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Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Human rhinoviruses (HRVs) evolve rapidly due in part to their error-prone RNA polymerase. Knowledge of the diversity of HRV populations emerging during the course of a natural infection is essential and represents a basis for the design of future potential vaccines and antiviral drugs. To evaluate HRV evolution in humans, nasal wash samples were collected daily for five days from 15 immunocompetent volunteers experimentally infected with a reference stock of HRV-39. In parallel, HeLa-OH cells were inoculated to compare HRV evolution in vitro. Nasal wash in vivo assessed by real-time PCR showed a viral load that peaked at 48-72 h. Ultra-deep sequencing was used to compare the low-frequency mutation populations present in the HRV-39 inoculum in two human subjects and one HeLa-OH supernatant collected 5 days post-infection. The analysis revealed hypervariable mutation locations in VP2, VP3, VP1, 2C and 3C genes and conserved regions in VP4, 2A, 2B, 3A, 3B and 3D genes. These results were confirmed by classical sequencing of additional samples, both from inoculated volunteers and independent cell infections, and suggest that HRV inter-host transmission is not associated with a strong bottleneck effect. A specific analysis of the VP1 capsid gene of 15 human cases confirmed the high mutation incidence in this capsid region, but not in the antiviral drug-binding pocket. We could also estimate a mutation frequency in vivo of 3.4x10(-4) mutations/nucleotides and 3.1x10(-4) over the entire ORF and VP1 gene, respectively. In vivo, HRV generate new variants rapidly during the course of an acute infection due to mutations that accumulate in hot spot regions located at the capsid level, as well as in 2C and 3C genes.

International audience; Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder that encompasses hypogonadism, deafness, alopecia, mental retardation, diabetes mellitus and progressive extrapyramidal defects. The syndrome is caused by mutation of the C2orf37 gene. Here we studied a cohort of seven new cases from three ethnic backgrounds, presenting with the hallmarks of WSS, in an effort to extend the mutational spectrum of this disorder. Genetic analysis revealed a novel mutation in each of the four families investigated, of which three were nonsense mutations and the fourth was a splice site ablation. We also examined a separate collection of 11 cases presenting with deafness and dystonia, two constituents of WSS, but found no pathogenic changes. This study doubles the number of known mutations for this disorder, confirms that truncating mutations in C2orf37 are the only known cause of WSS, and suggests that mutations in this gene do not contribute significantly to cases presenting with isolated elements of WSS such as deafness and dystonia. The lack of correlation between clinically expressivity of WSS and the site of the eight truncating mutations strongly supports that they are equally null, while the intrafamilial variability argues for an important role of modifiers in this disease.

Plasmodium parasites, the causal agents of malaria, result in more than 1 million deaths annually. Plasmodium are unicellular eukaryotes with small ∼23 Mb genomes encoding ∼5200 protein-coding genes. The protein-coding genes comprise about half of these genomes. Although evolutionary processes have a significant impact on malaria control, the selective pressures within Plasmodium genomes are poorly understood, particularly in the non-protein-coding portion of the genome. We use evolutionary methods to describe selective processes in both the coding and non-coding regions of these genomes. Based on genome alignments of seven Plasmodium species, we show that protein-coding, intergenic and intronic regions are all subject to purifying selection and we identify 670 conserved non-genic elements. We then use genome-wide polymorphism data from P. falciparum to describe short-term selective processes in this species and identify some candidate genes for balancing (diversifying) selection. Our analyses suggest that there are many functional elements in the non-genic regions of these genomes and that adaptive evolution has occurred more frequently in the protein-coding regions of the genome., Author Summary Malaria causes debilitating ill-health in millions of people and kills about one million people annually, mostly young children. It is caused by a single-cell Plasmodium parasite transmitted to humans via mosquito bites. It is difficult to control this parasite because variable genetic make-up enables it to evade detection by vaccines and because drug resistance has repeatedly evolved. Therefore any progress in our understanding of the evolution and genetic variation of the parasite will be central to controlling the parasite. Genic regions that encode proteins are comparatively easy to characterize, whereas non-genic regions are poorly understood. We compare the genomes of seven distantly-related Plasmodium species and find that some of the non-genic regions are very similar between species. The absence of significant evolutionary differences between these non-genic regions implies that they play an important role in the survival of the organism. We then compare the genomes of thirteen different strains of Plasmodium falciparum. It is currently accepted that several families of antigenic parasite genes evolve rapidly. However, using two methods we demonstrate that many other genes have also undergone adaptive evolution.

Methylation of histone H3K36 in higher eukaryotes is mediated by multiple methyltransferases. Set2-related H3K36 methyltransferases are targeted to genes by association with RNA Polymerase II and are involved in preventing aberrant transcription initiation within the body of genes. The targeting and roles of the NSD family of mammalian H3K36 methyltransferases, known to be involved in human developmental disorders and oncogenesis, are not known. We used genome-wide chromatin immunoprecipitation (ChIP) to investigate the targeting and roles of the Caenorhabditis elegans NSD homolog MES-4, which is maternally provided to progeny and is required for the survival of nascent germ cells. ChIP analysis in early C. elegans embryos revealed that, consistent with immunostaining results, MES-4 binding sites are concentrated on the autosomes and the leftmost ∼2% (300 kb) of the X chromosome. MES-4 overlies the coding regions of approximately 5,000 genes, with a modest elevation in the 5′ regions of gene bodies. Although MES-4 is generally found over Pol II-bound genes, analysis of gene sets with different temporal-spatial patterns of expression revealed that Pol II association with genes is neither necessary nor sufficient to recruit MES-4. In early embryos, MES-4 associates with genes that were previously expressed in the maternal germ line, an interaction that does not require continued association of Pol II with those loci. Conversely, Pol II association with genes newly expressed in embryos does not lead to recruitment of MES-4 to those genes. These and other findings suggest that MES-4, and perhaps the related mammalian NSD proteins, provide an epigenetic function for H3K36 methylation that is novel and likely to be unrelated to ongoing transcription. We propose that MES-4 transmits the memory of gene expression in the parental germ line to offspring and that this memory role is critical for the PGCs to execute a proper germline program., Author Summary Germ cells transmit the genome from one generation to the next. The identity and immortality of germ cells are crucial for the perpetuation of species, yet the mechanisms that regulate these properties remain elusive. In C.elegans, a histone methyltransferase MES-4 is required for survival of the primordial germ cells. MES-4 methylates histone H3 at lysine 36 (H3K36), a modification previously linked to transcription elongation and involved in preventing aberrant transcription initiation within the body of genes. Surprisingly, our genome-wide analysis of MES-4 binding sites in C. elegans embryos revealed that MES-4 is capable of associating with genes that were expressed in the germ line of the parent worms but are no longer being actively transcribed in embryos. To our knowledge, this is the first example of transcription-uncoupled H3K36 methylation. We suggest that MES-4-generated H3K36 methylation serves an “epigenetic role,” by marking germline-expressed genes and by carrying the memory of gene expression from one generation of germ cells to the next.

BackgroundTransposable elements (TEs) are major players in evolution. We know that they play an essential role in genome size determination, but we still have an incomplete understanding of the processes involved in their amplification and elimination from genomes and populations. Taking advantage of differences in the amount and distribution of the Long Interspersed Nuclear Element (LINE),helenainDrosophila melanogasterand D.simulans, we analyzed the DNA sequences of copies of this element in samples of various natural populations of these two species.ResultsIn situhybridization experiments revealed thathelenais absent from the chromosome arms ofD. melanogaster, while it is present in the chromosome arms ofD. simulans, which is an unusual feature for a TE in these species. Molecular analyses showed that thehelenasequences detected inD. melanogasterwere all deleted copies, which diverged from the canonical element. Natural populations ofD. simulanshave several copies, a few of them full-length, but most of them internally deleted.ConclusionOverall, our data suggest that a mechanism that induces internal deletions in thehelenasequences is active in theD. simulansgenome.

Comparative analyses of various mammalian genomes have identified numerous conserved non-coding (CNC) DNA elements that display striking conservation among species, suggesting that they have maintained specific functions throughout evolution. CNC function remains poorly understood, although recent studies have identified a role in gene regulation. We hypothesized that the identification of genomic loci that interact physically with CNCs would provide information on their functions. We have used circular chromosome conformation capture (4C) to characterize interactions of 10 CNCs from human chromosome 21 in K562 cells. The data provide evidence that CNCs are capable of interacting with loci that are enriched for CNCs. The number of trans interactions varies among CNCs; some show interactions with many loci, while others interact with few. Some of the tested CNCs are capable of driving the expression of a reporter gene in the mouse embryo, and associate with the oligodendrocyte genes OLIG1 and OLIG2. Our results underscore the power of chromosome conformation capture for the identification of targets of functional DNA elements and raise the possibility that CNCs exert their functions by physical association with defined genomic regions enriched in CNCs. These CNC-CNC interactions may in part explain their stringent conservation as a group of regulatory sequences.