Genetics and Genomics Commons^™

Patterns Of Feline Immunodeficiency Virus Multiple Infection And Genome Divergence In A Free-Ranging Population Of African Lions, Jennifer L. Troyer, Jill Pecon-Slattery, Melody E. Roelke, Lori Black, Craig Packer, Stephen J. O'Brien

Biology Faculty Articles

Feline immunodeficiency virus (FIV) is a lentivirus that causes AIDS-like immunodeficiency disease in domestic cats. Free-ranging lions, Panthera leo, carry a chronic species-specific strain of FIV, FIV-Ple, which so far has not been convincingly connected with immune pathology or mortality. FIV-Ple, harboring the three distinct strains A, B, and C defined by pol gene sequence divergences, is endemic in the large outbred population of lions in the Serengeti ecosystem in Tanzania. Here we describe the pattern of variation in the three FIV genes gag, pol-RT, and pol-RNase among lions within 13 prides to assess the occurrence of FIV infection and …

Genomically Intact Endogenous Feline Leukemia Viruses Of Recent Origin, Alfred L. Roca, Jill Pecon-Slattery, Stephen J. O'Brien

Biology Faculty Articles

We isolated and sequenced two complete endogenous feline leukemia viruses (enFeLVs), designated enFeLV-AGTT and enFeLV-GGAG. In enFeLV-AGTT, the open reading frames are reminiscent of a functioning FeLV genome, and the 5′ and 3′ long terminal repeat sequences are identical. Neither endogenous provirus is genetically fixed in cats but polymorphic, with 8.9 and 15.2% prevalence for enFeLV-AGTT and enFeLV-GGAG, respectively, among a survey of domestic cats. Neither provirus was found in the genomes of related species of the Felis genus, previously shown to harbor enFeLVs. The absence of mutational divergence, polymorphic incidence in cats, and absence in related species suggest that …

Seroprevalence Of Bartonella Infection In American Free-Ranging And Captive Pumas (Felis Concolor) And Bobcats (Lynx Rufus), Bruno B. Chomel, Yoko Kikuchi, Janice S. Martenson, Melodie E. Roelke-Parker, Chao Chin Chang, Rickie W. Kasten, Janet E. Foley, John Laudre, Kerry Murphy, Pamela K. Swift, Vicki L. Kramer, Stephen J. O'Brien

Biology Faculty Articles

Bartonella henselae is the main agent of cat scratch disease in humans and domestic cats are the main reservoir of this bacterium. We conducted a serosurvey to investigate the role of American wild felids as a potential reservoir of Bartonella species. A total of 479 samples (439 serum samples and 40 Nobuto strips) collected between 1984 and 1999 from pumas (Felis concolor) and 91 samples (58 serum samples and 33 Nobuto strips) collected from bobcats (Lynx rufus) in North America, Central America and South America were screened for B. henselae antibodies. The overall prevalence of B. henselae antibodies was respectively …

Comprehensive Analysis Of Class I And Class Ii Hla Antigens And Chronic Hepatitis B Virus Infection, Chloe L. Thio, David L. Thomas, Peter Karacki, Xiaojiang Gao, Darlene Marti, Richard A. Kaslow, James J. Goedert, Margaret Hilgartner, Steffanie A. Strathdee, Priya Duggal, Stephen J. O'Brien, Jacquie Astemborski, Mary Carrington

Biology Faculty Articles

Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by the vigor and breadth of the host immune response. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance. HLA class I and II genes were molecularly typed in 194 Caucasian individuals with viral persistence and 342 matched controls who had cleared the virus. A single class I allele, A*0301 (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.30 to 0.72; P = 0.0005) was …

Reconstructing The Genomic Architecture Of Mammalian Ancestors Using Multispecies Comparative Maps, William J. Murphy, Guillaume Bourque, Glenn Tesler, Pavel Pevzner, Stephen J. O'Brien

Biology Faculty Articles

Rapidly developing comparative gene maps in selected mammal species are providing an opportunity to reconstruct the genomic architecture of mammalian ancestors and study rearrangements that transformed this ancestral genome into existing mammalian genomes. Here, the recently developed Multiple Genome Rearrangement (MGR) algorithm is applied to human, mouse, cat and cattle comparative maps (with 311-470 shared markers) to impute the ancestral mammalian genome. Reconstructed ancestors consist of 70-100 conserved segments shared across the genomes that have been exchanged by rearrangement events along the ordinal lineages leading to modern species genomes. Genomic distances between species, dominated by inversions (reversals) and translocations, are …

Comparative Genome Organization Of Human, Murine, And Feline Mhc Class Ii Region, Naoya Yuhki, Thomas W. Beck, Robert M. Stephens, Yoko Nishigaki, Kymberly Newmann, Stephen J. O'Brien

Biology Faculty Articles

To study comparative molecular dynamics in the genesis of the major histocompatibility complex (MHC), we determined a complete nucleotide sequence spanning 758,291 bp of the domestic cat (Felis catus) extended and classical class II region. The feline class II MHC includes 44 genes (31 predicted to be expressed) which display DNA sequence homology and ordered gene synteny with human HLA and mouse H2, in extended class II and centromere proximal regions (DM to DO) of the classical class II region. However, remarkable genomic alterations including gene gain and loss plus size differentials of 250 kb are …

Feline Immunodeficiency Virus Integration In B-Cell Lymphoma Identifies A Candidate Tumor Suppressor Gene On Human Chromosome 15q151, Julia Beatty, Anne Terry, Julie Macdonald, Elizabeth Gault, Stanley Cevario, Stephen J. O'Brien, Ewan Cameron, James C. Neil

Biology Faculty Articles

Infection with immunosuppressive lentiviruses is associated with increased cancer risk,but most studies have implicated indirect mechanisms as the tumor cells generally lack integrated viral sequences.An exception wasfound in a B-cell lymphoma (Q254) where the tumor cells contained a single integrated feline immunodeficiency virus genome. Additional analysis now indicates that feline immunodeficiency virus integration in lymphoma Q254 resulted in promoter insertion and truncation of a conserved gene on feline chromosome B3, whereas the unaffected allele of the gene appeared to be transcriptionally down-regulated. The orthologous human gene (FLJ12973), is expressed ubiquitously and encodes a WD-repeat protein with structural similarity …

Sequencing The Genome Of The Domestic Cat Felis Catus, Stephen J. O'Brien, Eric S. Lander, M. E. Haskins, Urs Giger, Niels C. Pederson, David E. Wildt, William J. Murphy, Naoya Yuhki, Marilyn Menotti-Raymond

Biology Faculty Articles

No abstract provided.

The Meowplex: A New Dna Test Using Tetranucleotide Str Markers For The Domestic Cat, John M. Butler, Victor A. David, Stephen J. O'Brien, Marilyn Menotti-Raymond

Biology Faculty Articles

No abstract provided.

Hla-Cw*04 And Hepatitis C Virus Persistence, Chloe L. Thio, Xiaojiang Gao, James J. Goedert, David Vlahov, Kenrad E. Nelson, Margaret Hilgartner, Stephen J. O'Brien, Peter Karacki, Jacquie Astemborski, Mary Carrington, David L. Thomas

Biology Faculty Articles

In studies of acute hepatitis C virus (HCV) infection, the early host immune response is one of the determinants of viral persistence. The class I human leukocyte antigens (HLA), which present foreign antigen to cytolytic T cells, are integral components of this response. We hypothesized that the highly polymorphic HLA genes affect the outcome of an HCV infection. To test this hypothesis, we molecularly typed 231 persons with well-documented clearance of an HCV infection and 444 matched persistently infected persons. HLA-A*1101 (odds ratio [OR], 0.49; 95% confidence interval [95% CI], 0.27 to 0.89), HLA-B*57 (OR, 0.62; 95% CI, 0.39 to …

Genomic Microsatellites As Evolutionary Chronometers: A Test In Wild Cats, Carlos A. Driscoll, Marilyn Menotti-Raymond, George Nelson, David Goldstein, Stephen J. O'Brien

Biology Faculty Articles

Nuclear microsatellite loci (2- to 5-bp tandem repeats) would seem to be ideal markers for population genetic monitoring because of their abundant polymorphism, wide dispersal in vertebrate genomes, near selective neutrality, and ease of assessment; however, questions about their mode of generation, mutation rates and ascertainment bias have limited interpretation considerably. We have assessed the patterns of genomic diversity for ninety feline microsatellite loci among previously characterized populations of cheetahs, lions and pumas in recapitulating demographic history. The results imply that the microsatellite diversity measures (heterozygosity, allele reconstitution and microsatellite allele variance) offer proportionate indicators, albeit with large variance, of …

Mhc Class I Molecules And Progression To Aids, Mary Carrington, Xiaojiang Gao, Stephen J. O'Brien

Biology Faculty Articles

No abstract provided.

Genetic Evidence For Two Species Of Elephant In Africa, Alfred L. Roca, Nicholas Georgiadis, Jill Pecon-Slattery, Stephen J. O'Brien

Biology Faculty Articles

Elephants from the tropical forests of Africa are morphologically distinct from savannah or bush elephants. Dart-biopsy samples from 195 free-ranging African elephants in 21 populations were examined for DNA sequence variation in four nuclear genes (1732 base pairs). Phylogenetic distinctions between African forest elephant and savannah elephant populations corresponded to 58% of the difference in the same genes between elephant genera Loxodonta (African) and Elephas (Asian). Large genetic distance, multiple genetically fixed nucleotide site differences, morphological and habitat distinctions, and extremely limited hybridization of gene flow between forest and savannah elephants support the recognition and conservation management of two African …

Effect Of A Single Amino Acid Change In Mhc Class I Molecules On The Rate Of Progression To Aids, Xiaojiang Gao, George W. Nelson, Peter Karacki, Maureen P. Martin, John Phair, Richard A. Kaslow, James J. Goedert, Susan Buchbinder, Keith Hoots, David Vlahov, Stephen J. O'Brien, Mary Carrington

Biology Faculty Articles

Background From studies of genetic polymorphisms and the rate of progression from human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS), it appears that the strongest susceptibility is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B*3501, the most common HLA-B*35 subtype. We examined subtypes of HLA-B*35 in five cohorts and analyzed the relation of structural differences between HLA-B*35 subtypes to the risk of progression to AIDS. Methods Genotyping of HLA class I loci was performed for 850 patients who seroconverted and …

Canine And Feline Parvoviruses Can Use Human Or Feline Transferrin Receptors To Bind, Enter, And Infect Cells, John S. L. Parker, William J. Murphy, Dai Wang, Stephen J. O'Brien, Colin R. Parrish

Biology Faculty Articles

Canine parvovirus (CPV) enters and infects cells by a dynamin-dependent, clathrin-mediated endocytic pathway, and viral capsids colocalize with transferrin in perinuclear vesicles of cells shortly after entry (J. S. L. Parker and C. R. Parrish, J. Virol. 74:1919–1930, 2000). Here we report that CPV and feline panleukopenia virus (FPV), a closely related parvovirus, bind to the human and feline transferrin receptors (TfRs) and use these receptors to enter and infect cells. Capsids did not detectably bind or enter quail QT35 cells or a Chinese hamster ovary (CHO) cell-derived cell line that lacks any TfR (TRVb cells). However, capsids bound and …

Unusual Polymorphisms In Human Immunodeficiency Virus Type 1 Associated With Nonprogressive Infection, Louis Alexander, Emma Weiskopf, Thomas C. Greenough, Nathan C. Gaddis, Marcy C. Auerbach, Michael H. Malim, Stephen J. O'Brien, Bruce D. Walker, John L. Sullivan, Ronald C. Desrosiers

Biology Faculty Articles

Factors accounting for long-term nonprogression may include infection with an attenuated strain of human immunodeficiency virus type 1 (HIV-1), genetic polymorphisms in the host, and virus-specific immune responses. In this study, we examined eight individuals with nonprogressing or slowly progressing HIV-1 infection, none of whom were homozygous for host-specific polymorphisms (CCR5-Δ32, CCR2-64I, and SDF-1-3^'A) which have been associated with slower disease progression. HIV-1 was recovered from seven of the eight, and recovered virus was used for sequencing the full-length HIV-1 genome; full-length HIV-1 genome sequences from the eighth were determined following amplification of viral …

A Radiation Hybrid Map Of The Cat Genome: Implications For Comparative Mapping, William J. Murphy, Shan Sun, Zhang-Qun Chen, Naoya Yuhki, Deborah Hirschmann, Marilyn Menotti-Raymond, Stephen J. O'Brien

Biology Faculty Articles

Ordered gene maps of mammalian species are becoming increasingly valued in assigning gene variants to function in human and animal models, as well as recapitulating the natural history of genome organization. To extend this power to the domestic cat, a radiation hybrid (RH) map of the cat was constructed integrating 424 Type I-coding genes with 176 microsatellite markers, providing coverage over all 20 feline chromosomes. Alignment of parallel RH maps of human and cat reveal 100 conserved segments ordered (CSOs) between the species, nearly three times the number observed with reciprocal chromosome painting analyses. The observed number is equivalent to …

A Comparative Gene Map Of The Horse (Equus Caballus), Alexandre R. Caetano, Yow-Ling Shiue, Leslie A. Lyons, Stephen J. O'Brien, Thomas F. Laughlin, Ann T. Bowling, James D. Murray

Biology Faculty Articles

A comparative gene map of the horse genome composed of 127 loci was assembled based on the new assignment of 68 equine type I loci and on data published previously. PCR primers based on consensus gene sequences conserved across mammalian species were used to amplify markers for assigning 68 equine type I loci to 27 horse synteny groups established previously with a horse-mouse somatic cell hybrid panel (SCHP, UC Davis). This increased the number of coding genes mapped to the horse genome by over 2-fold and allowed refinements of the comparative mapping data available for this species. In conjunction with …

Extensive Conservation Of Sex Chromosome Organization Between Cat And Human Revealed By Parallel Radiation Hybrid Mapping, William J. Murphy, Shan Sun, Zhang-Qun Chen, Jill Pecon-Slattery, Stephen J. O'Brien

Biology Faculty Articles

A radiation hybrid (RH)-derived physical map of 25 markers on the feline X chromosome (including 19 Type I coding loci and 6 Type II microsatellite markers) was compared to homologous marker order on the human and mouse X chromosome maps. Complete conservation of synteny and marker order was observed between feline and human X chromosomes, whereas the same markers identified a minimum of seven rearranged syntenic segments between mouse and cat/human X chromosome marker order. Within the blocks, the feline, human, and mouse marker order was strongly conserved. Similarly, Y chromosome locus order was remarkably conserved between cat and human …

Phenotypic Expressions Of Ccr5-Δ32/Δ32 Homozygosity, Giang T. Nguyen, Mary Carrington, Judith A. Beeler, Michael Dean, Louis M. Aledort, Philip M. Blatt, Alan R. Cohen, Donna Dimichele, M. Elaine Eyster, Craig M. Kessler, Barbara Konkle, Cindy Leissinger, Naomi Luban, Stephen J. O'Brien, James J. Goedert, Thomas R. O'Brien

Biology Faculty Articles

Objective: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-Δ32/Δ32 homozygous genotype has phenotypic expressions other than those related to HIV-1.

Design: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-Δ32/Δ32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-Δ32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis.

Results: …

Effects Of Plasma Hiv Rna, Cd4+ T Lymphocytes, And The Chemokine Receptors Ccr5 And Ccr2b On Hiv Disease Progression In Hemophiliacs, Eric S. Daar, Sharyne Donfield, Edward Gomperts, Margaret Hilgartner, Keith Hoots, David Chernoff, Cheryl Winkler, Stephen J. O'Brien, Hemophilia Growth And Development Study

Biology Faculty Articles

We have investigated the effects of plasma HIV RNA, CD4⁺ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genotype variants CCR2b-641 and CCR5-Δ32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4⁺ T lymphocytes than did those without these …

Influence Of The Ccr2-V64i Polymorphism On Human Immunodeficiency Virus Type 1 Coreceptor Activity And On Chemokine Receptor Function Of Ccr2b, Ccr3, Ccr5, And Cxcr4, Benhur Lee, Benjamin J. Doranz, Shalini Rana, Yanji Yi, Mario Mellado, Jose M. R. Frade, Carlos Martinez-A., Stephen J. O'Brien, Michael Dean, Ronald G. Collman, Robert W. Doms

Biology Faculty Articles

The chemokine receptors CCR5 and CXCR4 are used by human immunodeficiency virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In addition, some virus strains can use alternative chemokine receptors, including CCR2b and CCR3, for infection. A polymorphism in CCR2 (CCR2-V64I) is associated with a 2- to 4-year delay in the progression to AIDS. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 coreceptor activities, and their effects on the expression and receptor activities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were expressed at …