Patterns of population differentiation of candidate genes for cardiovascular disease

<p>Abstract</p> <p>Background</p> <p>The basis for ethnic differences in cardiovascular disease (CVD) susceptibility is not fully understood. We investigated patterns of population differentiation (<it>F</it>_<it>ST</it>) of a set of genes in etiologic pathways of CVD among 3 ethnic groups: Yoruba in Nigeria (YRI), Utah residents with European ancestry (CEU), and Han Chinese (CHB) + Japanese (JPT). We identified 37 pathways implicated in CVD based on the PANTHER classification and 416 genes in these pathways were further studied; these genes belonged to 6 biological processes (apoptosis, blood circulation and gas exchange, blood clotting, homeostasis, immune response, and lipoprotein metabolism). Genotype data were obtained from the HapMap database.</p> <p>Results</p> <p>We calculated <it>F</it>_{<it>ST </it>}for 15,559 common SNPs (minor allele frequency ≥ 0.10 in at least one population) in genes that co-segregated among the populations, as well as an average-weighted <it>F</it>_{<it>ST </it>}for each gene. SNPs were classified as putatively functional (non-synonymous and untranslated regions) or non-functional (intronic and synonymous sites). Mean <it>F</it>_{<it>ST </it>}values for common putatively functional variants were significantly higher than <it>F</it>_{<it>ST </it>}values for nonfunctional variants. A significant variation in <it>F</it>_{<it>ST </it>}was also seen based on biological processes; the processes of 'apoptosis' and 'lipoprotein metabolism' showed an excess of genes with high <it>F</it>_<it>ST</it>. Thus, putative functional SNPs in genes in etiologic pathways for CVD show greater population differentiation than non-functional SNPs and a significant variance of <it>F</it>_{<it>ST </it>}values was noted among pairwise population comparisons for different biological processes.</p> <p>Conclusion</p> <p>These results suggest a possible basis for varying susceptibility to CVD among ethnic groups.</p

Similarity in Recombination Rate Estimates Highly Correlates with Genetic Differentiation in Humans

Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humans

Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans

Although recombination is essential to the successful completion of human meiosis, it remains unclear how tightly the process is regulated and over what scale. To assess the nature and stringency of constraints on human recombination, we examined crossover patterns in transmissions to viable, non-trisomic offspring, using dense genotyping data collected in a large set of pedigrees. Our analysis supports a requirement for one chiasma per chromosome rather than per arm to ensure proper disjunction, with additional chiasmata occurring in proportion to physical length. The requirement is not absolute, however, as chromosome 21 seems to be frequently transmitted properly in the absence of a chiasma in females, a finding that raises the possibility of a back-up mechanism aiding in its correct segregation. We also found a set of double crossovers in surprisingly close proximity, as expected from a second pathway that is not subject to crossover interference. These findings point to multiple mechanisms that shape the distribution of crossovers, influencing proper disjunction in humans

Berberine Improves Glucose Metabolism in Diabetic Rats by Inhibition of Hepatic Gluconeogenesis

Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway

The Impact of Divergence Time on the Nature of Population Structure: An Example from Iceland

The Icelandic population has been sampled in many disease association studies, providing a strong motivation to understand the structure of this population and its ramifications for disease gene mapping. Previous work using 40 microsatellites showed that the Icelandic population is relatively homogeneous, but exhibits subtle population structure that can bias disease association statistics. Here, we show that regional geographic ancestries of individuals from Iceland can be distinguished using 292,289 autosomal single-nucleotide polymorphisms (SNPs). We further show that subpopulation differences are due to genetic drift since the settlement of Iceland 1100 years ago, and not to varying contributions from different ancestral populations. A consequence of the recent origin of Icelandic population structure is that allele frequency differences follow a null distribution devoid of outliers, so that the risk of false positive associations due to stratification is minimal. Our results highlight an important distinction between population differences attributable to recent drift and those arising from more ancient divergence, which has implications both for association studies and for efforts to detect natural selection using population differentiation

Intra-operative spectroscopic assessment of surgical margins during breast conserving surgery

Background: In over 20% of breast conserving operations, postoperative pathological assessment of the excised tissue reveals positive margins, requiring additional surgery. Current techniques for intra-operative assessment of tumor margins are insufficient in accuracy or resolution to reliably detect small tumors. There is a distinct need for a fast technique to accurately identify tumors smaller than 1 mm2 in large tissue surfaces within 30 min. Methods: Multi-modal spectral histopathology (MSH), a multimodal imaging technique combining tissue auto-fluorescence and Raman spectroscopy was used to detect microscopic residual tumor at the surface of the excised breast tissue. New algorithms were developed to optimally utilize auto-fluorescence images to guide Raman measurements and achieve the required detection accuracy over large tissue surfaces (up to 4 × 6.5 cm2). Algorithms were trained on 91 breast tissue samples from 65 patients. Results: Independent tests on 121 samples from 107 patients - including 51 fresh, whole excision specimens - detected breast carcinoma on the tissue surface with 95% sensitivity and 82% specificity. One surface of each uncut excision specimen was measured in 12–24 min. The combination of high spatial-resolution auto-fluorescence with specific diagnosis by Raman spectroscopy allows reliable detection even for invasive carcinoma or ductal carcinoma in situ smaller than 1 mm2. Conclusions: This study provides evidence that this multimodal approach could provide an objective tool for intra-operative assessment of breast conserving surgery margins, reducing the risk for unnecessary second operations

Consent for Use of Clinical Leftover Biosample: A Survey among Chinese Patients and the General Public

Background: Storage of leftover biosamples generates rich biobanks for future studies, saving time and money and limiting physical impact to sample donors. Objective: To investigate the attitudes of Chinese patients and the general public on providing consent for storage and use of leftover biosamples. Design, Setting and Participants: Cross-sectional surveys were conducted among randomly selected patients admitted to a Shanghai city hospital (n = 648) and members of the general public (n = 492) from May 2010 to July 2010. Main Outcome Measures: Face-to-face interviews collected respondents-report of their willingness to donate residual biosample, trust in medical institutions, motivation for donation, concerns of donated sample use, expectations for research results return, and so on. Results: The response rate was 83.0%. Of the respondents, 89.1 % stated that they completely understood or understood most of questions. Willingness to donate residual sample was stated by 64.7%, of which 16.7 % desired the option to withdraw their donations anytime afterwards. Only 42.3 % of respondents stated they ‘‘trust’ ’ or ‘‘strongly trust’ ’ medical institutions, the attitude of trusting or strongly trusting medical institutions were significantly associated with willingness to donate in the general public group.(p,0.05) The overall assent rate for future research without specific consents was als

The power to detect artificial selection acting on single loci in recently domesticated species

<p>Abstract</p> <p>Background</p> <p>An increasing number of aquaculture species are subjected to artificial selection in systematic breeding programs. Rapid improvements of important commercial traits are reported, but little is known about the effects of the strong directional selection applied, on gene level variation. Large numbers of genetic markers are becoming available, making it feasible to detect and estimate these effects. Here a simulation tool was developed in order to explore the power by which single genetic loci subjected to uni-directional selection in parallel breeding populations may be detected.</p> <p>Findings</p> <p>Two simulation models were pursued: 1) screening for loci displaying higher genetic differentiation than expected (high-F_SToutliers), from neutral evolution between a pool of domesticated populations and a pool of wild populations; 2) screening for loci displaying lower genetic differentiation (low-F_SToutliers) between domesticated strains than expected from neutral evolution. The premise for both approaches was that the isolated domesticated strains are subjected to the same breeding goals. The power to detect outlier loci was calculated under the following parameter values: number of populations, effective population size per population, number of generations since onset of selection, initial F_ST, and the selection coefficient acting on the locus. Among the parameters investigated, selection coefficient, the number of generation since onset of selection, and number of populations, had the largest impact on power. The power to detect loci subjected to directional in breeding programmes was high when applying the between farmed and wild population approach, and low for the between farmed populations approach.</p> <p>Conclusions</p> <p>A simulation tool was developed for estimating the power to detect artificial selection acting directly on single loci. The simulation tool should be applicable to most species subject to domestication, as long as a reasonable high accuracy in input parameters such as effective population size, number of generations since the initiation of selection, and initial differentiation (F_ST) can be obtained. Identification of genetic loci under artificial selection would be highly valuable, since such loci could be used to monitor maintenance of genetic variation in the breeding populations and monitoring possible genetic changes in wild populations from genetic interaction between escapees and their wild counterpart.</p

A Bayesian Outlier Criterion to Detect SNPs under Selection in Large Data Sets

Background: The recent advent of high-throughput SNP genotyping technologies has opened new avenues of research for population genetics. In particular, a growing interest in the identification of footprints of selection, based on genome scans for adaptive differentiation, has emerged.[br/] Methodology/Principal Findings: The purpose of this study is to develop an efficient model-based approach to perform Bayesian exploratory analyses for adaptive differentiation in very large SNP data sets. The basic idea is to start with a very simple model for neutral loci that is easy to implement under a Bayesian framework and to identify selected loci as outliers via Posterior Predictive P-values (PPP-values). Applications of this strategy are considered using two different statistical models. The first one was initially interpreted in the context of populations evolving respectively under pure genetic drift from a common ancestral population while the second one relies on populations under migration-drift equilibrium. Robustness and power of the two resulting Bayesian model-based approaches to detect SNP under selection are further evaluated through extensive simulations. An application to a cattle data set is also provided.[br/] Conclusions/Significance: The procedure described turns out to be much faster than former Bayesian approaches and also reasonably efficient especially to detect loci under positive selection