Three Rules Explain Transgenerational Small RNA Inheritance in C. elegans, bioRxiv, 2020-01-09
Life experiences trigger transgenerational small RNA-based responses in C. elegans nematodes. Dedicated machinery ensures that heritable effects would re-set, typically after a few generations. Here we show that isogenic individuals differ dramatically in the persistence of transgenerational responses. By examining lineages composed of >20,000 worms we reveal 3 inheritance rules (1) Once a response is initiated, each isogenic mother stochastically assumes an “inheritance state”, establishing a commitment that determines the fate of the inheritance. (2) The response that each mother transfers is uniform in each generation of her descendants. (3) The likelihood that an RNAi response would transmit to the progeny increases the more generations the response lasts, according to a “hot hand” principle. Mechanistically, the different parental “inheritance states” correspond to global changes in the expression levels of endogenous small RNAs, immune response genes, and targets of the conserved transcription factor HSF-1. We show that these rules predict the descendants’ developmental rate and resistance to stress.
biorxiv genetics 100-200-users 2020Early replacement of West Eurasian male Y chromosomes from the east, bioRxiv, 2019-12-06
AbstractThe genomes of humans outside Africa originated almost entirely from a single migration out ∼50,000-60,000 years ago1,2, followed closely by mixture with Neanderthals contributing ∼2% to all non-Africans3,4. However, the details of this initial migration remain poorly-understood because no ancient DNA analyses are available from this key time period, and present-day autosomal data are uninformative due to subsequent population movementsreshaping5. One locus, however, does retain extensive information from this early period the Y-chromosome, where a detailed calibrated phylogeny has been constructed6. Three present-day Y lineages were carried by the initial migration the rare haplogroup D, the moderately rare C, and the very common FT lineage which now dominates most non-African populations6,7. We show that phylogenetic analyses of haplogroup C, D and FT sequences, including very rare deep-rooting lineages, together with phylogeographic analyses of ancient and present-day non-African Y-chromosomes, all point to EastSouth-east Asia as the origin 50,000-55,000 years ago of all known non-African male lineages (apart from recent migrants). This implies that the initial Y lineages in populations between Africa and eastern Asia have been entirely replaced by lineages from the east, contrasting with the expectations of the serial-founder model8,9, and thus informing and constraining models of the initial expansion.
biorxiv genetics 100-200-users 2019The GTEx Consortium atlas of genetic regulatory effects across human tissues, bioRxiv, 2019-10-03
AbstractThe Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
biorxiv genetics 500+-users 2019Massive gene presenceabsence variation in the mussel genome as an adaptive strategy first evidence of a pan-genome in Metazoa, bioRxiv, 2019-09-26
AbstractMussels are ecologically and economically relevant edible marine bivalves, highly invasive and resilient to biotic and abiotic stressors causing recurrent massive mortalities in other species. Here we show that the Mediterranean mussel Mytilus galloprovincialis has a complex pan-genomic architecture, which includes a core set of 45,000 genes shared by all individuals plus a surprisingly high number of dispensable genes (∼15,000). The latter are subject to presenceabsence variation (PAV), i.e., they may be entirely missing in a given individual and, when present, they are frequently found as a single copy. The enrichment of dispensable genes in survival functions suggests an adaptive value for PAV, which might be the key to explain the extraordinary capabilities of adaptation and invasiveness of this species. Our study underpins a unique metazoan pan-genome architecture only previously described in prokaryotes and in a few non-metazoan eukaryotes, but that might also characterize other marine invertebrates.Significance statementIn animals, intraspecific genomic diversity is generally thought to derive from relatively small-scale variants, such as single nucleotide polymorphisms, small indels, duplications, inversions and translocations. On the other hand, large-scale structural variations which involve the loss of genomic regions encoding protein-coding genes in some individuals (i.e. presenceabsence variation, PAV) have been so far only described in bacteria and, occasionally, in plants and fungi. Here we report the first evidence of a pan-genome in the animal kingdom, revealing that 25% of the genes of the Mediterranean mussel are subject to PAV. We show that this unique feature might have an adaptive value, due to the involvement of dispensable genes in functions related with defense and survival.
biorxiv genetics 100-200-users 2019Genetic “General Intelligence,” Objectively Determined and Measured, bioRxiv, 2019-09-13
AbstractIt has been known for 125 years that, in humans, diverse cognitive traits are positively intercorrelated; this forms the basis for the general factor of intelligence (g). We directly test for a genetic basis for g using data from seven different cognitive tests (N = 11,263 to N = 331,679) and genome-wide autosomal single nucleotide polymorphisms. A genetic g factor accounts for 58.4% (SE = 4.8%) of the genetic variance in the cognitive traits, with trait-specific genetic factors accounting for the remaining 41.6%. We distill genetic loci broadly relevant for many cognitive traits (g) from loci associated with only individual cognitive traits. These results elucidate the etiological basis for a long-known yet poorly-understood phenomenon, revealing a fundamental dimension of genetic sharing across diverse cognitive traits.
biorxiv genetics 100-200-users 2019Bayesian analysis of GWAS summary data reveals differential signatures of natural selection across human complex traits and functional genomic categories, bioRxiv, 2019-09-01
AbstractUnderstanding how natural selection has shaped the genetic architecture of complex traits and diseases is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level data to estimate multiple features of genetic architecture, including signatures of natural selection. Here, we present an enhanced method (SBayesS) that only requires GWAS summary statistics and incorporates functional genomic annotations. We analysed GWAS data with large sample sizes for 155 complex traits and detected pervasive signatures of negative selection with diverse estimates of SNP-based heritability and polygenicity. Projecting these estimates onto a map of genetic architecture obtained from evolutionary simulations revealed relatively strong natural selection on genetic variants associated with cardiorespiratory and cognitive traits and relatively small number of mutational targets for diseases. Averaging across traits, the joint distribution of SNP effect size and MAF varied across functional genomic regions (likely to be a consequence of natural selection), with enrichment in both the number of associated variants and the magnitude of effect sizes in regions such as transcriptional start sites, coding regions and 5’- and 3’-UTRs.
biorxiv genetics 100-200-users 2019