Sequencing era methods for identifying signatures of selection in the genome.

Insights into genetic loci which are under selection and their functional roles contribute to increased understanding of the patterns of phenotypic variation we observe today. The availability of whole-genome sequence data, for humans and other species, provides opportunities to investigate adaptation and evolution at unprecedented resolution. Many analytical methods have been developed to interrogate these large data sets and characterize signatures of selection in the genome. We review here recently developed methods and consider the impact of increased computing power and data availability on the detection of selection signatures. Consideration of demography, recombination and other confounding factors is important, and use of a range of methods in combination is a powerful route to resolving different forms of selection in genome sequence data. Overall, a substantial improvement in methods for application to whole-genome sequencing is evident, although further work is required to develop robust and computationally efficient approaches which may increase reproducibility across studies.

Gene-dense autosomal chromosomes show evidence for increased selection.

Purifying selection tends to reduce nucleotide and haplotype diversity leading to increased linkage disequilibrium. However, detection of evidence for selection is difficult as the signature is confounded by wide variation in the recombination rate which has a complex relationship with selection. The effective bottleneck time (the ratio of the linkage disequilibrium map to the genetic map in Morgans) controls for variability in the recombination rate. Reduced effective bottleneck times indicate stronger residual linkage disequilibrium, consistent with increased selection. Using whole genome sequence data from one European and three Sub-Saharan African human populations we find, in the African samples, strong correlations between high gene densities and reduced effective bottleneck time for autosomal chromosomes. This suggests that gene-dense autosomes have been subject to increased purifying selection reducing effective bottleneck times compared to gene-poor autosomes. Although previous studies have shown unusually strong linkage disequilibrium for the sex chromosomes variation within the autosomes has not been recognised. The strongest relationship is between effective bottleneck time and the density of essential genes, which are likely targets of greater selective pressure (p = 0.006, for the 22 autosomes). The magnitude of the reduction in chromosome-specific effective bottleneck times from the least to the most gene-dense autosomes is ~17-21% for Sub-Saharan African populations. The effect size is greater in Sub-Saharan African populations, compared to a European sample, consistent with increased efficiency of selection in populations with larger effective population sizes which have not been subject to intense population bottlenecks as experienced by populations of European ancestry. The findings highlight the value of deeper analyses of selection within Sub-Saharan African populations.

Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data.

Quantification of linkage disequilibrium (LD) patterns in the human genome is essential for genome-wide association studies, selection signature mapping and studies of recombination. Whole genome sequence (WGS) data provides optimal source data for this quantification as it is free from biases introduced by the design of array genotyping platforms. The Malécot-Morton model of LD allows the creation of a cumulative map for each choromosome, analogous to an LD form of a linkage map. Here we report LD maps generated from WGS data for a large population of European ancestry, as well as populations of Baganda, Ethiopian and Zulu ancestry. We achieve high average genetic marker densities of 2.3-4.6/kb. These maps show good agreement with prior, low resolution maps and are consistent between populations. Files are provided in BED format to allow researchers to readily utilise this resource.