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.

Complete (Classic) Hydatidiform Mole with 46,XY Karyotype of Paternal Origin

Abstract: Complete hydatidiform mole is a conceptus without an embryo, with visible general swelling of the placental villi and gross trophoblastic hyperplasia (Szulman and Surti, 1978 a and b). Such moles usually have a 46,XX karyotype, which was reported recently to be of androgenetic origin (Kajii and Ohama, 1977; Wake et al., 1978). A single X-carrying paternal haploid set 'takes over' the ovum, to which it imparts a diploid, 46,XX status by its own duplication, the other alternative being a 'take over' by a diploid XX sperm that resulted from a failure of the second meiotic division. Only a small proportion of moles are of 46,XY karyotype (3%--13%) (Wake et al., 1978; Bou6 and Bou6, 1975), and they have not yet been analyzed as to their genetic origin. They are of special interest since they must be different from the 46,XX variety in that they cannot develop by either mechanism postulated for the latter. We report here on the chromosomal origin of a complete mole with a 46,XY karyotype. A study of polymorphic chromosomal and enzyme markers of the molar and of the parental genomes revealed that the molar chromosomes are entirely of paternal origin derived from both paternal haploid sets, there being no maternal contribution. The patient is a 22-year-old Nigerian woman, recently arrived in the USA, who had a classic complete mole removed by suction curettage at 12 weeks' gestation. She subsequently developed malignant trophoblastic disease (complete with pulmonary lesions), which was successfully treated by chemotherapy, as will be published in detail elsewhere. Molar tissue was cultured as already described (Szulman and Surti, 1978a). Peripheral blood from both parents was also obtained for enzyme studies and cytogenetic analysis. At least ten metaphase spreads, from each individual were studied for polymorphic fluorescent (quinacrine dihydrochloride) markers (Table 1). Polymorphic enzyme systems were analyzed by a standard electrophoresis technique (O'Brien et al., 1979) (Table 2). Study of the polymorphic markers usually observable on chromosomes 3, 13, 14, 15, 21, and 22 revealed that such chromosome markers as were present in the mole (Table 1) were referable solely

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

Abstract: Polymorphisms in numerous human genes have been reported to confer differential susceptibility to human immunodeficiency virus (HIV) infection and rates of progression to AIDS [1, 2]. Genes encoding the major HIV-1 coreceptor chemokine (C-C motif) receptor 5 (CCR5), its ligands, and HLA class I genes are well documented and consistently replicated AIDS restriction genes. Homozygosity for the CCR5 Δ32 allele provides near absolute protection against HIV-1 infection, whereas Δ32 heterozygosity delays progression to clinical AIDS [3]. Certain HLA-B alleles are variously associated with increased or decreased rates of progression [3]. For example, B★5701 is strongly and consistently associated with slower disease progression [4, 5] and elite viral control [6]. Recent genomewide association studies (GWAS) involving HIV-infected individuals that use Illumina genotyping platforms have confirmed the strong associations between variation in HLA genes and the surrogate markers of plasma viral load and CD4+ T cell count [7–9]. However, the statistical noise introduced by a large number of tests generally require P values ≤5 × 10−8 for genomewide significance; in GWAS, true-positive signals with P values above this threshold cannot be distinguished from false-positive signals by purely statistical methods. This was observed in the failure of early HIV-related GWAS to identify previously identified AIDS restriction genes, such as CCR5 Δ32 or RANTES (CCL5). However, the effects of CCR5 Δ32 on disease progression were confirmed in a meta-analysis [10]. Approaches using replication or meta-analysis of GWAS results can help overcome these problems [11]. Although HIV-1 load is a robust prognostic marker for clinical disease progression, studies show that viral load explains <50% of the variation in time from primary infection to the development of clinical AIDS [12–14]. Therefore, it is important to assess the direct host genetic contribution to the actual clinical end point of HIV infection: AIDS or AIDS-related death. To address the potential differences between the virologic and clinical end points, we used a 2-stage strategy to identify host common genetic polymorphisms associated with variation among HIV-infected individuals in their rate of progression to clinical AIDS (Centers for Disease Control and Prevention [CDC] 1987 definition). First, we conducted a GWAS involving a population of HIV-1–infected men from the Multicenter AIDS Cohort Study (MACS) who were chosen to be enriched with participants representing the extreme ends of phenotypic distribution rates of HIV-1 disease progression to clinical AIDS: rapid progressors and long-term nonprogressors. A focus on extreme genotypes improves our power to detect differences between these readily discernible groups [15, 16], as seen elsewhere with AIDS phenotypes [17, 18]. Second, we selected the top-ranking single-nucleotide polymorphisms (SNPs) from the initial GWAS for replication tests in an independent cohort of 590 HIV-1 seroconverters. Third, we stratified the replication cohort by transmission mode (sexual or parenteral) and tested for consistent effects across these distinct populations.

Captive breeding of the cheetah (Acinonyx jubatus) in North American zoos (1871–1986)

Abstract: The African cheetah has been bred in North American zoological facilities since 1956. The captive population has since grown to around 200 animals because of a combined increase in importation plus captive births. From 1982 to 1986, the captive birth rate declined by 50%, primarily because of a low frequency of breeding individuals in the population. The 1986 population had an effective breeding size of 28.1 in a total population of over 193 cheetahs. The incidence of infant mortality has been high (36.7%) relative to other zoo-bred species, perhaps as a consequence of the previously observed genetic impoverishment of the species. The combination of low fecundity, high infant mortality, and population dynamics indicates that the North American captive cheetah population is neither a self-sustaining nor a theoretically “viable population” as defined by Soule et al. [ZOO BIOLOGY 5:101–114, 1986]. Possible recommendations for improving captive cheetah propagation are discussed.

Reproductive status of endemic felid species in Latin American zoos and implications for ex situ conservation

Abstract: Reproductive evaluations were conducted on 185 male cats representing eight endemic Latin American species that were maintained in 44 zoos and private facilities in 12 Latin American countries. Reproductive assessments (testicular measures, ejaculate quality, and blood testosterone/cortisol concentration) were used to establish normative values for large- and small-sized cats in Latin American collections. Data also were analyzed using multiple regression to study the impact of proven breeder status, diet, and various animal housing combinations. Most felids (>95%) in the survey were of wild-born origin, and 50% of males had low sperm counts (<1 million total sperm per ejaculate). Among large cats (jaguars and pumas), proven breeders had larger (P<0.05) testes, greater semen volume, and more normal sperm than nonbreeders. Males on adequate diets had higher (P<0.05) circulating cortisol. Among small-sized felids, proven breeders had higher (P<0.05) testosterone, and males housed alone or paired with a conspecific female had more (P<0.05) total sperm per ejaculate and greater (P<0.05) seminal and testicular volumes. Fifty-nine ejaculates (potentially representing ∼100 artificial insemination (AI) or 26,000 in vitro fertilization (IVF) procedures) were cryopreserved for a felid genome resource bank. In conclusion, breeding success and reproductive traits for many endemic felids in Latin American zoos appear to be suboptimal, and likely would benefit from improvements in diet and exhibitry. Technology transfer and continued training of zoo staff and scientists in Latin American countries are essential if these zoos are to achieve their tremendous conservation potential for felids and other threatened endemic species. Zoo Biol 22:421–441, 2003. © 2003 Wiley-Liss, Inc.

Searching for signals of evolutionary selection in 168 genes related to immune function

Abstract: Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH) Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data

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.