[Une approche de la recherche publique au travers de ses collectifs de recherche : une vue d'ensemble]

Le but principal de ce rapport est d'établir une comparaison internationale de la recherche publique dans les pays de l'Union européenne (et, plus largement, ceux de l'OCDE). Un deuxième volet propose une approche basée sur l'analyse des collectifs de recherche, afin de développer une méthodologie cohérente pour établir des analyses comparées par pays d'un secteur vital à la sécurité et au bien-être publics. Ce rapport est basé sur un travail qui a montré que l'activité de recherche est une préoccupation collective et que, en utilisant une image provocante, les unités de recherche ou les laboratoires sont à la science ce que les entreprises sont à l'économie : l'unité de production de base

[Une approche de la recherche publique au travers de ses collectifs de recherche : une vue d'ensemble]

Le but principal de ce rapport est d'établir une comparaison internationale de la recherche publique dans les pays de l'Union européenne (et, plus largement, ceux de l'OCDE). Un deuxième volet propose une approche basée sur l'analyse des collectifs de recherche, afin de développer une méthodologie cohérente pour établir des analyses comparées par pays d'un secteur vital à la sécurité et au bien-être publics. Ce rapport est basé sur un travail qui a montré que l'activité de recherche est une préoccupation collective et que, en utilisant une image provocante, les unités de recherche ou les laboratoires sont à la science ce que les entreprises sont à l'économie : l'unité de production de base

Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P&lt;5x10-8) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10-6). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.</p

Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P<5x10-8) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10-6). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.</p

Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes.

Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits

Mapping cis- and trans-regulatory effects across multiple tissues in twins.

Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes