scispace - formally typeset
Search or ask a question
Author

Stephen J. O'Brien

Bio: Stephen J. O'Brien is an academic researcher from Saint Petersburg State University of Information Technologies, Mechanics and Optics. The author has contributed to research in topics: Population & Gene. The author has an hindex of 153, co-authored 1062 publications receiving 93025 citations. Previous affiliations of Stephen J. O'Brien include University College Cork & QIMR Berghofer Medical Research Institute.


Papers
More filters
Journal ArticleDOI
TL;DR: Observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression, as observed for SNPs in the gene PARD3B.
Abstract: Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression. Methods. European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model). Results. Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10−9) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10−8). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025). Conclusions. These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.

61 citations

Journal ArticleDOI
TL;DR: The data are consistent with the hypothesis that higher levels of virus-specific CTL contribute to protection against HIV disease progression in infected individuals with B-35-PY, but not in those with B*35-px.
Abstract: Human immunodeficiency virus type 1 (HIV-1)-infected individuals with HLA-B*35 allelic variants B*3502/3503/3504/5301 (B*35-Px) progress more rapidly to AIDS than do those with B*3501 (B*35-PY). The mechanisms responsible for this phenomenon are not clear. To examine whether cellular immune responses may differ according to HLA-B*35 genotype, we quantified HIV-1-specific CD8+-T-cell (CTL) responses using an intracellular cytokine-staining assay with specimens from 32 HIV-1-positive individuals who have B*35 alleles. Among them, 75% had CTL responses to Pol, 69% had CTL responses to Gag, 50% had CTL responses to Nef, and 41% had CTL responses to Env. The overall magnitude of CTL responses did not differ between patients bearing B*35-Px genotypes and those bearing B*35-PY genotypes. A higher percentage of Gag-specific CTL was associated with lower HIV-1 RNA levels (P = 0.009) in individuals with B*35-PY. A negative association between CTL activity for each of the four HIV antigens and viral load was observed among individuals with B*35-PY, and the association reached significance for Gag. No significant relationship between CTL activity and viral load was observed in the B*35-Px group. The relationship between total CTL activity and HIV RNA among B*35-Px carriers differed significantly from that among B*35-PY carriers (P < 0.05). The data are consistent with the hypothesis that higher levels of virus-specific CTL contribute to protection against HIV disease progression in infected individuals with B*35-PY, but not in those with B*35-Px.

61 citations

Journal ArticleDOI
TL;DR: It is suggested that the Andean mountain cat diverged from a common ancestor with the ocelot (Leopardus paradalis) and margay and exhibits moderate levels of genetic variation.
Abstract: Rarely observed in the wild, the existence of the Andean mountain cat (Oreailurus jacobita) has been established based on only 3 skulls and 14 museum skins The Andean mountain cat's evolutionary relationship to other felids based on morphological characters is largely contradictory, with evidence aligning it with South American small spotted cats (ocelot lineage) or alternatively with pantherine lineage felids Here we describe the phylogenetic distinctiveness and placement of the Andean mountain cat using DNA extracted from pieces of nine independent pelt specimens, including one confiscated from a trapper in 1995 A phylogenetic analysis of DNA sequences from three rapidly evolving mitochondrial genes (16S rRNA, NADH-5, and ATP-8) indicate that the Andean mountain cat is a distinct species belonging to the ocelot lineage Our findings suggest that the Andean mountain cat diverged from a common ancestor with the ocelot (Leopardus paradalis) and margay (L wiedii) and exhibits moderate levels of genetic variation

61 citations

Journal ArticleDOI
TL;DR: Southern analysis of cat cellular DNA confirmed the conclusions about conserved restriction sites in endogenous sequences and indicated that a single locus may be responsible for the production of the major inducible form of RD-114.
Abstract: RD-114 is a replication-competent, xenotropic retrovirus which is homologous to a family of moderately repetitive DNA sequences present at ca. 20 copies in the normal cellular genome of domestic cats. To examine the extent and character of genomic divergence of the RD-114 gene family as well as to assess their positional association within the cat genome, we have prepared a series of molecular clones of endogenous RD-114 DNA segments from a genomic library of cat cellular DNA. Their restriction endonuclease maps were compared with each other as well as to that of the prototype-inducible RD-114 which was molecularly cloned from a chronically infected human cell line. The endogenous sequences analyzed were similar to each other in that they were colinear with RD-114 proviral DNA, were bounded by long terminal redundancies, and conserved many restriction sites in the gag and pol regions. However, the env regions of many of the sequences examined were substantially deleted. Several of the endogenous RD-114 genomes contained a novel envelope sequence which was unrelated to the env gene of the prototype RD-114 env gene but which, like RD-114 and endogenous feline leukemia virus provirus, was found only in species of the genus Felis, and not in other closely related Felidae genera. The endogenous RD-114 sequences each had a distinct cellular flank which indicates that these sequences are not tandem but dispersed nonspecifically throughout the genome. Southern analysis of cat cellular DNA confirmed the conclusions about conserved restriction sites in endogenous sequences and indicated that a single locus may be responsible for the production of the major inducible form of RD-114.

60 citations

Journal ArticleDOI
TL;DR: It is concluded that the LHBT does not play a significant role in either the rotator cuff–deficient or normal shoulder, and an EMG analysis of the LH BT in 10 shoulders supported this finding.
Abstract: found no significant increase in bicepsbrachii activity during isolated shoulder motion when thepatient’s elbow motion was controlled with a brace. Theyconcluded that the LHBT does not play a significant rolein either the rotator cuff–deficient or normal shoulder.Levy et al supported this finding in an EMG analysis ofthe LHBT in 10 shoulders, in which shoulder motion wasisolated by using a long arm brace to lock the elbow inextension and the forearm in the neutral position.

60 citations


Cited by
More filters
Journal ArticleDOI
Eric S. Lander1, Lauren Linton1, Bruce W. Birren1, Chad Nusbaum1  +245 moreInstitutions (29)
15 Feb 2001-Nature
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

22,269 citations

28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal Article
Fumio Tajima1
30 Oct 1989-Genomics
TL;DR: It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.

11,521 citations

Journal ArticleDOI
Paul Burton1, David Clayton2, Lon R. Cardon, Nicholas John Craddock3  +192 moreInstitutions (4)
07 Jun 2007-Nature
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

9,244 citations