September 5, 2015

Selection of dominant alleles vs recessive ones in population bottlenecks

Quantity over quality series

A technical study that however gives an interesting glimpse on the complex but generally reductive genetic effect of bottlenecks such as the Out-of-Africa migration of humankind is out in PLoS Genetics.

Daniel J. Ballick et al., Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck. PLoS Genetics 2015. Open accessLINK [doi:10.1371/journal.pgen.1005436]

Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, , where xi represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a BR indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection.

Author Summary
Dominance has played a central role in classical genetics since its inception. However, the effect of dominance introduces substantial technical complications into theoretical models describing dynamics of alleles in populations. As a result, dominance is often ignored in population genetic models. Statistical tests for selection built on these models do not discriminate between recessive and additive alleles. We show that historical changes in population size can provide a way to differentiate between recessive and additive selection. Our analysis compares two sub-populations with different demographic histories. History of our own species provides plenty of examples of sub-populations that went through population bottlenecks followed by re-expansions. We show that demographic differences, which generally complicate the analysis, can instead aid in the inference of features of natural selection.

Fig 3. The BR statistic at the time of observation.
ABOVE: At the time of observation tobs, the value of BR(tobs) is plotted as a function of the average strength of selection s and dominance coefficient h. Dominance coefficients appear as solid lines with fully recessive selection (h = 0) at the top and purely additive selection () at the bottom. For strong selection BR → 1 due to the rapid transient response. For weak selection BR → 1 due to the nearly neutral insensitivity to the bottleneck. For some intermediate dominance coefficient hc, a critical value occurs (hc ~ 0.25 in the example shown, but explored more generally in S1 Text) where additive and recessive effects cancel, yielding BR(hc) ~ 1. A low intensity bottleneck (IB = 0.05) is shown, with parameters 2N0 = 20000, 2NB = 2000, TB = 100, and tobs = 1000. BELOW: The same range of parameters is plotted for a realistic demographic model of the Out of Africa event comparing Africans and Europeans [48], where BR = 〈xAfrican/〈xEuropean. The European bottleneck has estimated intensity IB ~ 𝒪(0.5), an order of magnitude stronger than the simple bottleneck above, allowing for potentially observable deviations from BR ~ 1 if a large fraction of analyzed variants act recessively with h < hc ~ 0.25.

I emphasize from the erudite legend:
The European bottleneck has estimated intensity IB ~ 𝒪(0.5), an order of magnitude stronger than the simple bottleneck above.

Although Europeans are used for reference this bottleneck and the corresponding accumulation of deleterious alleles is the same for all non-Africans.

1 comment:

  1. Also, I would have said "no big deal" they just used bad terminology, except then they talk in depth about detecting selection events. Events that never happened because there was no die-off involved.


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