What is the definition of genetic drift?
- Genetic drift is a kind of random sampling of alleles entering the next generation
- Drift acts as a dispersive forces that removes variation
- Any population of finite size will be subject to genetic drift
- Can be thought of as ‘accidents of sampling’ - which influence which alleles make it into the next generation
Name 3 sources of randomness that contribute to genetic drift
- Which allele in gametes come together by chance - e.g., for a heterozygous individual there is a 50:50 chance as to which alleles ends up in the fertilised zygote
- Variation in chance of survival
- Variation in chance of reproductive success
What effect does drift have on variants?
- Rare variants are easily lost due to chance events
- Common variants are less sensitive to chance events
Give a famous example of drift in humans
Blood groups:
- Allele B of ABO, N allele of MN and Rh- allele are absent in Polynesia
- Alleles lost due to Founder effects during colonisation of islands across pacific by small groups
- Ioannidis et al., 2021 - Nature 597
How does the strength of drift change dependent on population size?
- Strength of drift is stronger on small population sizes (faster loss of variation)
- Over time, genetic drift leads to a decline in genetic variation due to a fixation/loss of alleles
- Larger the population, the longer this takes
What is the Wright-Fisher model?
- Drift effects all DNA - whether under selection or not
- Wright-Fisher model describes a population evolving from drift alone (no selection)
- Is used as null scenario for testing patterns of genetic variation
What assumptions are made for the Wright-Fisher model?
- Non-overlapping generations
- Constant size population (N individuals, 2N lineages)
- Random union of gametes (‘random mating’) - each child has 2 parents
- Sexual reproduction with all individuals hermaphrodite and able to self fertilise
- Poisson distribution for reproductive success
What is the effective population size (Ne)?
Ne is the size of the Wright-Fisher population equivalent to the real population being studied
- Is unlikely that a real population will conform exactly to the assumptions of the Wright-Fisher model
- However, these populations behave in a similar way to Wright-Fisher populations but with reduced population sizes
- Ne is always smaller than the real population size - N
How does N vs Ne change dependent on pop size?
- Drift is stronger in small pop - so genetic variation and Ne is lower in fluctuating pops compared to constant size populations with same max size (N)
- Implies individuals from populations with smaller Ne more likely share a common ancestor in the recent past
Give an example how variation in mating systems can cause deviation from Wright-Fisher assumptions?
E.g., elephant seals
- Have highly polygynous mating systems - small number of males monopolise matings with a large number of females
- This leads to a larger variation in reproductive success between individuals
- So deviates from Wright-Fisher - can have consequences for the expected amount of genetic variation in the population
What are the 4 key features of genetic drift?
- Random - unpredictable changes in allele frequencies between generations
- Dispersive force - reduces variation in populations - causes allele frequencies to diverge
- Neutral - all alleles influenced in same way
- Related inversely to Ne - drift stronger in small populations
What are the probabilities of fixation?
- 1/2N for specific allele copy
- = frequency in population for particular allelic variant
What different ways can you predict the expected amount of genetic variation in neutrally evolving populations (drift in constant sized populations)
- Wright-Fisher model and ‘forward in time’ perspective of genetic drift
- Neutral theory and infinite alleles model
- Mutation-drift equilibrium
- Molecular clocks
- Coalescent theory - ‘backwards in time’ perspective of genetic drift
- Gene genealogies
What is the decay of heterozygosity?
- Heterozygosity tending to 0 over time
- Tends to 0 faster with a smaller N (pop size)
- Ht = H0(1 - 1/2N)^t
- Decay is geometric
What is a population bottleneck and what effect does it have on genetic variation?
Is a sharp reduction in population due to an event - e.g., an earthquake/flood
- Pop size and genetic variation drops
- Pop size recovers fast
- Genetic variation recovers more slowly than population size - as only way to gain variation is through mutation
What is the infinite alleles (or sites - when referring to sequence variation) model?
- Is the case where each mutation is to a novel state
- In this case, under neutrality, a large number of alleles can be maintained in large populations
- However, when heterozygotes are the fittest genotype, a ‘genetic load’ is created due to the existence of homozygotes for less fit alleles
- Crow and Kimura - showed this creates an upper limit for the number of alleles - since selective advantage of fitter alleles is balanced out by the genetic load
- This limit appeared inconsistent with high levels of variation seen in protein variation of Drosophila - led to Kimura suggesting most mutations had to be neutral
What is the Nearly Neutral theory?
The idea that: In large pops with short generation times, noncoding DNA evolves faster while protein evolution is retarded by selection - which is more significant than drift for large pops
- Tomoko Ohta
Explain the Mutation-Drift balance?
- Mutation inputs new alleles into population
- Drift removes alleles from population
- Therefore, in neutrally evolving population, the amount of diversity will move to an equilibrium value - the magnitude of which depends on the balance of the 2 processes
- Larger populations are more likely to mutate and are less sensitive to drift - so should have greater equilibrium levels of variation than small populations in the neutral case
What is theta?
Population mutation parameter:
- Key parameter needed to estimate the level of genetic variation under neutral model
- Theta = 4Nu
What can you use to predict the amount of genetic variation that should be present in a population?
Mutation-Drift balance in the Wright-Fisher model
- Drift - decreases diversity (1/2N)
- Mutation increases diversity (2Nu) - u = mutation rate
- From infinite alleles model use 4Nu
- 4Nu = theta
What is the neutral theory of evolution?
- Mutation = new allele
- What is the probability that this new allele will become fixed?
- Mutation rate = mu (u) - probability of a new allele = 2Nu
- Probability of fixation of an allele = 1/2N
- Probability of a new allele fixing = 2Nu x 1/2N = u
Describe the molecular clock with its parameters
The hypothesis that DNA and protein sequences evolve at a constant rate over time and in different organisms
- p = rate of evolution (accumulation of mutations fixed between species)
- p = u - since we saw that the probability of fixation is equal to mutation rate
- For T1 in Species A - mutations are not substitutions but polymorphisms within species (transient entities)
- The number of mutations fixed between two species along one branch: T2u
- i.e. in neutral case, the expected number of mutations /genetic diversity along a branch is proportional to the time that separates them - so implies genetic variation is accumulating in a clock-like way where the ticks on the clock relate to the magnitude of the mutation rate
What is coalesence theory and how does it differ from the Wright-Fisher model?
- Alternative way of looking at drift - looking backwards in time
- Works out the time to the most recent common ancestor (TMRCA)
- Follow haplotypes back in time - seeing them ‘merge’ as they lose unique mutations
- Wright-Fisher model looks forward in time to predict variation in the future - but has limitations: under genetic drift, we cannot predict in which lineage/allele this will persist in future - and makes it difficult to understand what may have happened in the past. And, from an imperical standpoint - we can only collect samples from back in time - might be interested in projecting histories back in time
Why is coalesence important?
- Real world data - we only have access to contempary sequences or alleles, which form the tips of the genealogy - cant see full genealogy for every generation in past
- Coalescent allows us to reconstruct the history of surviving lineages and make inferences about the evolutionary processes which influenced them
- The coalescent provides important framework for working with sequence and other genetic data
