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1.
Cell ; 167(3): 657-669.e21, 2016 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-27768889

RESUMEN

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.

2.
Nature ; 611(7935): 312-319, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36261521

RESUMEN

Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.


Asunto(s)
ADN Antiguo , Predisposición Genética a la Enfermedad , Inmunidad , Peste , Selección Genética , Yersinia pestis , Humanos , Aminopeptidasas/genética , Aminopeptidasas/inmunología , Peste/genética , Peste/inmunología , Peste/microbiología , Peste/mortalidad , Yersinia pestis/inmunología , Yersinia pestis/patogenicidad , Selección Genética/inmunología , Europa (Continente)/epidemiología , Europa (Continente)/etnología , Inmunidad/genética , Conjuntos de Datos como Asunto , Londres/epidemiología , Dinamarca/epidemiología
3.
Nature ; 578(7796): 600-604, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32051586

RESUMEN

Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.


Asunto(s)
Enfermedad Celíaca/inmunología , Enfermedad Celíaca/patología , Glútenes/inmunología , Antígenos HLA-DQ/inmunología , Interleucina-15/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Femenino , Antígenos HLA-DQ/genética , Humanos , Interferón gamma/inmunología , Interleucina-15/genética , Masculino , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo
4.
Proc Natl Acad Sci U S A ; 118(13)2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33771921

RESUMEN

Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs) differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of interspecies differences in immune response to infection. However, because of the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole-genome transcriptomic responses of ape species (human and chimpanzee) and AAMs (rhesus macaque and baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of ∼40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, up-regulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.


Asunto(s)
Bacterias/inmunología , Metabolismo Energético/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , Virus/inmunología , Adulto , Animales , Evolución Biológica , Metabolismo Energético/genética , Femenino , Regulación de la Expresión Génica/inmunología , Interacciones Huésped-Patógeno/genética , Humanos , Macaca mulatta/genética , Macaca mulatta/inmunología , Masculino , Persona de Mediana Edad , Pan troglodytes/genética , Pan troglodytes/inmunología , Papio/genética , Papio/inmunología , RNA-Seq , Especificidad de la Especie , Secuenciación del Exoma , Adulto Joven
5.
Proc Natl Acad Sci U S A ; 116(14): 6938-6943, 2019 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-30886108

RESUMEN

DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.


Asunto(s)
Islas de CpG/inmunología , Desmetilación del ADN , Células Dendríticas/inmunología , Regulación de la Expresión Génica/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Células Dendríticas/microbiología , Células Dendríticas/patología , Femenino , Humanos , Masculino , Tuberculosis/patología
6.
PLoS Genet ; 12(9): e1006338, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27690314

RESUMEN

The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, characterized by an overall increase in isoform diversity after infection. In response to both bacteria, we found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3' UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Following infection, we identify candidate RNA processing factors whose expression is associated with individual-specific variation in isoform abundance. Finally, by profiling microRNA levels, we show that 3' UTRs with reduced abundance after infection are significantly enriched for target sites for particular miRNAs. These results suggest that the pervasive usage of shorter 3' UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results suggest that dynamic changes in RNA processing may play key roles in the regulation of innate immune responses.

7.
Genome Res ; 25(12): 1801-11, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26392366

RESUMEN

DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced demethylation rarely occurs at promoter regions and instead localizes to distal enhancer elements, including those that regulate the activation of key immune transcription factors. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and increased chromatin accessibility, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response to infection, even in nonproliferating cells.


Asunto(s)
Infecciones Bacterianas/genética , Metilación de ADN , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Interacciones Huésped-Patógeno/genética , 5-Metilcitosina/análogos & derivados , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/metabolismo , Islas de CpG , Citosina/análogos & derivados , Citosina/metabolismo , Células Dendríticas/inmunología , Epigénesis Genética , Epigenómica/métodos , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , Mycobacterium tuberculosis/inmunología , Factores de Transcripción/metabolismo , Tuberculosis/genética , Tuberculosis/inmunología , Tuberculosis/metabolismo , Tuberculosis/microbiología
8.
Nat Genet ; 56(3): 408-419, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38424460

RESUMEN

Humans display remarkable interindividual variation in their immune response to identical challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we performed in-depth genetic, epigenetic and transcriptional profiling on primary macrophages derived from individuals of European and African ancestry before and after infection with influenza A virus. We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to influenza A virus across individuals. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation, with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape can be genetically controlled, even more than gene expression. Lastly, among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, while the remaining genetic variants impact epigenetic marks, stressing the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.


Asunto(s)
Gripe Humana , Humanos , Gripe Humana/genética , Individualidad , Sitios de Carácter Cuantitativo/genética , Mapeo Cromosómico , Epigénesis Genética
9.
Cell Genom ; 3(5): 100292, 2023 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-37228757

RESUMEN

Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.

10.
medRxiv ; 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38076828

RESUMEN

Vertebrates differ greatly in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation, and may inform better selection of species for pre-clinical models.

11.
bioRxiv ; 2023 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-37066254

RESUMEN

Barton et al.1 raise several statistical concerns regarding our original analyses2 that highlight the challenge of inferring natural selection using ancient genomic data. We show here that these concerns have limited impact on our original conclusions. Specifically, we recover the same signature of enrichment for high FST values at the immune loci relative to putatively neutral sites after switching the allele frequency estimation method to a maximum likelihood approach, filtering to only consider known human variants, and down-sampling our data to the same mean coverage across sites. Furthermore, using permutations, we show that the rs2549794 variant near ERAP2 continues to emerge as the strongest candidate for selection (p = 1.2×10-5), falling below the Bonferroni-corrected significance threshold recommended by Barton et al. Importantly, the evidence for selection on ERAP2 is further supported by functional data demonstrating the impact of the ERAP2 genotype on the immune response to Y. pestis and by epidemiological data from an independent group showing that the putatively selected allele during the Black Death protects against severe respiratory infection in contemporary populations.

12.
Mol Biol Evol ; 28(7): 1957-62, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21266489

RESUMEN

Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal-derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet.


Asunto(s)
Evolución Molecular , Genes Ligados a X , Variación Genética , Hominidae/genética , Grupos Raciales/genética , África , Animales , Secuencia de Bases , Emigración e Inmigración , Frecuencia de los Genes , Haplotipos , Humanos , Datos de Secuencia Molecular
13.
Nat Ecol Evol ; 6(7): 955-964, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35654895

RESUMEN

Human gut microbial dynamics are highly individualized, making it challenging to link microbiota to health and to design universal microbiome therapies. This individuality is typically attributed to variation in host genetics, diets, environments and medications but it could also emerge from fundamental ecological forces that shape microbiota more generally. Here, we leverage extensive gut microbial time series from wild baboons-hosts who experience little interindividual dietary and environmental heterogeneity-to test whether gut microbial dynamics are synchronized across hosts or largely idiosyncratic. Despite their shared lifestyles, baboon microbiota were only weakly synchronized. The strongest synchrony occurred among baboons living in the same social group, probably because group members range over the same habitat and simultaneously encounter the same sources of food and water. However, this synchrony was modest compared to each host's personalized dynamics. In support, host-specific factors, especially host identity, explained, on average, more than three times the deviance in longitudinal dynamics compared to factors shared with social group members and ten times the deviance of factors shared across the host population. These results contribute to mounting evidence that highly idiosyncratic gut microbiomes are not an artefact of modern human environments and that synchronizing forces in the gut microbiome (for example, shared environments, diets and microbial dispersal) are not strong enough to overwhelm key drivers of microbiome personalization, such as host genetics, priority effects, horizontal gene transfer and functional redundancy.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Animales , Bacterias/genética , Dieta , Microbioma Gastrointestinal/genética , Humanos , Papio
14.
J Clin Invest ; 131(22)2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34473646

RESUMEN

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up- and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.


Asunto(s)
Epigénesis Genética , Infecciones por VIH/inmunología , Macrófagos Alveolares/inmunología , Mycobacterium tuberculosis/inmunología , Adulto , Anciano , Antirretrovirales/efectos adversos , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Macrófagos Alveolares/metabolismo , Masculino , Persona de Mediana Edad , Profilaxis Pre-Exposición , Transcriptoma
15.
Science ; 373(6551): 181-186, 2021 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-34244407

RESUMEN

Relatives have more similar gut microbiomes than nonrelatives, but the degree to which this similarity results from shared genotypes versus shared environments has been controversial. Here, we leveraged 16,234 gut microbiome profiles, collected over 14 years from 585 wild baboons, to reveal that host genetic effects on the gut microbiome are nearly universal. Controlling for diet, age, and socioecological variation, 97% of microbiome phenotypes were significantly heritable, including several reported as heritable in humans. Heritability was typically low (mean = 0.068) but was systematically greater in the dry season, with low diet diversity, and in older hosts. We show that longitudinal profiles and large sample sizes are crucial to quantifying microbiome heritability, and indicate scope for selection on microbiome characteristics as a host phenotype.


Asunto(s)
Bacterias/clasificación , Ambiente , Microbioma Gastrointestinal/genética , Papio/microbiología , Actinobacteria/clasificación , Actinobacteria/genética , Actinobacteria/crecimiento & desarrollo , Actinobacteria/aislamiento & purificación , Envejecimiento , Animales , Bacterias/genética , Bacterias/crecimiento & desarrollo , Bacterias/aislamiento & purificación , Bacteroidetes/clasificación , Bacteroidetes/genética , Bacteroidetes/crecimiento & desarrollo , Bacteroidetes/aislamiento & purificación , Dieta , Heces/microbiología , Femenino , Firmicutes/clasificación , Firmicutes/genética , Firmicutes/crecimiento & desarrollo , Firmicutes/aislamiento & purificación , Genotipo , Humanos , Masculino , Papio/genética , Fenotipo , Estaciones del Año , Conducta Social
16.
Am J Phys Anthropol ; 139(4): 512-22, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19226649

RESUMEN

Stable colonization of the Gaspe Peninsula by Europeans started in the middle of the 18th century at the time of the British conquest of New France. The earliest settlers were Acadians, escaping British deportation policies, followed by Loyalists from the US, who preferred to remain under British rule after the Declaration of Independence. In the 19th century, the developing fishing industry attracted French Canadians from the St. Lawrence Valley and newcomers from Europe including Channel Islanders from Jersey and Guernsey. We analyzed parental lineages of the self-declared descendants of these four groups of settlers by mtDNA D-loop sequencing and Y-chromosome genotyping and compared them with French, British, and Irish samples. Their representation in terms of haplotype frequency classes reveals different signatures of founder effects, such as a loss of rare haplotypes, modification of intermediate frequency haplotypes, reduction in genetic diversity (seen in Acadians), but also enrichment by admixture. Parental lineages correlate with group identity. Descendants of early settlers, Acadians and Loyalists, preserved their identity more than those of French Canadian and Channel Islander "latecomers." Although overall genetic diversity among Gaspesians is comparable with their European source populations, F(ST) analysis indicated their greater differentiation. Distinct settlement history, a limited number of founders and relative genetic isolation contributed to the regionalization of the Quebec gene pool that appears less homogenous than usually anticipated.


Asunto(s)
Variación Genética , Genética de Población , Población Blanca/genética , Cromosomas Humanos Y/genética , Cartilla de ADN/genética , ADN Mitocondrial/genética , Efecto Fundador , Haplotipos/genética , Humanos , Repeticiones de Microsatélite/genética , Modelos Genéticos , Linaje , Quebec , Análisis de Secuencia de ADN
17.
Am J Phys Anthropol ; 140(3): 417-28, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19425105

RESUMEN

Most genetic studies on the origins of Native Americans have examined data from mtDNA and Y-chromosome DNA. To complement these studies and to broaden our understanding of the origin of Native American populations, we present an analysis of 1,873 X-chromosomes representing Native American (n = 438) and other continental populations (n = 1,435). We genotyped 36 polymorphic sites, forming an informative haplotype within an 8-kb DNA segment spanning exon 44 of the dystrophin gene. The data reveal continuity from a common Eurasian ancestry between Europeans, Siberians, and Native Americans. However, the loss of two haplotypes frequent in Eurasia (18.8 and 7%) and the rise in frequency of a third haplotype rare elsewhere, indicate a major population bottleneck in the peopling of the Americas. Although genetic drift appears to have played a greater role in the genetic differentiation of Native Americans than in the latitudinally distributed Eurasians, we also observe a signal of a differentiated ancestry of southern and northern populations that cannot be simply explained by the serial southward dilution of genetic diversity. It is possible that the distribution of X-chromosome lineages reflects the genetic structure of the population of Beringia, itself issued from founder effects and a source of subsequent southern colonization(s).


Asunto(s)
Cromosomas Humanos X , Indígenas Norteamericanos/genética , Américas , Femenino , Flujo Genético , Geografía , Haplotipos , Humanos , Masculino , Polimorfismo Genético , Análisis de Componente Principal
18.
Nat Ecol Evol ; 3(8): 1253-1264, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31358949

RESUMEN

The shift from a hunter-gatherer to an agricultural mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture affected the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the early transcriptional response to viruses compared with that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune-response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations on the basis of the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.


Asunto(s)
Leucocitos Mononucleares , Selección Genética , Agricultura , Humanos , Bosque Lluvioso , Uganda
19.
Hum Genet ; 122(5): 431-43, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17680273

RESUMEN

Genetic variability of the compound interrupted microsatellite DXS1238, in intron 44 of the dystrophin gene, provides evidence for a complex structure of the ancestral population that led to the emergence of modern humans. We sequenced DXS1238 in 600 X-chromosomes from all over the world. Forty four percent of African-specific chromosomes belong to the ancestral lineage that did not participate in the out-of-Africa expansion and subsequent colonization of other continents. Based on the coalescence analysis these lineages separated from those that contributed to the out-of-Africa expansion 366 +/- 136 thousands years ago (Kya). Independently, the analysis of the variance in the repeat length and of the decay of the ancestral alleles of the two DXS1238 repeats, GT and GA, dates this separation at more than 200 Kya. This suggests a complex demographic history and genetic structure of the African melting pot that led to the emergence of modern humans and their out-of-Africa migration. The subsequent subdivisions of human populations among different continents appear to be preceded by even more structured population history within Africa itself, which resulted from a restricted gene flow between lineages allowing for genetic differences to accumulate. If the transition to modern humans occurred during that time, it necessarily follows that genes associated with this transformation spread between subpopulations via gene flow. Otherwise, in spite of subsequent anatomical variation, Homo sapiens as a species could have emerged in Africa already between 300 and 200 Kya, i.e. before the mitochondrial DNA and well before the Y-chromosome most recent common ancestors.


Asunto(s)
Cromosomas Humanos X/genética , Evolución Molecular , África , Secuencia de Bases , Cartilla de ADN/genética , Distrofina/genética , Flujo Génico , Variación Genética , Genética de Población , Haplotipos , Historia Antigua , Humanos , Intrones , Masculino , Repeticiones de Microsatélite , Modelos Genéticos , Mutación
20.
Genome Biol ; 17(1): 246, 2016 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-27899133

RESUMEN

BACKGROUND: The 2'-5' oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. RESULTS: Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. CONCLUSIONS: We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.


Asunto(s)
2',5'-Oligoadenilato Sintetasa/genética , Inmunidad Innata/genética , Infecciones/genética , Animales , Evolución Molecular , Regulación Enzimológica de la Expresión Génica , Genoma Humano , Haplotipos/genética , Humanos , Infecciones/inmunología , Infecciones/patología , Hombre de Neandertal/genética , Hombre de Neandertal/inmunología , Polimorfismo de Nucleótido Simple , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Selección Genética/genética , Selección Genética/inmunología
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