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Identifying loci under positive selection in complex population histories.

ABSTRACT: Detailed modeling of a species' history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past divergence and admixture events among any number of populations. The method-called graph-aware retrieval of selective sweeps (GRoSS)-has good power to detect loci in the genome with strong evidence for past selective sweeps and can also identify which branch of the graph was most affected by the sweep. As evidence of its utility, we apply the method to bovine, codfish, and human population genomic data containing panels of multiple populations related in complex ways. We find new candidate genes for important adaptive functions, including immunity and metabolism in understudied human populations, as well as muscle mass, milk production, and tameness in specific bovine breeds. We are also able to pinpoint the emergence of large regions of differentiation owing to inversions in the history of Atlantic codfish.

SUBMITTER: Refoyo-Martinez A

PROVIDER: S-EPMC6724678 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Identifying loci under positive selection in complex population histories.

Refoyo-Martínez Alba A da Fonseca Rute R RR Halldórsdóttir Katrín K Árnason Einar E Mailund Thomas T Racimo Fernando F

Genome research 20190730 9

Detailed modeling of a species' history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past div ...[more]

PMID: 31362936

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Project description:Intracellular pathogens secrete effectors to manipulate their host cells. Histoplasma capsulatum (Hc) is a fungal intracellular pathogen of humans that grows in a yeast form in the host. Hc yeasts are phagocytosed by macrophages, where fungal intracellular replication precedes macrophage lysis. The most abundant virulence factor secreted by Hc yeast cells is Calcium Binding Protein 1 (Cbp1), which is absolutely required for macrophage lysis. Here we take an evolutionary, structural, and cell biological approach to understand Cbp1 function. We find that Cbp1 is present only in the genomes of closely related dimorphic fungal species of the Ajellomycetaceae family that lead primarily intracellular lifestyles in their mammalian hosts (Histoplasma, Paracoccidioides, and Emergomyces), but not conserved in the extracellular fungal pathogen Blastomyces dermatitidis. We observe a high rate of fixation of non-synonymous substitutions in the Cbp1 coding sequences, indicating that Cbp1 is under positive selection. We determine the de novo structures of Hc H88 Cbp1 and the Paracoccidioides americana (Pb03) Cbp1, revealing a novel "binocular" fold consisting of a helical dimer arrangement wherein two helices from each monomer contribute to a four-helix bundle. In contrast to Pb03 Cbp1, we show that Emergomyces Cbp1 orthologs are unable to stimulate macrophage lysis when expressed in the Hc cbp1 mutant. Consistent with this result, we find that wild-type Emergomyces africanus yeast are able to grow within primary macrophages but are incapable of lysing them. Finally, we use subcellular fractionation of infected macrophages and indirect immunofluorescence to show that Cbp1 localizes to the macrophage cytosol during Hc infection, making this the first instance of a phagosomal human fungal pathogen directing an effector into the cytosol of the host cell. We additionally show that Cbp1 forms a complex with Yps-3, another known Hc virulence factor that accesses the cytosol. Taken together, these data imply that Cbp1 is a fungal virulence factor under positive selection that localizes to the cytosol to trigger host cell lysis.

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Identifying loci under positive selection in complex population histories.

Publications

Identifying loci under positive selection in complex population histories.

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