Population Genetics Flashcards
Population Genetics
The study of allele frequencies and changes in allele frequencies in populations
Four main evolutionary forces effecting allele frequency
natural selection
genetic drift
mutation
gene flow
How is population health used by scientists
use to predict allele (or disease) changes in populations
How is population genetics used by clinicians
Predict risk for individuals
Why is population genetics important?
It is important for understanding allele frequency in populations (an how those frequencies change)
How can we estimate allele frequency in a population?
Population sampling by phenotype can lead to estimates of allele frequency if the underlying genetic mechanism is known (i.e. dominant vs. recessive // autosomal vs. sex-linked)
Mutation
Any change in the nucleotide sequence and/or arrangement of DNA (as compared to some reference standard). Although some doctors use the word “mutation” to imply a disease-causing / pathogenic change, the technical definition does not require that the mutation lead to disease
Polymorphism
a genetic variant (mutations) which is common (>1%) in the population
Founder Effect
A high frequency of a mutant allele in a population founded by a small ancestral group when one or more of the original founders was a carrier of the mutant allele
Genetic drift
Random fluctuations of allele frequencies, usually over small populations
Selection
active selection of favorable alleles (confer fitness advantage) over unfavorable ones
Fitness measures what?
Reproductive success - it is a measure of the chance an allele will be transmitted to the next generation
Selection depends on what?
Fitness
When does natural selection occur?
Generally only occurs when the trait is expressed, which means that even severe recessive alleles are not selected against in the heterozygous state. Exceptions would be if genetic testing makes someone decide not to risk having a child
What is the consequence of migration / gene flow?
When populations with different allele frequencies for a disorder mix (typically seen in cases of immigration) then allele frequencies can change
e.g. CCR5
Fitness is measured how?
On a scale from 0-1 with 1 being normal reproductive success and 0 being non-heritable (i.e. gene is not passed on)
Coefficient of selection
Measure of forces reducing fitness
S = 1-F or
F = 1-S
Mutation rate?
The frequency of new mutation at given locus
Measured as mutations/generation
Mutation rates for autosomal dominant: Direct method
For autosomal dominant diseases with 100% penetrance, one can simply count the number of new cases that occur with no family history.
For example, if 12 disease cases are identified in 100,000 children and 10 of the 12 cases have a negative family history, then the mutation rate is 10/100,000 children -
Since each child has 2 alleles of each gene, the mutation rate would be 10/200,000
Mutation rate for autosomal dominant: Indirect method
For autosomal dominant conditions where the reproductive fitness is zero (i,e, effected persons do not survive to reproduce and/or are infertile) then all cases represent new mutations. Since each child inherits 2 genes, then the incidence (I) of the disease is really twice the mutation rate –> I = 2u
or u = 1/2I
What is the major utility of Hardy Weinberg in medicine?
Genetic counseling for autosomal recessive
Idealized assumptions of Hardy Weinberg
Large population mating randomly Allele frequencies remain constant over time because No appreciable rate of new mutation No selection for/against allele No appreciable immigration/emigration
Three types of non random mating that could occur?
Stratification
Assortive mating
Consanguinity
Stratrification
refers to populations containing 2 ore more subgroups which tend to preferentially mate within their own subgroup - mate selection is not dependent on the trait/disease of interest
Assortive mating
Refers to when the choice of mate is dependent (in part) on a particular trait (or sometimes a disease). This occurs because people tend to choose mates who resemble themselves (language, height, skin color, etc.)
Consanguinity
Occurs when persons marry closely-related blood relatives. This, non-random mating practice increases mating between carriers of autosomal recessive diseases, thereby increasing the number of cases of autosomal recessive diseases in the population.
African Americans have a higher rate of sickle cell anemia then would be predicted by HWE, what causes this?
Social stratification
Dwarfs, blind, and deaf selecting to mate with each other would throw off HWE, this is an example of?
Assortive mating
Do new mutations occur frequently?
Yes, new mutations are a regular occurance
Do most mutations cause disease?
No, most new mutations are benign (not disease causing)
How can we determine whether our estimates of mutation rates are accurate?
NextGen sequencing will determine whether the “estimates of mutation” turn out to be accurate
How can we calculate the rates of mutation for different conditions?
By observing the number of cases of disease in a population, it is possible to calculate the rates of mutation for different conditions
What is the utility of Hardy Weinberg?
It allows us to measure allele frequencies and use them to predict genotypes
p+q = 1
p^2 + 2pq + q^2 = 1
***Clinically useful for recessive conditions and carrier rates
Areas to focus on (3)
HWE (what does it tell us and what are the assumptions)
How to calculate q and 2pq from prevalence data
Mutation rate calculations and AD disease based on new incident cases
