L'Homme face à son environnement : une histoire génétique et épigénétique du génome humain

Human populations have faced a large number of environmental challenges during their evolutionary history and present today a wide range of habitats and mode of subsistence. However, the extent of genetic adaptation and epigenetic responses to such environmental variation remains controversial. We first explored the power of several statistics to detect hard selective sweeps in the context of whole-genome sequencing data, and evaluated their robustness to demography and other selection modes. Using data from the 1,000 Genomes Project and Complete Genomics, we showed that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution. The signals of selection detected were moreover enriched in functional variants detected by genome-wide association studies. We then evaluated the relative impacts of genetic and environmental factors on human epigenomic diversity. To do so, we generated genome-wide genetic and DNA methylation profiles for Central African populations differing in their current habitat or in their historical lifestyle and genetic background. We found that both factors have similar critical impacts on the shaping of the global methylome, but the biological functions affected and the mechanisms underlying DNA methylation variation strongly differ. More generally, methylation variation shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Together, this work provides new insight into the contribution of genetic adaptation and epigenetic responses to the adaptation of humans to environmental changes over different time scales.Les populations humaines ont été confrontées à de nombreux changements environnementaux au cours de leur histoire et présentent aujourd’hui une grande diversité d’habitats et de modes de subsistance. Cependant, l’ampleur de l’adaptation génétique et des réponses épigénétiques à ces changements est débattue. Nous avons d’abord étudié la puissance de diverses statistiques pour détecter les balayages sélectifs dans le contexte des données de séquençage à haut débit, et évalué leur robustesse à différents facteurs confondants. En utilisant des jeux de données de séquençage, nous montrons que les balayages sélectifs ont eu un impact modéré mais non négligeable dans l’évolution récente du génome humain. Les régions sous sélection sont enrichies en mutations associées à des variations phénotypiques. Nous avons ensuite évalué l’impact respectif des facteurs génétiques et environnementaux sur la diversité épigénétique humaine. Pour cela, nous avons obtenu les génotypes et les profiles de méthylation de l’ADN de populations d’Afrique Centrale présentant des différences récentes d’habitat ou historiques de modes de vie et de profil génétique. Nous montrons que les deux facteurs ont un effet similaire sur le méthylome mais diffèrent par les fonctions biologiques affectées et les mécanismes expliquant les variations observées. Plus généralement, les variations de méthylation sont fortement associées à des mutations génétiques qui sont enrichies en signaux de sélection positive. En conclusion, ce travail apporte un aperçu de la contribution des mutations génétiques et des réponses épigénétiques à l’adaptation humaine aux changements environnementaux sur plusieurs échelles de temps

The epigenomic landscape of African rainforest hunter-gatherers and farmers

International audienceThe genetic history of African populations is increasingly well documented, yet their patterns of epigenomic variation remain uncharacterized. Moreover, the relative impacts of DNA sequence variation and temporal changes in lifestyle and habitat on the human epigenome remain unknown. Here we generate genome-wide genotype and DNA methylation profiles for 362 rainforest hunter-gatherers and sedentary farmers. We find that the current habitat and historical lifestyle of a population have similarly critical impacts on the methylome, but the biological functions affected strongly differ. Specifically, methylation variation associated with recent changes in habitat mostly concerns immune and cellular functions, whereas that associated with historical lifestyle affects developmental processes. Furthermore, methylation variation—particularly that correlated with historical lifestyle—shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Our work provides new insight into the genetic and environmental factors affecting the epigenomic landscape of human populations over time

Ergänzungen zur iberischen Pseudoscorpioniden-Fauna

Die systematischen Aufsammlungen, die Prof. Dr. H. Franz in den letzten Jahren in weiten Teilen der iberischen Halbinsel durchführte, schliessen weitgehend die Lücken, die bisher noch zwischen den explorierten Gebieten klafften. Sie ergänzen und berichtigen daher unsere bisherigen, von mir letztmals 1955 (Eos, XXXI, pp. 87-122) zusammengefassten Kenntnisse in taxonomischer und faunistischer Hinsicht und runden das Faunenbild auch tiergeographisch zu erfreulicher Vollständigkeit ab. Die Ausbeuten enthielten wiederum 8 neue Arten beziehungsweise Unterarten. Drei weitere Arten waren für Spanien neu. In den cantabrischen Gebirgen tritt nunmehr die Gattung Microcreagris als charakteristisches Faunenelement noch stärker hervor.— Im folgenden werden die seither gemachten Funde angeführt.Peer reviewe

Humans in an adaptive world : genetic and epigenetic responses to environmental challenges

Les populations humaines ont été confrontées à de nombreux changements environnementaux au cours de leur histoire et présentent aujourd’hui une grande diversité d’habitats et de modes de subsistance. Cependant, l’ampleur de l’adaptation génétique et des réponses épigénétiques à ces changements est débattue. Nous avons d’abord étudié la puissance de diverses statistiques pour détecter les balayages sélectifs dans le contexte des données de séquençage à haut débit, et évalué leur robustesse à différents facteurs confondants. En utilisant des jeux de données de séquençage, nous montrons que les balayages sélectifs ont eu un impact modéré mais non négligeable dans l’évolution récente du génome humain. Les régions sous sélection sont enrichies en mutations associées à des variations phénotypiques. Nous avons ensuite évalué l’impact respectif des facteurs génétiques et environnementaux sur la diversité épigénétique humaine. Pour cela, nous avons obtenu les génotypes et les profiles de méthylation de l’ADN de populations d’Afrique Centrale présentant des différences récentes d’habitat ou historiques de modes de vie et de profil génétique. Nous montrons que les deux facteurs ont un effet similaire sur le méthylome mais diffèrent par les fonctions biologiques affectées et les mécanismes expliquant les variations observées. Plus généralement, les variations de méthylation sont fortement associées à des mutations génétiques qui sont enrichies en signaux de sélection positive. En conclusion, ce travail apporte un aperçu de la contribution des mutations génétiques et des réponses épigénétiques à l’adaptation humaine aux changements environnementaux sur plusieurs échelles de temps.Human populations have faced a large number of environmental challenges during their evolutionary history and present today a wide range of habitats and mode of subsistence. However, the extent of genetic adaptation and epigenetic responses to such environmental variation remains controversial. We first explored the power of several statistics to detect hard selective sweeps in the context of whole-genome sequencing data, and evaluated their robustness to demography and other selection modes. Using data from the 1,000 Genomes Project and Complete Genomics, we showed that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution. The signals of selection detected were moreover enriched in functional variants detected by genome-wide association studies. We then evaluated the relative impacts of genetic and environmental factors on human epigenomic diversity. To do so, we generated genome-wide genetic and DNA methylation profiles for Central African populations differing in their current habitat or in their historical lifestyle and genetic background. We found that both factors have similar critical impacts on the shaping of the global methylome, but the biological functions affected and the mechanisms underlying DNA methylation variation strongly differ. More generally, methylation variation shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Together, this work provides new insight into the contribution of genetic adaptation and epigenetic responses to the adaptation of humans to environmental changes over different time scales

PUMA: PANDA Using MicroRNA Associations

Abstract Motivation Conventional methods to analyze genomic data do not make use of the interplay between multiple factors, such as between microRNAs (miRNAs) and the messenger RNA (mRNA) transcripts they regulate, and thereby often fail to identify the cellular processes that are unique to specific tissues. We developed PUMA (PANDA Using MicroRNA Associations), a computational tool that uses message passing to integrate a prior network of miRNA target predictions with target gene co-expression information to model genome-wide gene regulation by miRNAs. We applied PUMA to 38 tissues from the Genotype-Tissue Expression project, integrating RNA-Seq data with two different miRNA target predictions priors, built on predictions from TargetScan and miRanda, respectively. We found that while target predictions obtained from these two different resources are considerably different, PUMA captures similar tissue-specific miRNA–target regulatory interactions in the different network models. Furthermore, the tissue-specific functions of miRNAs we identified based on regulatory profiles (available at: https://kuijjer.shinyapps.io/puma_gtex/) are highly similar between networks modeled on the two target prediction resources. This indicates that PUMA consistently captures important tissue-specific miRNA regulatory processes. In addition, using PUMA we identified miRNAs regulating important tissue-specific processes that, when mutated, may result in disease development in the same tissue. Availability and implementation PUMA is available in C++, MATLAB and Python on GitHub (https://github.com/kuijjerlab and https://netzoo.github.io/). Supplementary information Supplementary data are available at Bioinformatics online

Nongenic cancer-risk SNPs affect oncogenes, tumour-suppressor genes, and immune function

Background Genome-wide association studies (GWASes) have identified many noncoding germline single-nucleotide polymorphisms (SNPs) that are associated with an increased risk of developing cancer. However, how these SNPs affect cancer risk is still largely unknown. Methods We used a systems biology approach to analyse the regulatory role of cancer-risk SNPs in thirteen tissues. By using data from the Genotype-Tissue Expression (GTEx) project, we performed an expression quantitative trait locus (eQTL) analysis. We represented both significant cis- and trans-eQTLs as edges in tissue-specific eQTL bipartite networks. Results Each tissue-specific eQTL network is organised into communities that group sets of SNPs and functionally related genes. When mapping cancer-risk SNPs to these networks, we find that in each tissue, these SNPs are significantly overrepresented in communities enriched for immune response processes, as well as tissue-specific functions. Moreover, cancer-risk SNPs are more likely to be ‘cores’ of their communities, influencing the expression of many genes within the same biological processes. Finally, cancer-risk SNPs preferentially target oncogenes and tumour-suppressor genes, suggesting that they may alter the expression of these key cancer genes. Conclusions This approach provides a new way of understanding genetic effects on cancer risk and provides a biological context for interpreting the results of GWAS cancer studies

Exploring the Occurrence of Classic Selective Sweeps in Humans Using Whole-Genome Sequencing Data Sets

International audienceGenome-wide scans for selection have identified multiple regions of the human genome as being targeted by positive selection. However, only a small proportion has been replicated across studies, and the prevalence of positive selection as a mechanism of adaptive change in humans remains controversial. Here we explore the power of two haplotype-based statistics--the integrated haplotype score (iHS) and the Derived Intraallelic Nucleotide Diversity (DIND) test--in the context of next-generation sequencing data, and evaluate their robustness to demography and other selection modes. We show that these statistics are both powerful for the detection of recent positive selection, regardless of population history, and robust to variation in coverage, with DIND being insensitive to very low coverage. We apply these statistics to whole-genome sequence data sets from the 1000 Genomes Project and Complete Genomics. We found that putative targets of selection were highly significantly enriched in genic and nonsynonymous single nucleotide polymorphisms, and that DIND was more powerful than iHS in the context of small sample sizes, low-quality genotype calling, or poor coverage. As we excluded genomic confounders and alternative selection models, such as background selection, the observed enrichment attests to the action of recent, strong positive selection. Further support to the adaptive significance of these genomic regions came from their enrichment in functional variants detected by genome-wide association studies, informing the relationship between past selection and current benign and disease-related phenotypic variation. Our results indicate that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution