Genome partitioning of genetic variation for height from 11,214 sibling pairs

Height has been used for more than a century as a model by which to understand quantitative genetic variation in humans. We report that the entire genome appears to contribute to its additive genetic variance. We used genotypes and phenotypes of 11,214 sibling pairs from three countries to partition additive genetic variance across the genome. Using genome scans to estimate the proportion of the genomes of each chromosome from siblings that were identical by descent, we estimated the heritability of height contributed by each of the 22 autosomes and the X chromosome. We show that additive genetic variance is spread across multiple chromosomes and that at least six chromosomes (i.e., 3, 4, 8, 15, 17, and 18) are responsible for the observed variation. Indeed, the data are not inconsistent with a uniform spread of trait loci throughout the genome. Our estimate of the variance explained by a chromosome is correlated with the number of times suggestive or significant linkage with height has been reported for that chromosome. Variance due to dominance was not significant but was difficult to assess because of the high sampling correlation between additive and dominance components. Results were consistent with the absence of any large between-chromosome epistatic effects. Notwithstanding the proposed architecture of complex traits that involves widespread gene-gene and gene-environment interactions, our results suggest that variation in height in humans can be explained by many loci distributed over all autosomes, with an additive mode of gene action.     

Spectrophotometric determination of peptide transport with chromogenic peptide mimetics

A spectrophotometric assay to determine peptide transport has been developed. Using two chromogenic peptide mimetics, L-phenylalanyl-L-2-sulfanilylglycine (PSG) and L-phenylalanyl-L-3-thiaphenylalanine (PSP), the peptide transport patterns in individual cell species can be evaluated effectively. After the addition of PSG to a HeLa cell suspension, sulfanilic acid accumulated progressively inside, but not outside, the cells, demonstrating that PSG was transported wholly intact. The addition of PSP to the same cell suspension was followed immediately by extracellular thiophenol production. Measurement of the rate of thiophenol release thereby provided direct determination of PSP transport. The thiophenol release was consistent with Michaelis-Menten kinetics, with a K(m) of 0.016 mM and a V(max) of 5.07 nmol/min (1 x 10(6) cells/ml, pH 7.4, 37 degrees C). The resulting kinetic constants estimated were in agreement with values determined by single-substrate enzyme kinetics. Using PSP, transport kinetics of various dipeptides was examined by competitive spectrophotometry. As a result, dipeptides tested could be ranked in order of kinetic power for their transport.     

Both prothoracicotropic hormone and an autocrine factor are involved in control of prothoracic gland ecdysteroidogenesis in Locusta migratoria and Schistocerca gregaria

In Bombyx mori, ecdysteroidogenesis by the prothoracic glands (PGs) is controlled by both prothoracicotropic hormone (PTTH) and a factor secreted by the glands themselves. This factor, which is active both in vitro and in vivo, has been named 'autocrine factor' (AF). To find out whether or not this dual control also exists in other species, in particular in hemimetabolous ones, we applied similar methods as were used to discover AF in Bombyx to the locusts Locusta migratoria and Schistocerca gregaria. Our results unequivocally show that locust PGs also secrete an as yet unidentified autocrine factor. Possible roles of AF are discussed.     

Regulation of adiponectin and leptin secretion and expression by insulin through a PI3K-PDE3B dependent mechanism in rat primary adipocytes

Adiponectin is intimately involved in the regulation of insulin sensitivity, carbohydrate and lipid metabolism, and cardiovascular functions. The circulating concentration of adiponectin is decreased in obesity and Type 2 diabetes. The present study attempts to elucidate the mechanisms underlying the regulation of adiponectin secretion and expression in rat primary adipocytes. The beta-agonist, isoprenaline, decreased adiponectin secretion and expression in a dose-dependent manner in primary adipocytes. Importantly, such an inhibitory effect could be blocked by insulin. The opposing effects of isoprenaline and insulin could be explained by differential regulation of intracellular cAMP levels, since cAMP analogues suppressed adiponectin secretion and expression in a fashion similar to isoprenaline, and insulin blocked the inhibitory effects of the cAMP analogue hydrolysable by PDE (phosphodiesterase). A specific PDE3 inhibitor, milrinone, and PI3K (phosphoinositide 3-kinase) inhibitors abolished the effects of insulin on adiponectin secretion and expression. In the same studies, leptin secretion and expression displayed a similar pattern of regulation to adiponectin. We conclude that insulin and beta-agonists act directly at the adipocytes in opposing fashions to regulate the production of adiponectin and leptin, and that a PI3K-PDE3B-cAMP pathway mediates the effects of insulin to restore beta-agonist/cAMP-suppressed secretion and expression of these two adipokines.     

The Role of Climate in Settlement and Landscape Change in the North Atlantic Islands: An Assessment of Cumulative Deviations in High-Resolution Proxy Climate Records

In order to assess possible contributions of climate change to the human ecology of the North Atlantic islands we evaluate the utility of cumulative deviations from the mean, calculated for the Greenland ice core storm frequency proxy (GISP2 Na⁺) and sea ice proxy (GISP2 chloride excess). Our aim is to identify episodes of unpredictable change in the context of long-term trends of cultural and environmental development. Key changes are identified in the proxy climate records in 975 and 980 ad, 1025 and 1040 ad, 1180 ad, 1425 and 1450 ad, and 1520 and 1525 ad. Some of these changes are consistent with those inferred from new studies of the palaeoecological record of the Faroes. This indicates that the cumulative deviation measure could give greatest prominence to the most important climate changes affecting landscapes and settlement (such as the changes of 1425 and 1450 ad and their immediate aftermath), rather than extreme events, such as great single storms.     

Generalized substitution of isoencoding codons shortens the duration of papillomavirus L1 protein expression in transiently gene-transfected keratinocytes due to cell differentiation

Recently we reported that gene codon composition determines differentiation-dependent expression of the PV L1 genes in mouse primary keratinocytes (KCs) in vitro and in vivo (Zhao et al. 2005, Mol. Cell Biol. 25:8643–8655). Here, we investigated whether generalized substitution of isoencoding codons affects the duration of expression of PV L1 genes in mouse and human KCs in day 1 culture transiently transfected with native (Nat) and codon modified (Mod) L1 genes. Following transient transfection, KC continuously transcribed both Nat and Mod PV L1 genes for at least 12 days, with the levels of L1 mRNAs from the Mod L1 genes significantly higher than those from the Nat L1 genes. However, continuous L1 protein expression at day 9 post-transfection was observed for both mouse and human KCs transfected with the Nat L1 genes only. Further, aa-tRNAs prepared from D8 KC cultures enhanced translation of two PV Nat L1 DNAs in RRL lysate and PV Nat L1 mRNAs in D0 cell-free lysate, whereas aa-tRNAs from D0 KCs enhanced translation of PV Mod L1 mRNAs in D8 cell-free lysate. It appears that aa-tRNAs in less-differentiated and differentiated KCs differentially match the PV Nat and Mod L1 mRNAs to regulate their translations in vitro.