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. 2005 Sep;15(9):1211-21.
doi: 10.1101/gr.3413205.

Fitting background-selection predictions to levels of nucleotide variation and divergence along the human autosomes

Floyd A Reed  1 , Joshua M Akey, Charles F Aquadro
Affiliations

Fitting background-selection predictions to levels of nucleotide variation and divergence along the human autosomes

Floyd A Reed et al. Genome Res. 2005 Sep.

Abstract

The roles of positive directional selection (selective sweeps) and negative selection (background selection) in shaping the genome-wide distribution of genetic variation in humans remain largely unknown. Here, we optimize the parameter values of a model of the removal of deleterious mutations (background selection) to observed levels of human polymorphism, controlling for mutation rate heterogeneity by using interspecific divergence. A point of "best fit" was found between background-selection predictions and estimates of human effective population sizes, with reasonable parameter estimates whose uncertainty was assessed by bootstrapping. The results suggest that the purging of deleterious alleles has had some influence on shaping levels of human variation, although the effects may be subtle over the majority of the human genome. A significant relationship was found between background-selection predictions and measures of skew in the allele frequency distribution. The genome-wide action of selection (positive and/or negative) is required to explain this observation.

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Figures

Figure 1.
Figure 1.
Plots of the bootstrapping distribution of the estimated deleterious mutation rate (û/Mb), strength of selection (ŝĥ), and the effective population size without selection (N̂0). The best-fit value for all the data is contained in the weight of the outcomes. û and ŝĥ appear to be positively correlated (i.e., as the deleterious mutation rate increases, selection strength must also increase to maintain a similar outcome). û and N̂0 also appear to be correlated (as the deleterious mutation rate increases, the effective population size must also increase to maintain a similar outcome). A small number of points that were widely dispersed below ŝĥ = 0.00001 and/or û/Mb = 0.00001 are not included in the plot.
Figure 2.
Figure 2.
Predicted (lines) and estimated (circles) effective population size estimates (Ne) along the human autosomes under the model of background selection (equation 2). The upper and lower 90% bootstrapping-based confidence intervals are solely for the background-selection estimates. The deviations of individual gene regions depend on evolutionary variance and their individual sampling properties. Filled black circles correspond to positive Tajima's D values, filled gray circles correspond to Tajima's D values between 0 and -1; filled white circles correspond to Tajima's D values <-1.
Figure 3.
Figure 3.
A plot of Tajima's D versus f̂0 predictions. The observed frequency distribution is increasingly skewed toward an excess of rare alleles as predicted variation is reduced (assuming background selection). This could be a result of either positive or negative selection or both. The correlation between Tajima's D and f̂0 remains significant even if the apparent outliers (ABO, F2, and PROS1) are selectively removed (r2 = 0.045, P = 0.019). Note, if a linear extrapolation is made from the best-fit regression line to f0 = 1, in an effort to account for the effects of selection, there is little to no negative skew (D ≈ 0) predicted for humans, consistent with a nearly constant ancestral population size.
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References

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