Sciences of the USA 1418 -1421 ͉ PNAS

The discovery of the block-like structure of linkage disequilibrium (LD) in human populations holds the promise of delineating the etiology of common diseases. However, understanding the magnitude, mechanism, and utility of between-population LD sharing is critical for future genome-wide association studies. In this study, substantial LD sharing between six non-African populations was observed, although much less between African-American and non-African, based on 20,000 SNPs of chromosome 21. We also demonstrated the respective roles of recombination and demographic events in shaping LD sharing. Furthermore, we showed that the haplotype-tagged SNPs chosen from one population are portable to the others in East Asia. Therefore, we concluded that the magnitude of LD sharing between human populations justifies the use of representative populations for selecting haplotypetagged SNPs in genome-wide association studies of complex diseases. bottleneck ͉ genetic distance ͉ association study ͉ common disease ͉ genetic variant C omprehensive testing of the association between genetic variations in the human genome and common diseases holds the promise of delineating the genetic architecture of these diseases (1-5). Substantial sharing of the boundaries and specific haplotypes of linkage disequilibrium (LD) blocks between populations was observed (6). However, variations of haplotype and LD across populations were also reported, raising concerns on its practical hindrance for genomewide testing of association (7-9). Conflicting observations on the magnitude of LD sharing between human populations, therefore, call for a careful examination of the following three questions, which are fundamental in developing strategies for genomewide testing of association. First, measurement of LD sharing between populations should be made independent of the definition of LD blocks, which introduce inconsistent block boundaries (10). Second, the mechanisms that shape LD sharing between populations are yet to be fully explored although the roles of recombination hotspots and demographic events have been implicated To address the aforementioned questions, we typed Ͼ20,000 SNPs on chromosome 21 in seven populations: three representative continental populations [African-American (AFR), European (EUR), and Han Chinese (HAN)] and four other major East Asian (EA) populations. This design allows a close examination of LD sharing between continental groups as well as those within East Asia. In this report, we measured the LD sharing between populations independent of the definition of LD block; and we showed that bottleneck events play a critical role in shaping the LD sharing between Africans and nonAfricans, but much less so between non-Africans. An important question for applying HapMap results to disease studies is how tagSNPs selected from a HapMap population will be ported to disease studies performed in other populations. In this study, we showed that tagSNPs selected from representative continental populations are indeed portable to the others in the same continent for association studies, at least in East Asia, with reasonable efficiency. In addition, we proposed a simple guideline that allows a quick evaluation of the portability of tagSNPs between populations by typing a small number of SNPs. Results Overall 26,112 SNPs were selected and typed in this study, and the data from 19,060 SNPs passed the quality control criteria and were used for further analyses. The SNPs and quality control criteria for SNP selection are described in Materials and Methods. Seven world populations, including EUR, AFR, and five EA populations, were studied. The five EA populations, i.e., HAN, Miao (HMJ), Zhuang (CCY), Wa (WBM), and Uighur (UIG), represent five major linguistic families spoken in East Asia. Preservation of LD between populations, i.e., LD sharing (S, or S AB when the population A was given as reference), is measured by the proportion of SNP pairs in LD in one population (population A or the reference) that are also in LD in another (population B). In this study, LD sharing was estimated without invoking the inference of haplotype blocks; therefore, the measure is independent of the definition of haplotype blocks. LD between two loci was measured in r 2 (16). Detail for the measure of LD sharing is described in Materials and Methods. LD sharing between EAs ranges from 63-74% for r 2 Ն 0.1 and 70-84% for r 2 Ն 0.5 (se

China's transboundary waters: new paradigms for water and ecological security through applied ecology

1. China is Asia's most important upstream riparian country, sharing 110 rivers and lakes with 18 downstream countries. Consequently, China's management of transboundary water resources must consider both environmental and geopolitical risks. 2. The major threats to and conflicts over international rivers in China revolve around biotic homogenisation due to the installation of transport links, water allocation, water pollution, alteration of natural flow patterns and disruption of fisheries due to the installation of hydropower dams, and droughts and floods exacerbated by climate change. Because these problems have an international component, they fall under China's Peaceful Rise strategy, mandating that transboundary conflicts be resolved amicably as part of the overarching goal of increasing regional economic growth with as little conflict as possible. 3. Science-backed policy is more likely to result in long term, mutually agreeable solutions; the results of applied ecological research have already resulted in a number of mitigation measures, including setting operational thresholds to reduce the downstream impact of dams, designating protected areas along key river stretches where dams cannot be installed (one dam in a critical location has been cancelled), and the installation of terrestrial protected-area networks. 4. Synthesis and applications. Applied ecology will continue to play an important role in the diagnosis and resolution of environmental threats to China's transboundary waters. More importantly, applied ecology can inform the development of a transboundary environmental compensation mechanism and regional consultative mechanisms that support informed, cooperative decision-making for China and its riparian neighbours

Structure-Activity Relationships for Hydroxylated Polychlorinated Biphenyls as Substrates and Inhibitors of Rat Sulfotransferases and Modification of These Relationships by Changes in Thiol Status

Hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) are inhibitors and substrates for various human sulfotransferases (SULTs). Although the rat is often used in toxicological studies on PCBs, the interactions of OH-PCBs with rat SULTs are less well understood. In the present study, 15 OH-PCBs were investigated as potential substrates or inhibitors of purified recombinant rSULT1A1 and rSULT2A3, the major family 1 and family 2 SULTs present in rat liver, respectively. None of these OH-PCBs were substrates for rSULT2A3, 11 weakly inhibited rSULT2A3-catalyzed sulfation of dehydroepiandrosterone, and 4 had no effect on the reaction. With rSULT1A1, 4-OH-PCB 8, 4′-OH-PCB 3, 9, 12, 35, and 6′-OH-PCB 35 were substrates, whereas 4′-OH-PCB 6, 4-OH-PCB 14, 4′-OH-PCB 25, 4′-OH-PCB 33, 4-OH-PCB 34, 4-OH-PCB36, 4′-OH-PCB 36, 4′-OH-PCB 68, and 4-OH-PCB 78 inhibited the sulfation of 2-naphthol catalyzed by this enzyme. OH-PCBs with a 3,5-dichloro-4-hydroxy substitution were the most potent inhibitors of rSULT1A1, and the placement of chlorine atoms in the ortho- and meta-positions on either ring of para-OH-PCBs resulted in significant differences in activity as substrates and inhibitors. The specificity of rSULT1A1 for several inhibitory OH-PCBs was altered by pretreatment of the enzyme with oxidized glutathione (GSSG). Four OH-PCBs that were inhibitors of rSULT1A1 under reducing conditions became substrates after pretreatment of the enzyme with GSSG. This alteration in specificity of rSULT1A1 for certain OH-PCBs suggests that conditions of oxidative stress may significantly alter the sulfation of some OH-PCBs in the rat

The DRD4 exon III VNTR, bupropion, and associations with prospective abstinence.

IntroductionDRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive-behavioral mood management therapy.MethodsWe used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies. VNTR genotypes were coded with the long allele dominant resulting in 4 analysis categories. Covariates included demographics, dependence measures, depressive symptoms, and genetic ancestry. We also performed genotype-stratified secondary analyses.ResultsWe observed significant effects of time in longitudinal analyses of both abstinence outcomes, of treatment in individuals with VNTR long allele genotypes for both abstinence outcomes, and of covariates in some analyses. We observed non-significantly larger differences in active versus placebo effect sizes in individuals with VNTR long allele genotypes than in individuals without the VNTR long allele, in the directions previously reported.ConclusionsVNTR by treatment interaction differences between these and previous analyses may be attributable to insufficient size of the replication sample. Analyses of multiple randomized clinical trials will enable identification and validation of factors mediating treatment response