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Genetic ancestry and natural selection drive population differences in immune responses to pathogens in humans

ABSTRACT: Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. 12% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 569 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting eQTL. Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are central to coping with infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81046 | GEO | 2016/09/06

SECONDARY ACCESSION(S): PRJNA320361

REPOSITORIES: GEO

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Genetic ancestry and natural selection drive population differences in immune responses to pathogens in humans

Project description:Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. 12% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 569 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting eQTL. Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are central to coping with infection. Transcriptomic profiles of 503 infected (Listeria and Salmonella) and non-infected samples at 2hr time point.

2016-09-06 | E-GEOD-81046 | biostudies-arrayexpress

Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens

Project description:Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. A total of 9.3% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are key to controlling infection.

2019-08-29 | GSE136566 | GEO

Single-cell RNA-sequencing reveals pervasive but highly cell type-specific genetic ancestry effects on the response to viral infection

Project description:Humans show remarkable variation in susceptibility to infectious diseases as well as chronic inflammatory and autoimmune disorders. This heterogeneity arises partially from variation in the immune response, which is responsible for preventing and controlling infection. To better understand the major factors driving antiviral immune response differences, we used single-cell RNA-sequencing to measure the effects of genetic ancestry and cis-regulatory variation on the transcriptional response to influenza infection in various immune cell types in 90 European and African American individuals. We show that monocytes are the most responsive to infection but that all cell types engage a conserved, type I IFN response, which is stronger in European individuals. Further, we detect directional, polygenic differences in expression phenotypes between populations that are under cis-genetic control and show that recent positive selection has acted on putatively causal risk loci associated with common autoimmune disorders. Our findings establish genetic ancestry and common cis-regulatory variants as important determinants governing the antiviral immune response, thus improving our understanding of the factors that contribute to differences in infectious and complex disease susceptibility.

2021-11-26 | GSE162632 | GEO

African Ancestry Associated Gene Expression Profiles in Triple Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

Project description:Women of sub-Saharan African descent have disproportionately higher incidence of Triple Negative Breast Cancer (TNBC), and TNBC-specific mortality. Population comparative studies show racial differences in TNBC biology, including higher prevalence of basal-like and Quadruple-Negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily United States (US) populations. Due to heterogenous genetic admixture, and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNAseq on an international cohort of AAs, west and east Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed tumor-associated immunological profiles are distinct in patients of African descent.

2022-11-09 | GSE211167 | GEO

Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry

Project description:Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma (ULM) tissues combined resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.

2022-02-16 | PXD029323 | Pride

RNA splicing and aggregate gene expression differences between lung squamous cell carcinoma from patients of West African and European ancestry

Project description:Study of genes that are differentially spliced and differentially expressed between African Americans and whites with lung squamous cell cancer. Despite racial disparities in lung cancer, the molecular landscape of lung cancer in patients of African ancestry remains underexplored. Population-related differences in alternative RNA splicing have not been explored. We identified differentially spliced genes and differentially expressed genes between lung squamous cell carcinoma from patients of West African and European ancestry.

2021-01-31 | GSE137291 | GEO

Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer

Project description:The genomic and immune landscapes of prostate cancer differ by self-identified race. However, few studies have examined the genome-wide copy number landscape and immune content of matched cohorts with genetic ancestry data and clinical outcomes. Here, we assessed prostate cancer somatic copy number alterations (sCNA) and tumor immune content of a grade-matched, surgically-treated cohort of 145 self-identified Black (BL) and 145 self-identified white (WH) patients with genetic ancestry estimation. A generalized linear model adjusted with age, pre-operative PSA, and Grade Group and filtered for germline copy number variations (gCNV) identified 143 loci where copy number varied significantly by percent African ancestry, clustering on chromosomes 6p, 10q, 11p, 12p, and 17p. Multivariable Cox regression models adjusted for age, pre-operative PSA levels, and Grade Group revealed that chromosome 8q gains (including MYC) were significantly associated with biochemical recurrence and metastasis, independent of genetic ancestry. Finally, regulatory T-cell density in BL and WH patients was significantly correlated with percent genome altered, and these findings were validated in the TCGA cohort. Taken together, our findings identify specific sCNA linked to genetic ancestry and outcome in primary prostate cancer and demonstrate that regulatory T-cell infiltrate varies by global sCNA burden in primary disease.

2023-05-31 | GSE221219 | GEO

Differences in microRNA expression in breast cancer between women of African and European ancestry

Project description:Differences in microRNAs have not been well studied as potential mechanisms underlying the breast cancer disparity. A number of miRNAs were differentially expressed not only by tumor subtype but by ancestry, indicating differences in tumor biology of breast cancer between women of African and European ancestry. Findings may contribute to a better understanding of the biology of breast cancer disparities and help develop more targeted preventative and therapeutic strategies.

2018-12-06 | GSE117452 | GEO

Stable Patterns of Gene Expression Regulating Carbohydrate Metabolism Determined by Geographic Ancestry

Project description:Individuals of African descent in the United States suffer disproportionately from diseases with a metabolic etiology (obesity, metabolic syndrome, and diabetes), and from the pathological consequences of these disorders (hypertension and cardiovascular disease). Using a combination of genetic/genomic and bioinformatics approaches, we identified a large number of genes that were both differentially expressed between American subjects self-identified to be of either African or European ancestry and that also contained single nucleotide polymorphisms that distinguish distantly related ancestral populations. Several of these genes control the metabolism of simple carbohydrates and are direct targets for the SREBP1, a metabolic transcription factor also differentially expressed between our study populations. These data support the concept of stable patterns of gene transcription unique to a geographic ancestral lineage. The coordinated transcriptional adaptation of carbohydrate metabolism to dietary environmental pressures suggests a genetic and transcriptional mechanism for the disproportionate levels of obesity, diabetes, and cardiovascular disease observed in Americans with African ancestry. Keywords: Ancestry-dependent gene expression, functional genomics, personalized medicine, multi-factoral disease, nutrition, diabetes

2009-10-31 | GSE12959 | GEO

Gene expression levels in African Americans vary with genetic ancestry at most expressed genes

Project description:Variation in gene expression is a fundamental aspect of human phenotypic variation. Several studies have analyzed gene expression levels in populations of different continental ancestry, and concluded that there is variation across populations at a fraction of expressed genes. Here we analyze gene expression levels in African American cell lines, which differ from previously analyzed cell lines in that samples from this population have variable proportions of continental ancestry. We show that for most genes examined, gene expression varies with genetic ancestry. Keywords: Human Gene Expression Study

2008-12-05 | GSE10824 | GEO

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