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.

Phylogenetic Reconstruction of South American Felids Defined by Protein Electrophoresis

Abstract: Phylogenetic associations among six closely related South American felid species were defined by changes in protein-encoding gene loci. We analyzed proteins isolated from skin fibroblasts using two-dimensional electrophoresis and allozymes extracted from blood cells. Genotypes were determined for multiple individuals of ocelot, margay, tigrina, Geoffroy's cat, kodkod, and pampas cat at 548 loci resolved by two-dimensional electrophoresis and 44 allozyme loci. Phenograms were constructed using the methods of Fitch-Margoliash and neighbor-joining on a matrix of Nei's unbiased genetic distances for all pairs of species. Results of a relative-rate test indicate changes in two-dimensional electrophoresis data are constant among all South American felids with respect to a hyena outgroup. Allelic frequencies were transformed to discrete character states for maximum parsimony analysis. Phylogenetic reconstruction indicates a major split occurred approximately 5–6 million years ago, leading to three groups within the ocelot lineage. The earliest divergence led to Leopardus tigrina, followed by a split between an ancestor of an unresolved trichotomy of three species (Oncifelis guigna, O. geoffroyi, and Lynchaduris colocolo) and a recent common ancestor of Leopardus pardalis and L. wiedii. The results suggest that modern South American felids are monophyletic and evolved rapidly after the formation of the Panama land bridge between North and South America.

Mutation discovered in a feline model of human congenital retinal blinding disease.

Abstract: Purpose. To elucidate the gene defect in a pedigree of cats segregating for autosomal dominant rod–cone dysplasia (Rdy), a retinopathy characterized extensively from a clinical perspective. Disease expression in Rdy cats is comparable to that in young patients with congenital blindness (Leber congenital amaurosis [LCA] or retinitis pigmentosa [RP]).

Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans.

Abstract: CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G-->A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f<1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP.

Patterns of Size Homoplasy at 10 Microsatellite Loci in Pumas (Puma concolor)

Abstract: Microsatellites, repetitive simple sequences of 1–6 nt in length, are abundant in eukaryotic genomes (Weber 1990a). Because of extensive variability in the number of repeat units for any one locus among members of a population, microsatellite loci exhibit high polymorphism. Microsatellite variation has become a useful class of genetic markers in population assessment for numerous species for questions of genetic identification, parentage, kinship, and population variability assessment (Jarne and Lagoda 1996; Goldstein and Pollock 1997). The high level of polymorphism at microsatellite loci is believed to result from slipped-strand mispairing during DNA replication (Levinson and Gutman 1987; Weber 1990b; Weber and Wong 1993; Krugylak et al. 1998), most commonly causing the gain or loss of one or more repeat units. This mutation mechanism would be expected to generate allelic homoplasy, i.e., comigrating allele size fragments which are not identical by descent or in DNA sequence among different individuals. Because mutational slippage does not conform to the infinite-alleles model (Kimura and Crow 1964), a stepwise mutation model (SMM) (Ohta and Kimura 1973; Chakraborty and Nei 1982) has been invoked to explain allele frequency distributions and population variability at microsatellite loci (Valdez, Slatkin, and Freimer 1993; Kimmel et al. 1996). A distinguishing feature of the two models is that homoplasy is not considered under the infinite-alleles model, while it is an expectation of the stepwise mutation model (Viard et al. 1998). The SMM (but not the infinite-alleles model) makes the assumption that differences in allelic length are due to variation in the number of repeat units and not to insertions and deletions in the flanking sequences. Allelic size homoplasy, a condition under which comigrating alleles represent different sequence motifs, has been demonstrated through sequence analysis of electromorphs of compound or imperfect repeats of primates (Blanquer-Maumont and Crouau-Roy 1995), several fish species (Angers and Bernatchez 1997), invertebrates (Viard et al. 1998), and the fungus Candida albicans (Metzgar et al. 1998). Insertion and deletion events in genomic regions flanking microsatellites confer allelic size homoplasy in several marine turtle species (FitzSimmons et al. 1995) and humans (Homo sa-

The first whole genome and transcriptome of the cinereous vulture reveals adaptation in the gastric and immune defense systems and possible convergent evolution between the Old and New World vultures

Abstract: The cinereous vulture, Aegypius monachus, is the largest bird of prey and plays a key role in the ecosystem by removing carcasses, thus preventing the spread of diseases. Its feeding habits force it to cope with constant exposure to pathogens, making this species an interesting target for discovering functionally selected genetic variants. Furthermore, the presence of two independently evolved vulture groups, Old World and New World vultures, provides a natural experiment in which to investigate convergent evolution due to obligate scavenging. We sequenced the genome of a cinereous vulture, and mapped it to the bald eagle reference genome, a close relative with a divergence time of 18 million years. By comparing the cinereous vulture to other avian genomes, we find positively selected genetic variations in this species associated with respiration, likely linked to their ability of immune defense responses and gastric acid secretion, consistent with their ability to digest carcasses. Comparisons between the Old World and New World vulture groups suggest convergent gene evolution. We assemble the cinereous vulture blood transcriptome from a second individual, and annotate genes. Finally, we infer the demographic history of the cinereous vulture which shows marked fluctuations in effective population size during the late Pleistocene. We present the first genome and transcriptome analyses of the cinereous vulture compared to other avian genomes and transcriptomes, revealing genetic signatures of dietary and environmental adaptations accompanied by possible convergent evolution between the Old World and New World vultures.

Initial sequencing and analysis of the human genome.

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.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

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。

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

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.