) and other genes have low degree of polymorphism (histones) - In the human population, there are roughly 6 million single-nucleotide polymorphisms (SNPs) between unrelated individuals. 90% of world’s polymorphisms can be found within any given population and therefore only 10% of the polymorphisms truly set ethnic groups apart

Question 3

What characteristics does an ideal population follow in terms of HW?

Answer 3

• Large population size - Equal fitness among offspring - Random mating - No influx of new alleles by migration or mutation

Question 3

What is assortative mating and how does it affect the gene pool of a population?

Answer 3

• Assortative mating is the selection of partners based on specific genetic traits. - It disturbs the equilibrium distribution of alleles, specifically, the mating of genetically similar individuals increases the degree of homozygosity in a population. The allele frequencies in the gene pool don’t change, only change is increase in homozygote frequency.

Question 4

Explain linkage disequilibrium. Two characteristics needed to use this type of analysis. Clinical relevance?

Answer 4

• Two markers located in close proximity on same chromosome show some degree of linkage. In other words, in recombination in meiosis will unlikely separate these markers and they will therefore travel together. While unlikely, occasionally recombination event will occur that separates them. If sufficient time is given, rare recombination events will establish equilibrium and original combination of markers is found no more frequently than predicted by chance. Linkage disequilibrium refers to this original combination being found more frequently than predicted. - Characteristics: population must be genetically young and small. - Relevance: in order to find alleles that contribute to a certain disease, geneticists look for linkage disequilibrium bw disease trait and genetic markers all over genome. Goal is to find markers that are more often associated with disease trait than predicted by allele frequency alone. LD between disease allele and nearby marker is observed when disease causing mutations was introduced into population relatively recently.

Question 5

What is selection and how does it affect the gene pool of a population?

Answer 5

• Selection works against or in favor of certain genotypes. Over time, selection will reduce number of detrimental mutant alleles in a population. However, frequency of mutant alleles will stabilize at a low level. In this state of equilibrium, loss of mutant alleles by negative selection will be equal to spontaneous occurrence of new mutant alleles

Question 5

Explain genome-wide association studies

Answer 5

• GWAS refers to analysis of millions of SNPs to determine their connection with disease. Genetic polymorphisms underlie why certain individuals have a genetic susceptibility to certain disease or have different responsiveness to drugs. - From these studies, you get odds ratio that SNP is associated with disease state. - Note, SNPs are not necessarily disease-causing. SNPs often lie outside of coding regions, but show strong linkage with the mutation that causes the disease.

Question 6

What are population bottlenecks and founder effect and how does it affect the gene pool of a population? Example

Answer 6

• If a large part of a population is wiped out by a catastrophic event, population has to recover from a small founder population of survivors. This bottleneck leads to amplification of rare alleles in the founder’s genotype. - Example: Samuel King immigrated to Eastern PA and founded a large family. He carried a rare recessive mutation in EVC, which cause Ellis Van Creveld syndrome (skeletal dysplasia disorder). This was propagated through founder effect. Consanguineous matings were inevitable in this genetically isolated community and children homozygous for EVC mutation were born. Carrier frequency for EVC is 12.3% in Old Order Amish community in PA, which is only 0.8% in general population

Question 8

What influences cause deviations from HW equilibrium?

Answer 8

• Genetic drift (non-small populations) - Selection (fitness is unequal in offspring) - Assortative mating (mating is non-random) - Population bottlenecks/founder effect

Question 10

What is genetic drift and how does it affect the gene pool of a population? Example

Answer 10

• Genetic drift is the change in allele frequency within a population due to random sampling/statistical variation. This occurs in small populations. - Example: 10 couples stranded on deserted island. One of males is heterozygous carrier of CFTR mutation. Allele frequency is 1/40 (2.5%). Time goes by and couples have average of 2 children. By chance, none of children have inherited mutation from father. By genetic drift, CFTR allele is now completely lost from this island’s population.

Question 11

What is heterozygote advantage? Describe in respect to mutation affecting CFTR, beta-globin and HFE.

Answer 11

• Heterozygote advantage refers to positive selection of heterozygotes as a result of their genotype conferring increased fitness in a particular environment. - CFTR: protects against typhoid fever (population that benefits = European) - Beta-globin/sickle cell: protects against malaria (population that benefits = Mediterranean and African) - Beta-globin/beta-thalassemia: protects against malaria (population that benefits = Meditteranean) - HFE/hemochromatosis: protects against plague (population that benefits = European)

Question 12

Give examples of diseases that affect genetically isolated populations

Answer 12

1.) Ellis van Creveld Syndrome: Old Order Amish of Lancaster County 2.) Tay-Sachs Disease (ganglioside storage disease): Ashkenazi Jews 3.) Tyrosinema: French Canadians in Quebec