Genetic associations of variants in genes encoding HIV-dependency factors required for HIV-1 infection.

BACKGROUND: High-throughput genome-wide techniques have facilitated the identification of previously unknown host proteins involved in cellular human immunodeficiency virus (HIV) infection. Recently, 3 independent studies have used small interfering RNA technology to silence each gene in the human genome to determine the importance of each in HIV infection. Genes conferring a significant effect were termed HIV-dependency factors (HDFs). METHODS: We assembled high-density panels of 6380 single-nucleotide polymorphisms (SNPs) in 278 HDF genes and tested for genotype associations with HIV infection and AIDS progression in 1633 individuals from clinical AIDS cohorts. RESULTS: After statistical correction for multiple tests, significant associations with HIV acquisition were found for SNPs in 2 genes, NCOR2 and IDH1. Weaker associations with AIDS progression were revealed for SNPs within the TM9SF2 and EGFR genes. CONCLUSIONS: This study independently verifies the influence of NCOR2 and IDH1 on HIV transmission, and its findings suggest that variation in these genes affects susceptibility to HIV infection in exposed individuals.

Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS.

BACKGROUND: A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study. METHODS: The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters. RESULTS: Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P = 6.23 X 10(-7)). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 X 10(-6)). CONCLUSIONS: This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis.

Accounting for multiple comparisons in a genome-wide association study (GWAS).

BACKGROUND: As we enter an era when testing millions of SNPs in a single gene association study will become the standard, consideration of multiple comparisons is an essential part of determining statistical significance. Bonferroni adjustments can be made but are conservative due to the preponderance of linkage disequilibrium (LD) between genetic markers, and permutation testing is not always a viable option. Three major classes of corrections have been proposed to correct the dependent nature of genetic data in Bonferroni adjustments: permutation testing and related alternatives, principal components analysis (PCA), and analysis of blocks of LD across the genome. We consider seven implementations of these commonly used methods using data from 1514 European American participants genotyped for 700,078 SNPs in a GWAS for AIDS. RESULTS: A Bonferroni correction using the number of LD blocks found by the three algorithms implemented by Haploview resulted in an insufficiently conservative threshold, corresponding to a genome-wide significance level of α = 0.15 - 0.20. We observed a moderate increase in power when using PRESTO, SLIDE, and simpleℳ when compared with traditional Bonferroni methods for population data genotyped on the Affymetrix 6.0 platform in European Americans (α = 0.05 thresholds between 1 × 10(-7) and 7 × 10(-8)). CONCLUSIONS: Correcting for the number of LD blocks resulted in an anti-conservative Bonferroni adjustment. SLIDE and simpleℳ are particularly useful when using a statistical test not handled in optimized permutation testing packages, and genome-wide corrected p-values using SLIDE, are much easier to interpret for consumers of GWAS studies.

POPULATION BIOLOGY OF THE TRANS-ARCTIC EXCHANGE: MtDNA SEQUENCE SIMILARITY BETWEEN PACIFIC AND ATLANTIC SEA URCHINS.

MtDNAs from 2 protein coding regions comprising 576 base pairs were sequenced from 17 individual sea urchins of the species Strongylocentrotus pallidus collected from the north Pacific and north Atlantic oceans. Twelve of 17 individual sequences were identical. Two of these were further sequenced in a third, 441 base pair region, and were also found to be identical. We show how to interpret these results using a simplified Markov model of mtDNA evolution at silent sites. The model was calibrated using 3 urchin species with a published fossil record, and shows that identical S. pallidus mtDNAs in different oceans shared a common ancestor at most 90,000-150,000 years ago (95% confidence interval of upper limit of divergence). The Markov model, used to examine patterns of genetic distance within and between species, shows unexpected variation in the rate of base substitution. The rate of change of G's at fourfold sites is nearly 20 times greater than the rate of change of C's. At twofold sites, this range is less extreme, although purines consistently have a higher rate of change than pyrimidines. Striking genetic similarity and recent genetic exchange between oceans for these urchins is in marked contrast to most other trans-Arctic marine populations, which usually show morphological and genetic differentiation at the species or subspecies level. Recent fossil evidence shows that the north Atlantic and northeastern Pacific have been the scene of radical faunal changes during the Pliocene and Pleistocene. The genetic results presented here extend this conclusion to intraspecific patterns of genetic variability, and direct attention to the northwest Pacific where higher productivity and less environmental change may have left a heritage of greater marine genetic diversity.

Phylogeny and development of marine model species: strongylocentrotid sea urchins.

The phylogenetic relationships of ten strongy-locentrotid sea urchin species were determined using mitochondrial DNA sequences. This phylogeny provides a backdrop for the evolutionary history of one of the most studied groups of sea urchins. Our phylogeny indicates that a major revision of this group is in order. All else remaining unchanged, it supports the inclusion of three additional species into the genus Strongylocentrotus (Hemicentrotus pulcherrimus, Allocentrotus fragilis, and Pseudocentrotus depressus). All were once thought to be closely related to this genus, but subsequent revisions separated them into other taxonomic groupings. Most strongylocentrotid species are the result of a recent burst of speciation in the North Pacific that resulted in an ecological diversification. There has been a steady reduction in the complexity of larval skeletons during the expansion of this group. Gamete attributes like egg size, on the other hand, are not correlated with phylogenetic position. In addition, our results indicate that the rate of replacement substitutions is highly variable among phylogenetic lineages. The branches leading to S. purpuratus and S. franciscanus were three to six times longer than those leading to closely related species.

A high-density admixture map for disease gene discovery in african americans.

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) provides a way of localizing genes that cause disease, in admixed ethnic groups such as African Americans, with approximately 100 times fewer markers than are required for whole-genome haplotype scans. However, it has not been possible to perform powerful scans with admixture mapping because the method requires a dense map of validated markers known to have large frequency differences between Europeans and Africans. To create such a map, we screened through databases containing approximately 450000 single-nucleotide polymorphisms (SNPs) for which frequencies had been estimated in African and European population samples. We experimentally confirmed the frequencies of the most promising SNPs in a multiethnic panel of unrelated samples and identified 3011 as a MALD map (1.2 cM average spacing). We estimate that this map is approximately 70% informative in differentiating African versus European origins of chromosomal segments. This map provides a practical and powerful tool, which is freely available without restriction, for screening for disease genes in African American patient cohorts. The map is especially appropriate for those diseases that differ in incidence between the parental African and European populations.