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Associative Overdominance and Negative Epistasis Shape Genome-Wide Ancestry Landscape in Supplemented Fish Populations.

ABSTRACT: The interplay between recombination rate, genetic drift and selection modulates variation in genome-wide ancestry. Understanding the selective processes at play is of prime importance toward predicting potential beneficial or negative effects of supplementation with domestic strains (i.e., human-introduced strains). In a system of lacustrine populations supplemented with a single domestic strain, we documented how population genetic diversity and stocking intensity produced lake-specific patterns of domestic ancestry by taking the species' local recombination rate into consideration. We used 552 Brook Charr (Salvelinus fontinalis) from 22 small lacustrine populations, genotyped at ~32,400 mapped SNPs. We observed highly variable patterns of domestic ancestry between each of the 22 populations without any consistency in introgression patterns of the domestic ancestry. Our results suggest that such lake-specific ancestry patterns were mainly due to variable associative overdominance (AOD) effects among populations (i.e., potential positive effects due to the masking of possible deleterious alleles in low recombining regions). Signatures of AOD effects were also emphasized by highly variable patterns of genetic diversity among and within lakes, potentially driven by predominant genetic drift in those small isolated populations. Local negative effects such as negative epistasis (i.e., potential genetic incompatibilities between the native and the introduced population) potentially reflecting precursory signs of outbreeding depression were also observed at a chromosomal scale. Consequently, in order to improve conservation practices and management strategies, it became necessary to assess the consequences of supplementation at the population level by taking into account both genetic diversity and stocking intensity when available.

SUBMITTER: Leitwein M

PROVIDER: S-EPMC8065892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:African American (AA) women have an excessive risk of developing triple-negative breast cancer (TNBC). We employed Assay for Transposase-Accessible Chromatin using sequencing to characterize differences in chromatin accessibility between nine commonly used TNBC cell lines derived from patients of European and African ancestry. Principal component and chromosome mapping analyses of accessibility peaks with the most variance revealed separation of chromatin profiles by patient group. Motif enrichment and footprinting analyses of disparate open chromatin regions revealed differences in transcription factor activity, identifying 79 with ancestry-associated binding patterns (FDR < 0.01). AA TNBC cell lines exhibited increased accessibility for 62 transcription factors associated with epithelial-to-mesenchymal transition, cancer stemness/chemotherapeutic resistance, proliferation, and aberrant p53 regulation, as well as KAISO, which has been previously linked to aggressive tumor characteristics in AA patients with cancer. Differential Assay for Transposase-Accessible Chromatin signal analysis identified 1,596 genes located within promoters of differentially open chromatin regions in AA-derived TNBC, identifying DNA methyltransferase 1 as the top upregulated gene associated with African ancestry. Pathway analyses with these genes revealed enrichment in several pathways, including hypoxia. Culturing cells under hypoxia showed ancestry-specific stress responses that led to the identification of a core set of AA-associated transcription factors, which included members of the Kruppel-like factor and Sp subfamilies, as well as KAISO, and identified ZDHHC1, a gene previously implicated in immunity and STING activation, as the top upregulated AA-specific gene under hypoxia. Together, these data reveal a differential chromatin landscape in TNBC associated with donor ancestry. The open chromatin structure of AA TNBC may contribute to a more lethal disease.SignificanceWe identify an ancestry-associated open chromatin landscape and related transcription factors that may contribute to aggressive TNBC in AA women. Furthermore, this study advocates for the inclusion of diversely sourced cell lines in experimental in vitro studies to advance health equity at all levels of scientific research.

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Associative Overdominance and Negative Epistasis Shape Genome-Wide Ancestry Landscape in Supplemented Fish Populations.

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