To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation.

The shift from terrestrial to aquatic life by whales was a substantial evolutionary event. Here we report the whole-genome sequencing and de novo assembly of the minke whale genome, as well as the whole-genome sequences of three minke whales, a fin whale, a bottlenose dolphin and a finless porpoise. Our comparative genomic analysis identified an expansion in the whale lineage of gene families associated with stress-responsive proteins and anaerobic metabolism, whereas gene families related to body hair and sensory receptors were contracted. Our analysis also identified whale-specific mutations in genes encoding antioxidants and enzymes controlling blood pressure and salt concentration. Overall the whale-genome sequences exhibited distinct features that are associated with the physiological and morphological changes needed for life in an aquatic environment, marked by resistance to physiological stresses caused by a lack of oxygen, increased amounts of reactive oxygen species and high salt levels.

Tigers and their close relatives (Panthera) are some of the world’s most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats’ hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met39>Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G>A mutation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species.

The Tax oncoprotein of human T cell leukemia virus type 1 constitutively activates transcription factor NF-B by a mechanism involving Tax-induced phosphorylation of IB␣, a labile cytoplasmic inhibitor of NF-B. To trigger this signaling cascade, Tax associates stably with and persistently activates a cellular IB kinase (IKK) containing both catalytic (IKK␣ and IKK␤) and noncatalytic (IKK␥) subunits. We now demonstrate that IKK␥ enables Tax to dock with the IKK␤ catalytic subunit, resulting in chronic IB kinase activation. Mutations in either IKK␥ or Tax that prevent formation of these higher order Tax⅐IKK complexes also interfere with the ability of Tax to induce IKK␤ catalytic function in vivo. Deletion mapping studies indicate that amino acids 1-100 of IKK␥ are required for this Tax targeting function. Together, these findings identify IKK␥ as an adaptor protein that directs the stable formation of pathologic Tax⅐IKK complexes in virally infected T cells.During an adaptive immune response, antigen-stimulated CD4 ϩ T lymphocytes become committed to an activation program that triggers a transient phase of clonal expansion (1). In contrast, infection with human T cell leukemia virus type 1 (HTLV-1) 1 can lead to the loss of cell cycle control and development of an aggressive malignancy called adult T cell leukemia (2). The Tax oncoprotein encoded by HTLV-1 stimulates the constitutive nuclear expression of transcription factor NF-B, which regulates antigen-directed T cell proliferation (3, 4).Studies with Tax-transgenic mice suggest that this viral/host interaction is required to maintain the transformed phenotype of HTLV-1-infected cells (5).In quiescent T cells, the activity of NF-B is controlled from the cytoplasmic compartment by virtue of its signal-dependent interaction with inhibitors, including IB␣ (6). Recent studies have identified two cytokine-inducible IB kinases (IKKs), termed IKK␣ and IKK␤, that target IB␣ for degradation via phosphorylation at Ser-32 and Ser-36 (7). These two kinases form heterodimers and function as catalytic subunits within a 700 -900-kDa multicomponent complex (8). Whereas IKK␣ and IKK␤ are activated transiently in cells treated with the cytokine tumor necrosis factor-␣ (TNF) (8 -10), Tax induces their constitutive expression in HTLV-1-infected T cells (11,12). We have recently found that Tax-induced activation of both IKK and NF-B requires the formation of Tax⅐IKK complexes (12). However, the precise mechanism of Tax action on IKKs remains unclear.Here we provide several lines of experimental evidence indicating that Tax-directed IKK activation is mediated by IKK␥ (also called NEMO, IKKAP1, or FIP-3), a recently identified subunit of TNF-responsive IKKs whose precise signaling function is unknown (13-16). First, interference with IKK␥ expression in T cell transfectants inhibits Tax-mediated activation of NF-B. Second, IKK␥ and Tax interact stably in the context of a high molecular mass IB kinase derived from HTLV-1-infected T cells. Third, overexpression of IKK␥ in vivo is suffic...

Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 × 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 × 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.