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. Our goal is to determine the comparative mammalian genetic principles that 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 genetic map of the domestic cat containing over one hundred Type I (coding gene) marker anchor loci distributed over 17 of the 19 feline chromosomes, which was built using somatic cell hybrid panels, high resolution G-banding karyology, fluorescence in situ hybridization (FISH), and pedigree analysis and revealed extensive syntenic conservation between feline and human genomes, in several cases spanning entire chromosomes; (2) identification of 321 Type I marker anchor loci selected to provide a 5-10-centiMorgan density of gene markers for use in comparative mapping of all vertebrate species; (3) isolation, sequencing, and polymerase chain reaction primer design of 370 hypervariable short tandem repeat polymorphisms (STRPs or microsatellites), and (4) 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 co-evolution of both host and pathogen genomes, which today are punctuated with the molecular footprints of these outbreaks. The specific objectives of this project are the identification of 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 co-evolution and co-adaptation 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 three viruses, human T-cell lymphotropic virus (HTLV-I), feline infectious peritonitis virus (FIPV), and feline immunodeficiency virus (FIV). 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 which 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. 

Last Updated on August 30, 2001 by Shawn Palmer