Population genetics Flashcards
Population Genetics =
the study of allele frequencies and changes in allele frequencies in ‘populations’
Basic Pop Gen Principles:
– mutation rates, fitness, consangunity
mutation:
any change in the DNA sequence or arrangement
germline
in gonadal tissue (usually in all cells) can be passed onto next generation
polymorphism
any genetic variant (mutation) found in >1% of population
forces affecting allele frequencies
- mutation: new mutations
- Natural selection: survival of the fittest
- genetic drift: random changes
- gene flow: addition/subtraction
Heterozygous advantage:
deleterious mutation in homozygous state, maintained as an “advantage” in heterozygous state (protect against malaria for heterozygous for sickle cell anemia)
New mutations rate
1.18 x10^-8
we transmit ______ novel SNPs per genome per generation
74
diseases due to novel mutatiosn
schinzel-Giedion,
Kabuki
Bohring–Opitz
Fitness (f)
the probability of transmitting one’s genes to the next generation
f=1 (same as normal population)
f=0 (gene is not passed on)
coefficient of selection
a measure of forces that reduces fitness
s=1 - f
mutation rate (u)
frequency of new mutations at a given genetic locus, expressed as mutations/generation
how to measure autosomal dominant
- direct method
2. indirect method
direct method
fully penetrant (no hidden mutations)–> count the cases with no family history (the new mutations)
indirect method
if f=0, then all cases represent new mutations –> then use incidence (I) of disease to calculate u –> I = 2 u, since each of us inherits two alleles
if f/=/ 0, then can estimate u using u = 1/2/ F (1 - f)
autosomal recessive equation
u = F (1 - f)
X-linked recessive equation
u = 1/3 F (1-f)
u=mutation rate/gene/generation
F= frequency of the disease
f= reproduction fitness
Hardy-Weinberg Law
p + q = 1 = p2 + 2pq + q2
Hardy weinberg assumptions
- population is large and matings are random
- allele frequencies remain constant over time
- no appreciable rate of mutation
- all genotypes are equally fit
- equal chance to pass allele to the next generation
- no significant immigration/emigration of individuals with different allele frequencies
Hardy weinburg do not appear in reality, but cane used because
Populations are large enough
how is hardy weinberg used
- used in genetic counseling to predict risks for a couple to have an affected child
- prevalence of disease is approximately: q^2
- freom q^2, you can calculate q, p, and then the carrier frequency 2pq
for rare autosomal recessive disease, 2q can estimate
2pq
genome mutation
mechanism: chromosome missegregation
Frequency: 2-4 x 10 ^-2 per cell division
example: aneuploidy (e.g. trisomy 21)
chromosome mutation
mechanism: chromosome rearrangement
Frequency: 6 x 10^ -4
example: translocation
gene mutation
mechanism: base pair mutation
Frequency: 10^ -5 – 10^-6 per locus/generation
example: point mutation
mutation
any change in nucleotide sequence and arrangemtn of DNA
polymorphism
a genetic variant (mutation) which is common (>1%) in the populations
founder effects
a high frequency of mutant allele in a population founded by a small ancestral group when one or more original founders was a carrier of the mutant allele
genetic drift
random fluctuation of allele frequencies, usually in small populations
selection
active selection of favorable alleles over non favorable ones
selection depends on
fitness
fitness is
a measure of the chance an allele will be transmitted to the next generation
Scale of 0-1
Fitness 0
lethal and severe disorders that have low fitness because an individual doesn’t live long enough or is not healthy enough to reproduce and pass on the disease allele
fitness measures
reproductive success
reproductive success
means survival is not the only consideration (e.g. your fitness is still low if you possess superhuman strength and health, but suffer from infertility or are an intolerable egomaniac and are unable to have biological children)
Natural selection generally occurs only when the trait is _______, which means that even severe recessive alleles are not selected against in the ______. Exceptions to this statement could occur if _______
expressed
heterozygous state
genetic testing of asymptomatic persons identifies heterozygotes persons who then elect to not have children or terminate an affected pregnancy for instance.
Doctors theoretically affect fitness through _______. If medical care improves the health (and reproductive fitness) of persons with disease X then mutation frequencies for disease X may _______. Rate of increase depend on the _____
through improving health and altering one’s chances of reproductive success
rise
inheritance (as well as the severity of the disease and the absolute increase in fitness).
Recessive diseases:
mutant allele increases are slow
Dominant diseases / X-linked diseases
the rates could be higher
Hardy-Weinberg useful in _____________
recessive conditions for calculating carrier rates
By observing the number of cases of disease in a population it is possible to calculate ________
rates of mutation for different conditions
NextGeneration DNA sequencing will determine _________
whether the ‘estimates’ of mutation rates turn out to be correct
Forces affecting allele frequencies
- Natural selection – Survival of fittest
- Genetic drift – Random changes
- Mutation
– New mutations - Gene flow
– Addition/Subtraction
Autosomal Dominant Polycystic Kidney Disease
- Prevalence estimated at 1
in 400 - ~400,000 affected in US
- ~10% of cases are due to novel mutations
Population sampling by phenotype can lead to estimates of ________if the underlying _______ is known.
allele frequency
underlying genetic mechanism (i.e. dominant vs. recessive // autosomal vs. sex-linked)
Population genetics is important for understanding _____________
allele frequency in populations (and how those frequencies change)
direct method is used for
autosomal dominant conditions with 100% penetrance.
You can count the new cases that occur with no family history. Since each child has 2 alleles, multiple that by two.
‘mutation-rate’ (μ)
the number of alleles for each new cases with no family history
Indirect method is used for
For an autosomal dominant condition where the reproductive fitness (f) is zero (i.e. affected persons do not survive to reproduce and/or are infertile) then all cases represent new mutations.
Incidence
2 alleles for autosomal dominant where fitness is zero
when the fitness is not 0, Autosomal dominant=
μ= 1/2 F (1-f)
when the fitness is not 0, Autosomal recessive=
μ= F (1-f)
When fitness is not 0, X-linked recessive=
μ= 1/3 F (1-f)
Hardy-Weinberg principle describes the________
the frequency of two alleles in a population in terms of allele frequency and genotype frequency. It is useful to physicians because it can predict expected frequencies for the next generation
q is the
q is usually reserved for the less common (minor allele)
Hardy Weinberg assumes the absence of:
- Non-random mating
- mutation
- selection
- migration/drift
- small population size
The major use of Hardy-Weinberg in medical genetics is in __________
genetic counseling for autosomal recessive disorders.
Cystic fibrosis (CF) is an autosomal _______ lung disease with a prevalence of _______
recessive
1/2,500.
rarer diseases (< 1/10,000) 2pq = ________
2q
Random Mating does not always occur:
- Stratification
- Assortive Mating
- Consanguity
Stratification:
refers to populations containing 2 or more subgroups which tend preferentially mate within their own subgroup. Mate selection is not dependent on the trait/disease or interest.
Stratification example
Example: sickle cell anemia in African Americans (AAs) has higher incidence social stratification favoring mating of AAs with other AAs, than is predicted by HWE
Assortive mating:
refers to when the choice of mate is dependent (in part) on a particular trait (or sometimes a disease).
Assortive mating has been observed for:
for congenital short stature (previously called ‘dwarfism’), blindness, and deafness.
Consanguinity increases matings between _______, thereby increasing the __________ in the population.
carriers of autosomal recessive diseases,
number of cases of autosomal recessive diseases
