 model (S11 Fig) suggests an Out-of-Africa migration 51 kya (51 thousand years ago), followed by a European and East Asian split 23 kya. It also suggests bottlenecks that reduced the effective population sizes of the European (NEu0 = 1032), and East-Asian (NAs0 = 550) populations, and exponential growth in the populations following the bottleneck events. We simulated populations based on this model, as well as selection events (hard sweep) at different times after the Out-of-Africa migration, and partitioned all samples into two categories depending on whether the selection event happened before or after the bottleneck. These scenarios are challenging for most tests of adaptation (see, e.g., [23]). However, there are still significant differences in the 1-HAF scores of carriers and non-carriers. The balanced accuracy of PreCIOSS is shown in Fig 6A for ancient selection and Fig 6B for recent (after bottleneck) selection. The performance is quite robust, although somewhat worse in the early stages of the sweep. Once the favored allele frequency reaches 60%, the median accuracy is at 0.9. The accuracy is improved for recent adaptation, compared to ancient adaptation. Even for very recent sweeps, where the carrier frequency is 30–40%, the median balanced accuracy is close to 0.8. We used a lower selection coefficient for ancient selection compared to recent selection to ensure that we have sufficient cases of incomplete sweeps. Not surprisingly, the performance of PreCIOSS is worse for ancient selection compared to recent selection.
Fig 6. Balanced accuracy of PreCIOSS on a model of European demography.
Populations were simulated for a popular model of human demography (S11 Fig and Gravel et al. (2011) [50]). The onset times of selection were separated into (A) pre-bottleneck (51 kya–23 kya) and (B) post-bottleneck (23 kya–current) epochs, with 10000 start times in each bin. All samples were simulated with n = 200, θ = 48, ρ = 25. Samples were simulated with selection coefficient s = 0.005 in the pre-bottleneck epoch and s = 0.02 in the post-bottleneck epoch.
Our results suggest that for cases of recent adaptation (e.g., lactase adaptation, shown in Fig 7A, which happened between 2 kya and 20 kya and rapidly spread to high frequencies in the European population), PreCIOSS would show good performance in separating the carriers and non-carriers.
Fig 7. Predicting carriers of well-known selective sweeps.
(Left): Haplotype 1-HAF scores in a 50 kb window centered at known favored sites indicated by the gene name, and the SNP identifier. (A) LCT/rs4988235, (C) TRPV/rs4987682, (E) PSCA/rs2294008, (G) ADH1B/rs1229984, and (I) EDAR/rs3827760. Points represent haplotype 1-HAF scores, red indicating a carrier of the favored allele and blue indicating a non-carrier. At the top of each panel, the number of haplotypes, n, is shown, with the number of carriers in parenthesis. Areas shaded in gray indicate haplotypes designated as ‘carrier’ by PreCIOSS. (Right) classification Balanced Accuracy (black) and −log2(P) values (blue) as function of window size around the favored allele in (B) LCT, (D) TRPV6, (F) PSCA, (H) ADH1B, and (J) EDAR. P-values are for Wilcoxon rank sum tests rejecting the null hypothesis of identically distributed 1-HAF scores among carriers and non-carriers. Red circles indicate the 50 kb windows shown on the left.
To evaluate the effectiveness of PreCIOSS in distinguishing carriers of a selective sweep from non-carriers, we applied it to several genomic regions (e.g., [39]) where (i) there is strong evidence of a selective sweep, and (ii) the favored allele has been characterized. In applying PreCIOSS to the datasets, we assumed that the region was known, but did not supply the favored allele to PreCIOSS. In each case, we tested if PreCIOSS could separate the haplotypes that carried the favored allele. We use phased haplotypes from the HapMap project [51], setting the ancestral allele to that observed in orthologous Chimpanzee sequence [52].
We consider the well-known sweep in the lactase (LCT) gene region in Northern Europeans. The best characterized variant is C/T-13910 (rs4988235), for which the T allele was found to be 100% associated with lactase persistence in the Finnish population [53]. T-13910 was further shown to be causal by in-vitro analysis, where it was found to increase enhancer activity [54, 55]. We considered haplotypes from the CEU population, applying PreCIOSS to a 50 kb window centered at C/T-13910 (Fig 7A). This yielded 100% accuracy in classifying carriers from non-carriers. Increasing the window size above 50 kb, the balanced classification accuracy reduced to ∼90% (Fig 7B). LCT shows the highest and most prolonged (with increasing distance from the causal site) statistical significance in separating carrier and non-carrier HAF scores, remaining highly significant for haplotypes of 1.5 Mb (Fig 7B, blue line). Despite this highly significant separation, the classification accuracy is initially unstable, alternating between ∼100% (perfect classification) and 90%. This is due to the pattern of HAF scores observed in the LCT region, where carriers form a tight cluster with the highest scores, but several non-carriers cluster closer to carriers than to the majority of other non-carriers (Fig 7A). These haplotypes are therefore sometimes included (90% accuracy) and sometimes excluded (100% accuracy) from the reported ‘carriers’ class.
Transient Receptor Potential Cation Channel, Subfamily V, Member 6 (TRPV6) is a membrane calcium channel thought to mediate the rate-limiting step of dietary calcium absorption. It is reportedly under strong positive selection in several non-African populations [56, 57]. Following Peter et al. (2012) [39], we focus on the CEU population and set rs4987682 as the favored allele. This site, of the three non-synonymous SNPs with highest allele frequency differentiation among human populations, is the only one located in the the N-terminal region of TRPV6, thought to be the target of selection [58]. Applying PreCIOSS to a 50 kb window centered at this site, we obtain ∼99% balanced classification accuracy (Fig 7C), which gradually decays to ∼80% when considering a 1.5 Mb window (Fig 7D). As with LCT, the separation in HAF scores between carriers and non-carriers of the allele is highly statistically significant (P < 10−7; see Fig 7D). Unlike LCT, accuracy decays stably with distance from the favored site. This appears to be due to the less complex clustering pattern of non-carrier HAF scores in the region (Fig 7C).
Prostate Stem Cell Antigen (PSCA) has been proposed to be under selection in a global analysis of allele frequency differentiation [59]. The putative causal site is a non-synonymous SNP (rs2294008) known to be involved in several cancer types [60, 61]. Interestingly, the derived allele is observed in all human populations, but at vastly different frequencies. It is most common in West Africa and East Asia, where it segregates at ∼75% frequency. We consider haplotypes from the YRI population and apply PreCIOSS to a 50 kb window centered at rs2294008, yielding balanced accuracy of 97% (Fig 7E). Unlike LCT and TRPV6, accuracy decays more noticeably with distance, reaching 63% at 1.25 Mb (Fig 7F). This sharper decay in accuracy is even more pronounced when considering the sweep in the CHB population (S12 Fig). Such decay is consistent with a (soft) sweep from the standing variation, which would allow more time for recombination to break the linkage between the favored allele and hitchhiking variation. Indeed, the sweep in PSCA was proposed to be from the standing variation by Bhatia et al. (2011) [59], and further substantiated as such by Peter et al. (2012) [39].
ADH1B encodes one of four subunits of Alcohol dehydrogenase (ADH1), which plays a key role in alcohol degradation. ADH1 genes (including ADH1B) have been studied extensively on both a functional and a population-genetic level, as they are thought to be one of the major drivers of alcoholism risk [62]. These genes have also been suggested to cause the “alcohol flush” phenotype common in Asian populations [63]. A specific non-synonymous mutation in ADH1B (Arg47His, rs1229984) has been proposed to be the target of selection. This is because (i) the derived allele has been shown to cause increased enzymatic activity [64, 65], and (ii) the estimated age of the allele coincides with rice domestication [63, 66] and the availability of fermented beverages [67]. Computing HAF scores for phased haplotypes from East Asian populations (CHB+JPT) and applying PreCIOSS, we obtained balanced classification accuracy of 92% using a 50 kb window centered at rs1229984 (Fig 7G). Both accuracy and statistical significance (of class separation) gradually decay with increasing window size (Fig