Recommendations of the 2006 Human Variome Project meeting

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.     

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.     

Genome-wide association study identifies multiple loci influencing human serum metabolite levels

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.     

Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis

Leber congenital amaurosis (LCA) is an autosomal recessive retinal dystrophy that manifests with genetic heterogeneity. We sequenced the exome of an individual with LCA and identified nonsense (c.507G>A, p.Trp169*) and missense (c.769G>A, p.Glu257Lys) mutations in NMNAT1, which encodes an enzyme in the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway implicated in protection against axonal degeneration. We also found NMNAT1 mutations in ten other individuals with LCA, all of whom carry the p.Glu257Lys variant.     

Development and longevity of ephemeral and perennial leaves on Artemisia tridentata Nutt. ssp. wyomingensis

Big sagebrush ( Artemisia tridentata Nutt.) is one of the most successful plants in the Great Basin based on its abundance and wide distribution. The development of dimorphic leaves may be an important mechanism attributing to its adaptive and competitive abilities. Development, persistence, and proportions of ephemeral and perennial leaves on Wyoming big sagebrush ( Artemisia tridentata Nutt. ssp. wyomingensis ) were studied for two years. The large ephemeral leaves are the first to develop in early spring. As early developing ephemerals mature and stems elongate, new ephemeral and perennial leaves develop in the axes of these large ephemerals. Perennial leaves expanded in the summer of their first growing season, persisting on the shrub until their abscission during summer drought of the second growing season. Plants maintained 33% of their leaf weight through the winters of 1985 and 1986. Active leaf and stem growth occurred at soil water potentials above &ndash;0.2 MPa.     

Vegetation response to prescribed fire in Dinosaur National Monument

Much of western North America is dominated by dense, monotypic, late seral stands of big sagebrush ( Artemisia tridentata Nutt.). These stands often have depauperate understories with limited species richness, diversity, and herbaceous cover. The National Park Service at Dinosaur National Monument, Colorado, is using both strategic and natural prescribed fire in Wyoming big sagebrush ( Artemisia tridentata ssp. wyomingensis Beetle and Young) communities to foster intra-community (α -scale) and landscape diversity. This study analyzed an accumulated foliar cover data set between paired burn and control areas on 6 different sites during the last 20 years. Across the monitoring period, mean total vegetation cover of all combined sites was 44% control and 42% burn. Total vegetation cover in burn areas was higher than or equal to paired control areas within 2-3 years post-burn. Shrubs were essentially eliminated in burn areas, but perennial grass cover was 10-35% higher. Mean number of species on all sites and years combined was 17 control and 18 burn. Species richness was different on only 1 site-year, Dry Woman 1995 ( P = 0.001, 15 control, 9 burn). Species similarity by site and between treatments ranged from 44% to 75%. Differences in Shannon-Weiner diversity index values between paired sites occurred in 6 of 20 years ( P < 0.05). Index value differences on these 6 sites were due to a large annual grass component in burn areas. Prescribed burning successfully shifted late successional sagebrushdominated communities to earlier herbaceous-dominated successional stages without lowering total vegetation cover, while maintaining -scale diversity and species richness.     

Seed production in Gentiana newberryi (Gentianaceae)

Experimental manipulations and observations in one population of Gentiana newberryi Gray flowers over 2 years showed significant variation in seed production relative to pollinator and soil water availability. When pollinators were rare, there was a significant relationship between number of bees present and number of mature seeds produced, and supplemental hand cross-pollination (xenogamy) did improve seed set in Gentiana newberryi Gray. When pollinators were abundant, supplemental hand cross-pollination did not increase seed set. Self-fertilized seeds (autogamy) germinated at the same rate as cross-pollinated seeds. Seed production in unvisited flowers is probably limited anatomically and is not influenced by the type of fertilization. There was a significant relationship between soil moisture and flower size in G. newberryi , with larger flowers found in wetter areas.     

Genetically determined epithelial dysfunction and its consequences for microflora–host interactions

The intestinal epithelium forms a highly active functional interface between the relatively sterile internal body surfaces and the enormously complex and diverse microbiota that are contained within the lumen. Genetic models that allow for manipulation of genes specifically in the intestinal epithelium have provided an avenue to understand the diverse set of pathways whereby intestinal epithelial cells (IECs) direct the immune state of the mucosa associated with homeostasis versus either productive or non-productive inflammation as occurs during enteropathogen invasion or inflammatory bowel disease (IBD), respectively. These pathways include the unfolded protein response (UPR) induced by stress in the endoplasmic reticulum (ER), autophagy, a self-cannibalistic pathway important for intracellular bacterial killing and proper Paneth cell function as well as the interrelated functions of NOD2/NF-κB signaling which also regulate autophagy induction. Multiple genes controlling these IEC pathways have been shown to be genetic risk factors for human IBD. This highlights the importance of these pathways not only for proper IEC function but also suggesting that IECs may be one of the cellular originators of organ-specific and systemic inflammation as in IBD.     

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10??) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.