Biology subjects

Patin, E.

Publications and source records attributed to Patin, E..

5 recordsLinked to original sources

bioRxiv2018

Exploring the Genetic Basis of Human Population Differences in DNA Methylation and their Causal Impact on Immune Gene Regulation

DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, its genetic determinants, and their respective causal impact on immune gene regulation remain elusive. We report extensive population differences in DNA methylation between individuals of African and European descent -- detected in primary monocytes that were used as a model of a major innate immunity cell type. Most of these differences (~70%) were driven by DNA sequence variants nearby CpG sites (meQTLs), which account for ~60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.

genomics↗

bioRxiv2018

Polygenic adaptation and convergent evolution across both growth and cardiac genetic pathways in African and Asian rainforest hunter-gatherers

Different human populations facing similar environmental challenges have sometimes evolved convergent biological adaptations, for example hypoxia resistance at high altitudes and depigmented skin in northern latitudes on separate continents. The pygmy phenotype (small adult body size), a characteristic of hunter-gatherer populations inhabiting both African and Asian tropical rainforests, is often highlighted as another case of convergent adaptation in humans. However, the degree to which phenotypic convergence in this polygenic trait is due to convergent vs. population-specific genetic changes is unknown. To address this question, we analyzed high-coverage sequence data from the protein-coding portion of the genomes (exomes) of two pairs of populations, Batwa rainforest hunter-gatherers and neighboring Bakiga agriculturalists from Uganda, and Andamanese rainforest hunter-gatherers (Jarawa and Onge) and Brahmin agriculturalists from India. We observed signatures of convergent positive selection between the Batwa and Andamanese rainforest hunter-gatherers across the set of genes with annotated growth factor binding functions (p < 0.001). Unexpectedly, for the rainforest groups we also observed convergent and population-specific signatures of positive selection in pathways related to cardiac development (e.g. cardiac muscle tissue development; p = 0.001). We hypothesize that the growth hormone sub-responsiveness likely underlying the pygmy phenotype may have led to compensatory changes in cardiac pathways, in which this hormone also plays an essential role. Importantly, in the agriculturalist populations we did not observe similar patterns of positive selection on sets of genes associated with either growth or cardiac development, indicating that our results most likely reflect a history of convergent adaptation to the similar ecology of rainforest hunter-gatherers rather than a more common or general evolutionary pattern for human populations.

genomics↗

bioRxiv2018

Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

IntroductionHumoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.\n\nMethodsWe characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1,000 healthy individuals (Milieu Interieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.\n\nResults and discussionWe identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DR{beta}1 and HLA-DP{beta}1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.\n\nConclusionsUsing extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.

genomics↗

bioRxiv2017

IRF4 haploinsufficiency in a family with Whipples disease

The pathogenesis of Whipples disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected with Tropheryma whipplei (Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant of IRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rare IRF4 alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found that IRF4 had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at the IRF4 locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.

immunology↗

bioRxiv2017

The demographic history and mutational load of African hunter-gatherers and farmers

The distribution of deleterious genetic variation across human populations is a key issue in evolutionary biology and medical genetics. However, the impact of different modes of subsistence on recent changes in population size, patterns of gene flow, and deleterious mutational load remains unclear. Here, we report high-coverage exome sequencing data from various populations of rainforest hunter-gatherers and farmers from central Africa. We find that the recent demographic histories of hunter-gatherers and farmers differed considerably, with population collapses for hunter-gatherers and expansions for farmers, accompanied by increased gene flow. We show that purifying selection against deleterious alleles is of similar efficiency across African populations, in contrast with Europeans where we detect weaker purifying selection. Furthermore, the per-individual mutation load of rainforest hunter-gatherers is similar to that of farmers, under both additive and recessive models. Our results indicate that differences in the cultural practices and demographic regimes of African populations have not resulted in large differences in mutational burden, and highlight the beneficial role of gene flow in reshaping the distribution of deleterious genetic variation across human populations.

evolutionary biology↗