Recommendations for improving statistical inference in population genomics

PLoS Biology, Год журнала: 2022, Номер 20(5), С. e3001669 - e3001669

Опубликована: Май 31, 2022

The field of population genomics has grown rapidly in response to the recent advent affordable, large-scale sequencing technologies. As opposed situation during majority 20th century, which development theoretical and statistical genetic insights outpaced generation data they could be applied, genomic are now being produced at a far greater rate than can meaningfully analyzed interpreted. With this wealth come tendency focus on fitting specific (and often rather idiosyncratic) models data, expense careful exploration range possible underlying evolutionary processes. For example, approach directly investigating adaptive evolution each newly sequenced or species neglects fact that thorough characterization ubiquitous nonadaptive processes is prerequisite for accurate inference. We here describe perils these tendencies, present our consensus views current best practices analysis, highlight areas inference theory need further attention. Thereby, we argue importance defining biologically relevant baseline model tuned details new skepticism scrutiny interpreting results, carefully addressable hypotheses uncertainties.

Язык: Английский

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Genome Resequencing Reveals Rapid, Repeated Evolution in the Colorado Potato Beetle

Molecular Biology and Evolution, Год журнала: 2022, Номер 39(2)

Опубликована: Янв. 15, 2022

Abstract Insecticide resistance and rapid pest evolution threatens food security the development of sustainable agricultural practices, yet evolutionary mechanisms that allow pests to rapidly adapt control tactics remains unclear. Here, we examine how a global super-pest, Colorado potato beetle (CPB), Leptinotarsa decemlineata, evolves insecticides. Using whole-genome resequencing transcriptomic data focused on its ancestral range in North America, assess evidence for three, nonmutually exclusive models evolution: pervasive selection novel mutations, regulatory evolution, repeated standing genetic variation. Population genomic analysis demonstrates CPB is geographically structured, even among recently established populations. Pest populations exhibit similar levels nucleotide diversity, relative nonpest populations, show recent expansion. Genome scans provide clear signatures adaptation across with especially strong insecticide genes different Analyses gene expression constitutive upregulation candidate drives distinctive population patterns. repeatedly regions, leveraging pathways but genes, demonstrating polygenic trait architecture can evolve from Despite expectations, do not find support or genes. These results suggest integrated management practices must mitigate phenotypes local order maintain efficacy sustainability techniques.

Язык: Английский

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A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans

Cell Genomics, Год журнала: 2025, Номер unknown, С. 100782 - 100782

Опубликована: Март 1, 2025

To identify genomic regions subject to positive selection that might contain genes involved in high-altitude adaptation (HAA), we performed a genome-wide scan by whole-genome sequencing of Tibetan highlanders and Han lowlanders. We revealed collection candidate located 30 loci under selection. Among them, MCUR1 at 6p23 was novel pronounced candidate. By single-cell RNA comprehensive functional studies, demonstrated depletion leads impairment erythropoiesis hypoxia normoxia. Mechanistically, knockdown reduced mitochondrial Ca2+ uptake then concomitantly increased cytosolic levels, which thereby via the CAMKK2-AMPK-mTOR axis. Further, rs61644582 as an expression quantitative trait locus for variant confers allele-specific transcriptional regulation MCUR1. Overall, MCUR1-mediated homeostasis is highlighted regulator erythropoiesis, deepening our understanding genetic mechanism HAA.

Язык: Английский

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The population genomics of adaptive loss of function

Heredity, Год журнала: 2021, Номер 126(3), С. 383 - 395

Опубликована: Фев. 11, 2021

Abstract Discoveries of adaptive gene knockouts and widespread losses complete genes have in recent years led to a major rethink the early view that loss-of-function alleles are almost always deleterious. Today, surveys population genomic diversity revealing extensive content variation, yet significance much this variation remains unknown. Here we examine evolutionary dynamics loss function through lens genomics consider challenges opportunities studying using genetics models. We discuss how theoretically expected existence allelic heterogeneity, defined as multiple functionally analogous mutations at same locus, has proven consistent with empirical evidence why impedes both detection selection causal relationships phenotypes. then review technical progress towards new explicit tools genotype-phenotype methods overcome these limitations. More broadly, highlight value classifying way functional concept an allele from classical genetics.

Язык: Английский

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How Can We Resolve Lewontin’s Paradox?

Genome Biology and Evolution, Год журнала: 2022, Номер 14(7)

Опубликована: Июнь 23, 2022

Abstract We discuss the genetic, demographic, and selective forces that are likely to be at play in restricting observed levels of DNA sequence variation natural populations a much smaller range values than would expected from distribution census population sizes alone—Lewontin’s Paradox. While several processes have previously been strongly emphasized must involved, including effects direct selection genetic hitchhiking, it seems unlikely they sufficient explain this observation without contributions other factors. highlight potentially important role for less-appreciated contribution size change; specifically, likelihood many species may quite far reaching relatively high equilibrium diversity given their current sizes.

Язык: Английский

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Developing an Evolutionary Baseline Model for Humans: Jointly Inferring Purifying Selection with Population History

Molecular Biology and Evolution, Год журнала: 2023, Номер 40(5)

Опубликована: Май 1, 2023

Abstract Building evolutionarily appropriate baseline models for natural populations is not only important answering fundamental questions in population genetics—including quantifying the relative contributions of adaptive versus nonadaptive processes—but also essential identifying candidate loci experiencing relatively rare and episodic forms selection (e.g., positive or balancing selection). Here, a model was developed human West African ancestry, Yoruba, comprising processes constantly operating on genome (i.e., purifying background selection, size changes, recombination rate heterogeneity, gene conversion). Specifically, to perform joint inference selective effects with demography, an approximate Bayesian approach employed that utilizes decay around functional elements, taking into account genomic architecture. This inferred recent 6-fold growth together distribution fitness skewed towards effectively neutral mutations. Importantly, these results further suggest that, although strong and/or frequent recurrent inconsistent observed data, weak moderate consistent but unidentifiable if rare.

Язык: Английский

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Strong Positive Selection inAedes aegyptiand the Rapid Evolution of Insecticide Resistance

Molecular Biology and Evolution, Год журнала: 2023, Номер 40(4)

Опубликована: Март 23, 2023

Aedes aegypti vectors the pathogens that cause dengue, yellow fever, Zika virus, and chikungunya is a serious threat to public health in tropical regions. Decades of work has illuminated many aspects Ae. aegypti's biology global population structure identified insecticide resistance genes; however, size repetitive nature genome have limited our ability detect positive selection this mosquito. Combining new whole sequences from Colombia with publicly available data Africa Americas, we identify multiple strong candidate selective sweeps aegypti, which overlap genes linked or implicated resistance. We examine voltage-gated sodium channel gene three American cohorts find evidence for successive Colombia. The most recent sweep encompasses an intermediate-frequency haplotype containing four mutations are near-perfect linkage disequilibrium one another Colombian sample. hypothesize may continue rapidly increase frequency perhaps spread geographically coming years. These results extend knowledge how evolved species add growing body suggesting extensive genomic capacity adapt insecticide-based vector control.

Язык: Английский

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The clarifying role of time series data in the population genetics of HIV

PLoS Genetics, Год журнала: 2021, Номер 17(1), С. e1009050 - e1009050

Опубликована: Янв. 14, 2021

HIV can evolve remarkably quickly in response to antiretroviral therapies and the immune system. This evolution stymies treatment effectiveness prevents development of an vaccine. Consequently, there has been a great interest using population genetics disentangle forces that govern adaptive landscape (selection, drift, mutation, recombination). Traditional approaches look at current state genetic variation infer processes generate it. However, because evolves rapidly, we also sample populations repeatedly over time watch action. In this paper, demonstrate how series data bound evolutionary parameters way complements informs traditional approaches. Specifically, focus on our recent paper (Feder et al., 2016, eLife), which show that, as improved drugs have led fewer patients failing therapy due resistance evolution, less diversity maintained following fixation drug mutations. Because soft sweeps multiple mutations spreading simultaneously previously documented effective used early epidemic, interpret maintenance post-sweep poor further evidence therefore high mutation rate (θ) these intra-patient populations. resulted rarer accompanied by lower diversity, suggest both observations be explained decreased rates resultant transition hard selective sweeps. A (Harris 2018, PLOS Genetics) proposed alternative interpretation: Diversity may driven recombination during slow, single Then, if better faster resistance, will rescue sweep, recapitulating decrease improved. use ineffective is very fast, providing new drove failure.

Язык: Английский

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Soft selective sweeps: Addressing new definitions, evaluating competing models, and interpreting empirical outliers

PLoS Genetics, Год журнала: 2022, Номер 18(2), С. e1010022 - e1010022

Опубликована: Фев. 24, 2022

The ability to accurately identify and quantify genetic signatures associated with soft selective sweeps based on patterns of nucleotide variation has remained controversial. We here provide counter viewpoints recent publications in PLOS Genetics that have argued not only for the statistical identifiability sweeps, but also their pervasive evolutionary role both Drosophila HIV populations. present evidence these claims owe a lack consideration competing models, unjustified interpretations empirical outliers, as well new definitions processes themselves. Our results highlight dangers fitting models hypothesized episodic without properly first considering common and, more generally, tendency certain research areas view positive selection foregone conclusion.

Язык: Английский

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Admixture has obscured signals of historical hard sweeps in humans

Nature Ecology & Evolution, Год журнала: 2022, Номер 6(12), С. 2003 - 2015

Опубликована: Окт. 31, 2022

The role of natural selection in shaping biological diversity is an area intense interest modern biology. To date, studies positive have primarily relied on genomic datasets from contemporary populations, which are susceptible to confounding factors associated with complex and often unknown aspects population history. In particular, admixture between diverged populations can distort or hide prior events genomes, though this process not explicitly accounted for most despite its apparent ubiquity humans other species. Through analyses ancient human we show that previously reported Holocene-era has masked more than 50 historic hard sweeps European genomes. Our results imply canonical mode probably been underappreciated the evolutionary history suggest our current understanding tempo may be inaccurate.

Язык: Английский

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