Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?相似文献   

Quantifying the risk of extreme seasonal precipitation events in a changing climate

Increasing concentrations of atmospheric carbon dioxide will almost certainly lead to changes in global mean climate. But because--by definition--extreme events are rare, it is significantly more difficult to quantify the risk of extremes. Ensemble-based probabilistic predictions, as used in short- and medium-term forecasts of weather and climate, are more useful than deterministic forecasts using a 'best guess' scenario to address this sort of problem. Here we present a probabilistic analysis of 19 global climate model simulations with a generic binary decision model. We estimate that the probability of total boreal winter precipitation exceeding two standard deviations above normal will increase by a factor of five over parts of the UK over the next 100 years. We find similar increases in probability for the Asian monsoon region in boreal summer, with implications for flooding in Bangladesh. Further practical applications of our techniques would be helped by the use of larger ensembles (for a more complete sampling of model uncertainty) and a wider range of scenarios at a resolution adequate to analyse average-size river basins.     

Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease.

The human prion diseases, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Str?ussler syndrome (GSS), are neurodegenerative diseases that are unique in being both infectious and genetic. Transmission of both diseases and the animal spongiform encephalopathies (for example, scrapie and bovine spongiform encephalopathy) to experimental animals by intracerebral inoculation with brain homogenates is well documented. Despite their experimental transmissibility, missense and insertional mutations in the prion protein gene are associated with both GSS and familial CJD, demonstrating that the human familial cases are autosomal dominant diseases. More than 80% of CJD cases occur sporadically, however, and are not known to be associated with mutations. Here we report that 21 of 22 sporadic CJD cases and a further 19 of 23 suspected sporadic CJD cases are homozygous at the polymorphic amino-acid residue 129; 51% of the normal population are heterozygous at this site. We argue that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.     

Evolutionary transfer of the chloroplast tufA gene to the nucleus

Evolutionary gene transfer is a basic corollary of the now widely accepted endosymbiotic theory, which proposes that mitochondria and chloroplasts originated from once free-living eubacteria. The small organellar chromosomes are remnants of larger bacterial genomes, with most endosymbiont genes having been either transferred to the nucleus soon after endosymbiosis or lost entirely, with some being functionally replaced by pre-existing nuclear genes. Several lines of evidence indicate that relocation of some organelle genes could have been more recent. These include the abundance of non-functional organelle sequences of recent origin in nuclear DNA, successful artificial transfer of functional organelle genes to the nucleus, and several examples of recently lost organelle genes, although none of these is known to have been replaced by a nuclear homologue that is clearly of organellar ancestry. We present gene sequence and molecular phylogenetic evidence for the transfer of the chloroplast tufA gene to the nucleus in the green algal ancestor of land plants.     

SUMO modification is required for in vivo Hox gene regulation by the Caenorhabditis elegans Polycomb group protein SOP-2

Post-translational modification of proteins by the ubiquitin-like molecule SUMO (sumoylation) regulates their subcellular localization and affects their functional properties in vitro, but the physiological function of sumoylation in multicellular organisms is largely unknown. Here, we show that the C. elegans Polycomb group (PcG) protein SOP-2 interacts with the SUMO-conjugating enzyme UBC-9 through its evolutionarily conserved SAM domain. Sumoylation of SOP-2 is required for its localization to nuclear bodies in vivo and for its physiological repression of Hox genes. Global disruption of sumoylation phenocopies a sop-2 mutation by causing ectopic Hox gene expression and homeotic transformations. Chimeric constructs in which the SOP-2 SAM domain is replaced with that derived from fruit fly or mammalian PcG proteins, but not those in which the SOP-2 SAM domain is replaced with the SAM domains of non-PcG proteins, confer appropriate in vivo nuclear localization and Hox gene repression. These observations indicate that sumoylation of PcG proteins, modulated by their evolutionarily conserved SAM domain, is essential to their physiological repression of Hox genes.     

Plant genetics: gene transfer from parasitic to host plants

Plant mitochondrial genes are transmitted horizontally across mating barriers with surprising frequency, but the mechanism of transfer is unclear. Here we describe two new cases of horizontal gene transfer, from parasitic flowering plants to their host flowering plants, and present phylogenetic and biogeographic evidence that this occurred as a result of direct physical contact between the two. Our findings complement the discovery that genes can be transferred in the opposite direction, from host to parasite plant.