Positive selection causes beneficial alleles to rise to high frequency, resulting in a selective sweep of the diversity surrounding the selected sites. Accordingly, the signature of a selective sweep in an ancestral population may still remain in its descendants. Identifying signatures of selection in the ancestor that are shared among its descendants is important to contextualize the timing of a sweep, but few methods exist for this purpose. We introduce the statistic SS-H12, which can identify genomic regions under shared positive selection across populations and is based on the theory of the expected haplotype homozygosity statistic H12, which detects recent hard and soft sweeps from the presence of high-frequency haplotypes. SS-H12 is distinct from comparable statistics because it requires a minimum of only two populations, and properly identifies and differentiates between independent convergent sweeps and true ancestral sweeps, with high power and robustness to a variety of demographic models. Furthermore, we can apply SS-H12 in conjunction with the ratio of statistics we term Embedded Image and Embedded Image to further classify identified shared sweeps as hard or soft. Finally, we identified both previously reported and novel shared sweep candidates from human whole-genome sequences. Previously reported candidates include the well-characterized ancestral sweeps at LCT and SLC24A5 in Indo-Europeans, as well as GPHN worldwide. Novel candidates include an ancestral sweep at RGS18 in sub-Saharan Africans involved in regulating the platelet response and implicated in sudden cardiac death, and a convergent sweep at C2CD5 between European and East Asian populations that may explain their different insulin responses.
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Versatile Detection of Diverse Selective Sweeps with Flex-Sweep
Understanding the impacts of selection pressures influencing modern-day genomic diversity is a major goal of evolutionary genomics. In particular, the contribution of selective sweeps to adaptation remains an open question, with persistent statistical limitations on the power and specificity of sweep detection methods. Sweeps with subtle genomic signals have been particularly challenging to detect. Although many existing methods powerfully detect specific types of sweeps and/or those with strong signals, their power comes at the expense of versatility. We present Flex-sweep, a machine learning–based tool designed to detect sweeps with a variety of subtle signals, including those thousands of generations old. It is especially valuable for nonmodel organisms, for which we have neither expectations about the overall characteristics of sweeps nor outgroups with population-level sequencing to otherwise facilitate detecting very old sweeps. We show that Flex-sweep has the power to detect sweeps with subtle signals, even in the face of demographic model misspecification, recombination rate heterogeneity, and background selection. Flex-sweep detects sweeps up to 0.125*4Ne generations old, including those that are weak, soft, and/or incomplete; it can also detect strong, complete sweeps up to 0.25*4Ne generations old. We apply Flex-sweep to the 1000 Genomes Yoruba data set and, in addition to recovering previously identified sweeps, show that sweeps disproportionately occur within genic regions and are close to regulatory regions. In addition, we show that virus-interacting proteins (VIPs) are strongly enriched for selective sweeps, recapitulating previous results that demonstrate the importance of viruses as a driver of adaptive evolution in humans.
more » « less- Award ID(s):
- 2010884
- PAR ID:
- 10519552
- Editor(s):
- Kim, Yuseob
- Publisher / Repository:
- Oxford Academic
- Date Published:
- Journal Name:
- Molecular Biology and Evolution
- Volume:
- 40
- Issue:
- 6
- ISSN:
- 0737-4038
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Kim, Yuseob (Ed.)Abstract Selective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverages the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statistic T to probe whole-genome polymorphism data sets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that the T statistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied the T statistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, including LCT, RSPH3, and ZNF211 in CEU, SYT1, RGS18, and NNT in YRI, and HLA genes in both populations. We also searched for sweep signatures in Drosophila melanogaster, finding expected candidates at Ace, Uhg1, and Pimet. Finally, we provide open-source software to compute the T statistic and the inferred number of presently sweeping haplotypes from whole-genome data.more » « less
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Kim, Yuseob (Ed.)Abstract Natural selection leaves a spatial pattern along the genome, with a haplotype distribution distortion near the selected locus that fades with distance. Evaluating the spatial signal of a population-genetic summary statistic across the genome allows for patterns of natural selection to be distinguished from neutrality. Considering the genomic spatial distribution of multiple summary statistics is expected to aid in uncovering subtle signatures of selection. In recent years, numerous methods have been devised that consider genomic spatial distributions across summary statistics, utilizing both classical machine learning and deep learning architectures. However, better predictions may be attainable by improving the way in which features are extracted from these summary statistics. We apply wavelet transform, multitaper spectral analysis, and S-transform to summary statistic arrays to achieve this goal. Each analysis method converts one-dimensional summary statistic arrays to two-dimensional images of spectral analysis, allowing simultaneous temporal and spectral assessment. We feed these images into convolutional neural networks and consider combining models using ensemble stacking. Our modeling framework achieves high accuracy and power across a diverse set of evolutionary settings, including population size changes and test sets of varying sweep strength, softness, and timing. A scan of central European whole-genome sequences recapitulated well-established sweep candidates and predicted novel cancer-associated genes as sweeps with high support. Given that this modeling framework is also robust to missing genomic segments, we believe that it will represent a welcome addition to the population-genomic toolkit for learning about adaptive processes from genomic data.more » « less
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Abstract In recent years, advances in image processing and machine learning have fueled a paradigm shift in detecting genomic regions under natural selection. Early machine learning techniques employed population-genetic summary statistics as features, which focus on specific genomic patterns expected by adaptive and neutral processes. Though such engineered features are important when training data are limited, the ease at which simulated data can now be generated has led to the recent development of approaches that take in image representations of haplotype alignments and automatically extract important features using convolutional neural networks. Digital image processing methods termed α-molecules are a class of techniques for multiscale representation of objects that can extract a diverse set of features from images. One such α-molecule method, termed wavelet decomposition, lends greater control over high-frequency components of images. Another α-molecule method, termed curvelet decomposition, is an extension of the wavelet concept that considers events occurring along curves within images. We show that application of these α-molecule techniques to extract features from image representations of haplotype alignments yield high true positive rate and accuracy to detect hard and soft selective sweep signatures from genomic data with both linear and nonlinear machine learning classifiers. Moreover, we find that such models are easy to visualize and interpret, with performance rivaling those of contemporary deep learning approaches for detecting sweeps.
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Numerous studies of emerging species have identified genomic “islands” of elevated differentiation against a background of relative homogeneity. The causes of these islands remain unclear, however, with some signs pointing toward “speciation genes” that locally restrict gene flow and others suggesting selective sweeps that have occurred within nascent species after speciation. Here, we examine this question through the lens of genome sequence data for five species of southern capuchino seedeaters, finch-like birds from South America that have undergone a species radiation during the last ∼50,000 generations. By applying newly developed statistical methods for ancestral recombination graph inference and machine-learning methods for the prediction of selective sweeps, we show that previously identified islands of differentiation in these birds appear to be generally associated with relatively recent, species-specific selective sweeps, most of which are predicted to be soft sweeps acting on standing genetic variation. Many of these sweeps coincide with genes associated with melanin-based variation in plumage, suggesting a prominent role for sexual selection. At the same time, a few loci also exhibit indications of possible selection against gene flow. These observations shed light on the complex manner in which natural selection shapes genome sequences during speciation.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/molbev/msad139
