Our Science – O'Brien Website

Stephen J. O'Brien, Ph.D.

Laboratory of Genomic Diversity Head, Genetics Section Laboratory Chief Building 560, Room 21-105 NCI-Frederick Frederick, MD 21702-1201 Phone:   301-846-1296 Fax:   301-846-1686 E-Mail:   obrien@ncifcrf.gov Link: Other Homepage

Biography

Dr. O'Brien is Chief of The Laboratory of Genomic Diversity and is recognized for research contributions in human and comparative genetics, evolutionary biology, HIV/AIDS, retro-virology, and species conservation. In collaboration with his students, fellows and colleagues a list of noted achievements include: 1) Description of the first human gene to influence HIV-1 infection and AIDS progression, CCR5-Δ32. Since CCR5-Δ32, his group has discovered and validated 20 AIDS Restriction Genes that regulate HIV entry, innate or acquired immunity, and HIV gene control, pioneering the science of genetic epidemiology; 2) Stewardship of the Feline Genome Projects including annotation of the cat whole genome sequence for medical and comparative genome analyses; 3.) Mapping of over 200 human genes including onco-genes, virus resistance genes and heredity disease genes 4.) Documenting the epidemic prevalence and immunological cost of feline immunodeficiency virus (FIV) among wildcat species; 5.) Solving the evolutionary history of the Mammalian radiations, the Chiroptera and Felidae Families plus defining new species of orangutan, clouded leopard, and elephant; and 6.) Developing the discipline of Conservation Genetics by describing the remarkable genetic uniformity of the African cheetah, a prelude to genetic assessment of endangered species.

Research

Comparative Genetics, Emerging Viruses, and Host Responses in Natural Populations

The principal focus of our investigation concerns the collaborative interaction of mammalian cellular genes operative in concordant evolutionary descent of the immune system, retroviruses, and cancer onset in pursuit of comparative mammalian genetic principles which participate in these processes. Three sharply focused research projects are currently in progress.

The Development of the Domestic Cat, Felis catus, as a Model for Genetic Analysis
To facilitate the understanding of mammalian development, infectious disease, and neoplasia, and also to provide a balance to possible biological exceptions that may occur in rodent modeling of human genetics, we are developing a comparative genetic map of the domestic cat (Felis catus). The cat was an attractive candidate for laboratory genetics for several reasons, including abundant polymorphic morphological loci, heritable defects homologous to human genetic diseases, and epidemics of two viruses, feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV), that cause neoplasias and immunodeficiencies, respectively. Recent advances include (1) a radiation hybrid map of the domestic cat containing 424 Type I (coding gene) marker loci and 176 hypervariable short tandem repeat polymorphisms (STRPs or microsatellites); (2) a genetic map containing over 100 Type I marker anchor loci distributed over 17 of the 19 feline chromosomes, a map built using somatic cell hybrid panels, high-resolution G-banding karyology, fluorescence in situ hybridization (FISH), and pedigree analysis, which revealed extensive syntenic conservation between feline and human genomes in several cases spanning entire chromosomes; (3) identification of 321 Type I marker anchor loci selected to provide a 5- to 10-centiMorgan density of gene markers for use in comparative mapping of all vertebrate species, termed 'comparative anchor tagged sequences' (CATS); (4) isolation, sequencing, and polymerase chain reaction primer design, and genetic mapping of 235 STRPs; and (5) development of interspecies sexual crosses and backcrosses between the domestic cat and Asian leopard cat suitable for rapid mapping of Type I and STRP loci.

Emerging Viruses and Host Responses in Natural Populations
Throughout evolution, animal species have been continually afflicted with devastating viral disease outbreaks that have driven the coevolution of both host and pathogen genomes, which today are punctuated with the molecular footprints of these outbreaks. The specific objectives of this project are to identify new viruses and disease agents which influence the health of individuals and the demographic stability of the population, to monitor the dynamics of emerging viruses and associated epidemics in situ, and to track the coevolution and coadaptation of parasite and host genomes driven by natural epidemics, using genetic and phylogenetic inference. Current work is focused on the natural history and acute epidemic emergence of four viruses: human T cell lymphotropic virus (HTLV-1), feline infectious peritonitis virus (FIPV), feline immunodeficiency virus (FIV), and canine distemper morbillivirus. Recent results include: (1) the demonstration that FIV exposure is a widespread occurrence in felid species, and (2) a phylogenetic analysis of lion FIV pol gene sequences from four geographically isolated African populations revealed remarkably high intra- and inter-individual genetic diversity at the sequence level resolvable into three phylogenetic clusters. The latter study suggests that the ancestors of lion FIV evolved in allopatric (geographically isolated) populations that converged recently and, since there is no clear evidence of lion FIV-associated pathology, raises the possibility of a historic genetic accommodation between the lion lentivirus and its host.

The Identification of Human Genetic Loci Which Influence Susceptibility to HIV Infection, Disease Progression, and Host Immune Response
The HIV-AIDS epidemic is characterized by considerable epidemiologic heterogeneity in infection, rate of progression of HIV-infected patients to AIDS, and disease sequelae. Epidemiologic explanations for heterogeneity generally involve either virus or host genetic differences, another pathogen, or an environmental component. The specific objective of this project is to discover and characterize human genetic loci operative in differential host responses to two pathological viruses, HIV and hepatitis B virus, using the combined methods of human molecular genetics, population genetic theory, and epidemiology. Towards this goal, we have developed a new approach to mapping disease loci in populations when family studies are not feasible (as in the case of infectious disease susceptibility). The method, termed 'mapping by admixture linkage disequilibrium' (MALD), takes advantage of linkage disequilibrium that occurs temporarily in admixed racial groups, such as African Americans and Hispanics. We have recently discovered mutations in the HIV macrophage coreceptors and one of the coreceptor ligands that provide genetic resistance to disease progression among HIV-infected patients.

This page was last updated on 7/18/2008.