Efficient mapping of mendelian traits in dogs through genome-wide association

With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.     

A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction

Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.     

The emergence and spread of dysentery

Shigella sonnei is an important cause of bacterial dysentery in the developed world and has also recently emerged in transitional countries. Phylogenetic analysis based on whole-genome sequencing of a global sample has detailed the recent evolutionary history of this pathogen and shed light on the genetic changes associated with this epidemiological shift.     

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.     

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.     

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.     

Galanin – 25 years with a multitalented neuropeptide

Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.     

火药燃气应急吹除装置的设计

利用火药燃气进行潜艇的应急吹除,是世界各海军国家普遍关注的新技术。本文仅就其中的关键问题——火药选择的原则以及燃气发生器的结构和设计——作必要的探讨。并且提出冷却水箱与燃烧室一体化的新设计方案,在减少热应力、提高总强度等方面具有不少优点可供参考。