New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage

Background: We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.Results: Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.Conclusions: Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe

Effects of Mutations of the Active Site Arginine Residues in 4-Oxalocrotonate Tautomerase on the pK a Values of Active Site Residues and on the pH Dependence of Catalysis

The unusually low pK a value of the general base catalyst Pro-1 (pK a = 6.4) in 4-oxalocrotonate tautomerase (4-OT) has been ascribed to both a low dielectric constant at the active site and the proximity of the cationic residues Arg-11 and Arg-39 [Stivers, J. T., Abeygunawardana, C., Mildvan, A. S., Hajipour, G., and Whitman, C. P. (1996) Biochemistry 35, 814−823]. In addition, the pH−rate profiles in that study showed an unidentified protonated group essential for catalysis with a pK a of 9.0. To address these issues, the pK a values of the active site Pro-1 and lower limit pK a values of arginine residues were determined by direct 15N NMR pH titrations. The pK a values of Pro-1 and of the essential acid group were determined independently from pH−rate profiles of the kinetic parameters of 4-OT in arginine mutants of 4-OT and compared with those of wild type. The chemical shifts of all of the Arg Nε resonances in wild-type 4-OT and in the R11A and R39Q mutants were found to be independent of pH over the range 4.9−9.7, indicating that no arginine is responsible for the kinetically determined pK a of 9.0 for an acidic group in free 4-OT. With the R11A mutant, where k cat/K m was reduced by a factor of 102.9, the pK a of Pro-1 was not significantly altered from that of the wild-type enzyme (pK a = 6.4 ± 0.2) as revealed by both direct 15N NMR titration (pK a = 6.3 ± 0.1) and the pH dependence of k cat/K m (pK a = 6.4 ± 0.2). The pH−rate profiles of both k cat/K m and k cat for the reaction of the R11A mutant with the dicarboxylate substrate, 2-hydroxymuconate, showed humps, i.e., sharply defined maxima followed by nonzero plateaus. The humps disappeared in the reaction with the monocarboxylate substrate, 2-hydroxy-2,4-pentadienoate, indicating that, unlike the wild-type enzyme which reacts only with the dianionic form of the dicarboxylic substrate, the R11A mutant reacts with both the 6-COOH and 6-COO- forms, with the 6-COOH form being 12-fold more active. This reversal in the preferred ionization state of the 6-carboxyl group of the substrate that occurs upon mutation of Arg-11 to Ala provides strong evidence that Arg-11 interacts with the 6-carboxylate of the substrate. In the R39Q mutant, where k cat/K m was reduced by a factor of 103, the kinetically determined pK a value for Pro-1 was 4.6 ± 0.2, while the ionization of Pro-1 showed negative cooperativity with an apparent pK a of 7.1 ± 0.1 determined by 1D 15N NMR. From the Hill coefficient of 0.54, it can be shown that the apparent pK a value of 7.1 could result most simply from the averaging of two limiting pK a values of 4.6 and 8.2. Mutation of Arg-39, by altering the structure of the β-hairpin which covers the active site, could result in an increase in the solvent exposure of Pro-1, raising its upper limit pK a value to 8.2. In the R39A mutant, the kinetically determined pK a of Pro-1 was also low, 5.0 ± 0.2, indicating that in both the R39Q and R39A mutants, only the sites with low pK a values were kinetically operative. With the fully active R61A mutant, the kinetically determined pK a of Pro-1 (pK a = 6.5 ± 0.2) agreed with that of wild-type 4-OT. It is concluded that the unusually low pK a of Pro-1 shows little contribution from electrostatic effects of the nearby cationic Arg-11, Arg-39, and Arg-61 residues but results primarily from a site of low local dielectric constant