Evaluating the performance of selection scans to detect selective sweeps in domestic dogs

Schlamp, Florencia; Made, Julian van der; Stambler, Rebecca; Chesebrough, Lewis; Boyko, Adam R.; Messer, Philipp W.

doi:10.1101/028647

Cited by 9 publications

(22 citation statements)

References 61 publications

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“…nS L , a modification of iHS, obviates the need for a genetic map, reduces its dependence on recombination and demographic events, and may afford increased sensitivity to detect soft selective sweeps (23). This statistic has proved sensitive in identifying selection in other nonmodel organisms (90). As a secondary test, we constructed recombination maps using LDhat interval and performed the iHS haplotypebased test for directional selection (91,92).…”

Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

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Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Though the DARC promoter region has the fewest SNPs in African populations, it has more pairwise differences likely due to two divergent FY Ã O haplotypes in these populations. To further investigate the underlying characteristics that prevents detecting this locus as non-neutral in genome-wide scans of selection, we analyzed statistics from three main classes of selection scans: population differentiation (F ST ), site frequency spectrum (Sweepfinder [52,53]), and linkage disequilibrium (H-scan [54] Tables). For example, using Sweepfinder, a method designed to detect recently completed hard selective sweeps based on the site frequency spectrum, the region is in the 97th percentile (corresponding to P-value = 0.032 in Table 1) genome-wide in African populations.…”

Section: Evidence Of Selection In Darcmentioning

confidence: 99%

“…We analyzed methods in three main categories of selection detection: population differentiation (F ST ), site frequency spectra (Sweepfinder [52,53]), and linkage disequilibrium (H-scan [54]). Genomic regions that have undergone a recent hard selective sweep are expected to have site frequency spectrums skewed toward rare and high frequency derived variants, increased homozygosity and, if local adaptation, high population differentiation.…”

Section: Population Structure Analysesmentioning

confidence: 99%

“…Sweepfinder, a method designed to detect recent hard selective sweeps based on the site frequency spectrum was ran via the SweeD software [52,53]. H-scan, a statistic designed to detect hard and soft sweeps [54], measures the average length of pairwise homozygosity tracts in a population. By utilizing pairwise homozygosity tracts, this method can detect soft sweeps, sweeps that have resulted in multiple haplotypes reaching high frequency.…”

Section: Population Structure Analysesmentioning

confidence: 99%

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Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

McManus

Taravella

Henn

et al. 2016

Preprint

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The human DARC (Duffy antigen receptor for chemokines) gene encodes a membranebound chemokine receptor crucial for the infection of red blood cells by Plasmodium vivax, a major causative agent of malaria. Of the three major allelic classes segregating in human populations, the FY*O allele has been shown to protect against P. vivax infection and is at near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of positive selection in humans. Despite this, details of the timing and mode of selection at DARC remain poorly understood. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human genomes, to perform a fine-scale investigation of the evolutionary history of DARC. We estimate the time to most recent common ancestor (T MRCA ) of the most common FY*O haplotype to be 42 kya (95% CI: 34-49 kya). We infer the FY*O null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011-0.18), which is among the strongest estimated in the human genome. We estimate the T MRCA of the FY*A mutation in non-Africans to be 57 kya (95% CI: 48-65 kya) and infer that, prior to the sweep of FY*O, all three alleles were segregating in Africa, as highly diverged populations from Asia and 6 ¼Khomani San hunter-gatherers share the same FY*A haplotypes. We test multiple models of admixture that may account for this observation and reject recent Asian or European admixture as the cause.

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“…For example, soft sweeps, in which the ultimate fixation of an allele is caused by selection acting on more than one copy of that allele (Hermisson and Pennings 2005; also figure 1 of Messer and Petrov 2013), may also occur due to multiple advantageous mutations occurring at a single locus, a scenario we do not explore. Various factors contribute to the relative frequency of different types of selective sweep (Messer and Petrov 2013); both explicitly hard and soft sweeps have been inferred from genetic data (e.g., Peter et al 2012;Garud et al 2015;Schlamp et al 2016).More broadly, the frequency at which selective sweeps occurred in recent human evolution remains a subject of debate (Hernandez et al 2011;Enard et al 2014). Some signals may be driven by other selective processes that are known to have affected human genetic variation, in particular purifying (e.g., Bustamante et al 2005) and balancing (e.g., Andrés et al 2009) selection.…”

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confidence: 99%

Refining the Use of Linkage Disequilibrium as a Robust Signature of Selective Sweeps

2016

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During a selective sweep, characteristic patterns of linkage disequilibrium can arise in the genomic region surrounding a selected locus. These have been used to infer past selective sweeps. However, the recombination rate is known to vary substantially along the genome for many species. We here investigate the effectiveness of current (Kelly's Z nS and v max ) and novel statistics at inferring hard selective sweeps based on linkage disequilibrium distortions under different conditions, including a human-realistic demographic model and recombination rate variation. When the recombination rate is constant, Kelly's Z nS offers high power, but is outperformed by a novel statistic that we test, which we call Z a : We also find this statistic to be effective at detecting sweeps from standing variation. When recombination rate fluctuations are included, there is a considerable reduction in power for all linkage disequilibrium-based statistics. However, this can largely be reversed by appropriately controlling for expected linkage disequilibrium using a genetic map. To further test these different methods, we perform selection scans on well-characterized HapMap data, finding that all three statistics-v max ; Kelly's Z nS ; and Z a -are able to replicate signals at regions previously identified as selection candidates based on population differentiation or the site frequency spectrum. While v max replicates most candidates when recombination map data are not available, the Z nS and Z a statistics are more successful when recombination rate variation is controlled for. Given both this and their higher power in simulations of selective sweeps, these statistics are preferred when information on local recombination rate variation is available.KEYWORDS linkage disequilibrium; positive selection; recombination rate; genetic map G ENOME-WIDE selection scans now form part of the standard repertoire of techniques through which to probe the evolutionary past of a population. These attempt to identify genomic regions showing evidence of nonneutral evolution by iteratively calculating a test statistic at different locations for a sample of genetic data. As the availability of genetic data and computational power has increased, so too have the number of scans performed and the range of statistics used. In the case of human genetics, thousands of putative selection signals have been suggested (Akey 2009). For the vast majority of these, it is unclear what phenotypic association may have allowed selection to operate, and a relatively small number of signals are replicated between studies.Given the large number of hypotheses tested in genome scans for selection, many signals are likely to be false positives (Kelley et al. 2006;Akey 2009;Nei et al. 2010). This concern is compounded by systematic biases related to ascertainment or data quality (Mallick et al. 2009). Distinguishing true signatures of selection is challenging, requiring a multifaceted approach (Barrett and Hoekstra 2011), but improving statistics used to infer se...

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Evaluating the performance of selection scans to detect selective sweeps in domestic dogs

Cited by 9 publications

References 61 publications

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

Refining the Use of Linkage Disequilibrium as a Robust Signature of Selective Sweeps

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