Showing papers by "Stephen J. O'Brien published in 2007"
TL;DR: The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.
Abstract: Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.
712 citations
TL;DR: A genetic assessment of 979 domestic cats and their wild progenitors revealed that cats were domesticated in the Near East, probably coincident with agricultural village development in the Fertile Crescent.
Abstract: The world's domestic cats carry patterns of sequence variation in their genome that reflect a history of domestication and breed development. A genetic assessment of 979 domestic cats and their wild progenitors-Felis silvestris silvestris (European wildcat), F. s. lybica (Near Eastern wildcat), F. s. ornata (central Asian wildcat), F. s. cafra (southern African wildcat), and F. s. bieti (Chinese desert cat)-indicated that each wild group represents a distinctive subspecies of Felis silvestris. Further analysis revealed that cats were domesticated in the Near East, probably coincident with agricultural village development in the Fertile Crescent. Domestic cats derive from at least five founders from across this region, whose descendants were transported across the world by human assistance.
430 citations
TL;DR: The genome sequence of an inbred Abyssinian domestic cat was assembled, mapped, and annotated with a comparative approach that involved cross-reference to annotated genome assemblies of six mammals, shedding new light on the tempo and mode of gene/genome evolution in mammals and promising several research applications for the cat.
Abstract: The genome sequence (1.9-fold coverage) of an inbred Abyssinian domestic cat was assembled, mapped, and annotated with a comparative approach that involved cross-reference to annotated genome assemblies of six mammals (human, chimpanzee, mouse, rat, dog, and cow). The results resolved chromosomal positions for 663,480 contigs, 20,285 putative feline gene orthologs, and 133,499 conserved sequence blocks (CSBs). Additional annotated features include repetitive elements, endogenous retroviral sequences, nuclear mitochondrial (numt) sequences, micro-RNAs, and evolutionary breakpoints that suggest historic balancing of translocation and inversion incidences in distinct mammalian lineages. Large numbers of single nucleotide polymorphisms (SNPs), deletion insertion polymorphisms (DIPs), and short tandem repeats (STRs), suitable for linkage or association studies were characterized in the context of long stretches of chromosome homozygosity. In spite of the light coverage capturing approximately 65% of euchromatin sequence from the cat genome, these comparative insights shed new light on the tempo and mode of gene/genome evolution in mammals, promise several research applications for the cat, and also illustrate that a comparative approach using more deeply covered mammals provides an informative, preliminary annotation of a light (1.9-fold) coverage mammal genome sequence.
340 citations
TL;DR: The authors' data confirm the distinctiveness of Miniopterus, and support previous recommendations to elevate these bats to full familial status, and estimate that they diverged from all other bat species approximately 49-38 MYA, which is comparable to most other bat families.
Abstract: The long-fingered bats (Miniopterus sp.) are among the most widely distributed mammals in the world. However, despite recent focus on the systematics of these bats, their taxonomic position has not been resolved. Traditionally, they are considered to be sole members of Miniopterinae, 1 of 5 subfamilies within the largest family of bats, the Vespertilionidae. However, this classification has increasingly been called into question. Miniopterines differ extensively from other vespertilionids in numerous aspects of morphology, embryology, immunology, and, most recently, genetics. Recent molecular studies have proposed that the miniopterines are sufficiently distinct from vespertilionids that Miniopterinae should be elevated to full familial status. However, controversy remains regarding the relationship of the putative family, Miniopteridae to existing Vespertilionidae and to the closely related free-tailed bats, the Molossidae. We report here the first conclusive analysis of the taxonomic position of Miniopterus relative to all other bat families. We generated one of the largest chiropteran data sets to date, incorporating ∼11 kb of sequence data from 16 nuclear genes, from representatives of all bat families and 2 Miniopterus species. Our data confirm the distinctiveness of Miniopterus, and we support previous recommendations to elevate these bats to full familial status. We estimate that they diverged from all other bat species approximately 49-38 MYA, which is comparable to most other bat families. Furthermore, we find very strong support from all phylogenetic methods for a sister group relationship between Miniopteridae and Vespertilionidae. The Molossidae diverged from these lineages approximately 54-43 MYA and form a sister group to the Miniopteridae-Vespertilionidae clade.
186 citations
TL;DR: It is shown the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats, suggesting TSH directly affects bone remodeling in vivo.
Abstract: We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSH's actions are mediated by its inhibitory effects on RANKL-induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo. Introduction Thyroid-stimulating hormone (TSH) receptor haploinsufficient mice with normal circulating thyroid hormone levels have reduced bone mass, suggesting that TSH directly affects bone remodeling. We examined whether systemic TSH administration restored bone volume in aged ovariectomized (OVX) rats and influenced osteoclast formation and osteoblast differentiation in vitro. Materials and methods Sprague-Dawley rats were OVX at 6 months, and TSH therapy was started immediately after surgery (prevention mode; n = 80) or 7 mo later (restoration mode; n = 152). Hind limbs and lumbar spine BMD was measured at 2- or 4-wk intervals in vivo and ex vivo on termination at 8-16 wk. Long bones were subjected to microCT, histomorphometric, and biomechanical analyses. The direct effect of TSH was examined in osteoclast and osteoblast progenitor cultures and established rat osteosarcoma-derived osteoblastic cells. Data were analyzed by ANOVA Dunnett test. Results In the prevention mode, low doses (0.1 and 0.3 microg) of native rat TSH prevented the progressive bone loss, and importantly, did not increase serum triiodothyroxine (T3) and thyroxine (T4) levels in aged OVX rats. In restoration mode, animals receiving 0.1 and 0.3 microg TSH had increased BMD (10-11%), trabecular bone volume (100-130%), trabecular number (25-40%), trabecular thickness (45-60%), cortical thickness (5-16%), mineral apposition and bone formation rate (200-300%), and enhanced mechanical strength of the femur (51-60%) compared with control OVX rats. In vitro studies suggest that TSH's action is mediated by its inhibitory effects on RANKL-induced osteoclast formation, as shown in hematopoietic stem cells cultivated from TSH-treated OVX rats. TSH also stimulates osteoblast differentiation, as shown by effects on alkaline phosphatase activity, osteocalcin expression, and mineralization rate. Conclusions These results show for the first time that systemically administered TSH prevents bone loss and restores bone mass in aged OVX rats through both antiresorptive and anabolic effects on bone remodeling.
134 citations
TL;DR: The Adequacy of Morphology for Reconstructing the Early History of Placental Mammals shows the need for further investigation into the role of E.coli in the early history of placental mammals.
Abstract: Systematic Biology Publication details, including instructions for authors and subscription information: http://www.informaworld.com/smpp/title~content=t713658732 The Adequacy of Morphology for Reconstructing the Early History of Placental Mammals Mark S. Springer a; Angela Burk-Herrick a; Robert Meredith a; Eduardo Eizirik b; Emma Teeling c; Stephen J. O'Brien d; William J. Murphy e a Department of Biology, University of California, Riverside, Riverside, CA, USA b Faculdade de Biociencias, PUCRS, Porto Allegre, RS, Brazil c School of Biological and Environmental Sciences, University College Dublin Belfield, Dublin, Ireland d Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, MD, USA e Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
119 citations
TL;DR: Patients who undergo revision anterior cruciate ligament surgery should be counseled as to the expected outcome and cautioned that this procedure probably represents a salvage situation and may not allow them to return to their desired levels of function.
Abstract: BackgroundRevision anterior cruciate ligament surgery remains challenging.PurposeTo analyze the authors’ experience with revision anterior cruciate ligament surgery and determine the association between stability and functional results.Study DesignCase series; Level of evidence, 4.MethodsBetween 1991 and 2002, 95 of 102 patients who underwent revision anterior cruciate ligament reconstruction at the authors’ institution met the criteria for inclusion in the study. Of those, the 63 (66%) who returned for complete clinical and radiologic evaluation (mean follow-up, 72.7 months) formed the study group. Subjective evaluation focused on return to sports, arthritic symptoms, and subjective International Knee Documentation Committee criteria. Clinical evaluation included examination, KT-1000 arthrometer and functional testing, and radiographic analysis of alignment and arthritis.ResultsBased on International Knee Documentation Committee subjective scores and return to sports, results were rated as excellent/good...
99 citations
TL;DR: This identification of a large animal model for human retinal blindness offers considerable promise in developing gene-based therapies.
Abstract: A mutation in the CEP290 gene is reported in a cat pedigree segregating for autosomal recessive (AR) late-onset photoreceptor degeneration (rdAc). An initial screen of 39 candidate genes and genomic locations failed to detect linkage to cat rdAc. Linkage was ultimately established on cat B4 with 15 simple tandem repeat markers (logarithm of odds [LOD] range 4.83–15.53, H 5 0.0), in a region demonstrating conserved synteny to human chromosome 12, 84.9–90.63 Mb. The sequence of 10 genes with feline retinal expression was examined in affected and unaffected individuals. A single-nucleotide polymorphism was characterized in intron 50 of CEP290 (IVS50 þ 9T.G) that creates a strong canonical splice donor site, resulting in a 4-bp insertion and frameshift in the mRNA transcript, with subsequent introduction of a stop codon and premature truncation of the protein. A population genetic survey of 136 cats demonstrated that the rdAc mutation is in low frequency in Abyssinian populations (0.13, Sweden; 0.07, United States) and absent in breeds of non-Abyssinian heritage. Mutations inCEP290have recently been shown to cause two human diseases, Joubert syndrome, a syndromic retinal degeneration, and Leber’s congenital amaurosis, an AR early-onset retinal dystrophy. Human AR retinitis pigmentosa is among the most common causes of retinal degeneration and blindness, with no therapeutic intervention available. This identification of a large animal model for human retinal blindness offers considerable promise in developing gene-based therapies.
99 citations
TL;DR: It is indicated that a combined type II SLAP repair and acromioplasty had no negative effect clinically and, furthermore, appeared to prevent residual clinical impingement.
Abstract: Background: The treatment of type II superior labral anterior posterior (SLAP) lesions remains controversial. Many surgeons are reluctant to combine a SLAP repair with an acromioplasty for fear of postoperative shoulder stiffness and a poor clinical outcome.Hypothesis: A SLAP repair and an acromioplasty done concomitantly may yield acceptable outcomes.Study Design: Case series; Level of evidence, 4.Methods: We compared the clinical results of 50 patients who had either an isolated type II SLAP repair (SLAP group, 34 patients) or a combined type II SLAP repair and acromioplasty (combined group, 16 patients). Patients were excluded for full-thickness rotator cuff tears or instability. All patients were evaluated with the L'Insalata Functional Shoulder Rating Questionnaire, with the American Shoulder and Elbow Surgeons (ASES) questionnaire, and by subjective evaluation.Results: At an average of 3.4 years postoperatively, the L'Insalata and ASES scores were similar for the 2 groups: 87.1 and 85.8 for the SLAP...
91 citations
TL;DR: A whole-genome scan and association analyses demonstrated that FGF5 is the major genetic determinant of hair length in the domestic cat.
Abstract: To determine the genetic regulation of "hair length" in the domestic cat, a whole-genome scan was performed in a multigenerational pedigree in which the "long-haired" phenotype was segregating. The 2 markers that demonstrated the greatest linkage to the long-haired trait (log of the odds � 6) flanked an estimated 10-Mb region on cat chromosome B1 containing the Fibroblast Growth Factor 5 (FGF5) gene, a candidate gene implicated in regulating hair follicle growth cycle in other species. Sequence analyses of FGF5 in 26 cat breeds and 2 pedigrees of nonbreed cats revealed 4 separate mutations predicted to disrupt the biological activity of the FGF5 protein. Pedigree analyses demonstrated that different combinations of paired mutant FGF5 alleles segregated with the long-haired phenotype in an autosomal recessive manner. Association analyses of more than 380 genotyped breed and nonbreed cats were consistent with mutations in the FGF5 gene causing the long-haired phenotype in an autosomal recessive manner. In combination, these genomic approaches demonstrated that FGF5 is the major genetic determinant of hair length in the domestic cat.
74 citations
TL;DR: In this article, a nonfunctional CCR5 (CCR5Δ32) allele containing a 32-bp deletion was found to increase the likelihood of recovery from hepatitis B in humans.
Abstract: Recovery from acute hepatitis B virus (HBV) infection requires a broad, vigorous T-cell response, which is enhanced in mice when chemokine receptor 5 (CCR5) is missing. To test the hypothesis that production of a nonfunctional CCR5 (CCR5Δ32 [a functionally null allele containing a 32-bp deletion]) increases the likelihood of recovery from hepatitis B in humans, we studied 526 persons from three cohorts in which one person with HBV persistence was matched to two persons who recovered from an HBV infection. Recovery or persistence was determined prior to availability of lamivudine. We determined genotypes for CCR5Δ32 and for polymorphisms in the CCR5 promoter and in coding regions of the neighboring genes, chemokine receptor 2 (CCR2) and chemokine receptor-like 2 (CCRL2). Allele and haplotype frequencies were compared among the 190 persons with viral recovery and the 336 with persistence by use of conditional logistic regression. CCR5Δ32 reduced the risk of developing a persistent HBV infection by nearly half (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33 to 0.83; P = 0.006). This association was virtually identical in persons with and without a concomitant human immunodeficiency virus infection. Of the nine individuals who were homozygous for the deletion, eight recovered from infection (OR, 0.25; 95% CI, 0.03 to 1.99; P = 0.19). None of the other neighboring polymorphisms examined were associated with HBV outcome. These data demonstrate a protective effect of CCR5Δ32 in recovery from an HBV infection, provide genetic epidemiological evidence for a role of CCR5 in the immune response to HBV, and suggest a potential therapeutic treatment for patients persistently infected with HBV.
TL;DR: In this paper, the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the peptidyl prolyl isomerase A (PPIA) gene on HIV-1 infection and disease progression was examined.
Abstract: Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4+ T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5′ UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.
TL;DR: It is concluded that carboxyl terminal fragments of FGF-23 are phosphaturic and that a short, 26-amino acid fragment of F GF-23 retains significant phosphaturing activity.
Abstract: The phosphaturic activity of intact, full-length, fibroblast growth factor-23 (FGF-23) is well documented. FGF-23 circulates as the intact protein and as fragments generated as the result of proteolysis of the full-length protein. To assess whether short fragments of FGF-23 are phosphaturic, we compared the effect of acute, equimolar infusions of full-length FGF-23 and various FGF-23 fragments carboxyl-terminal to amino acid 176. In rats, intravenous infusions of full-length FGF-23 and FGF-23 176-251 significantly and equivalently increased fractional phosphate excretion (FE Pi) from 14 +/- 3 to 32 +/- 5% and 15 +/- 2 to 33 +/- 2% (p < 0.001), respectively. Chronic administration of FGF-23 176-251 reduced serum Pi and serum concentrations of 1alpha,25-dihydroxyvitamin D. Shorter forms of FGF-23 (FGF-23 180-251 and FGF-23 184-251) retained phosphaturic activity. Further shortening of the FGF-23 carboxyl-terminal domain, however, abolished phosphaturic activity, as infusion of FGF-23 206-251 did not increase urinary phosphate excretion. Infusion of a short fragment of the FGF-23 molecule, FGF-23 180-205, significantly increased FE Pi in rats and reduced serum Pi in hyperphosphatemic Fgf-23 ( -/- ) knockout mice. The activity of FGF-23 180-251 was confirmed in opossum kidney cells in which the peptide reduced Na(+)-dependent Pi uptake and enhanced internalization of the Na(+)-Pi IIa co-transporter. We conclude that carboxyl terminal fragments of FGF-23 are phosphaturic and that a short, 26-amino acid fragment of FGF-23 retains significant phosphaturic activity.
TL;DR: The improved RH comparative map provides a useful tool to facilitate positional cloning studies in the feline model and refined the pseudoautosomal region and boundary in the cat and show that it is markedly longer than those of human or mouse.
TL;DR: Comparisons of the genomic structure of 3 mammalian major histocompatibility complexes (MHCs), human HLA, canine DLA, and feline FLA revealed remarkable structural differences between HLA and the other 2 MHCs, suggesting the dynamic nature in the evolution of MHC class I genes.
Abstract: Comparisons of the genomic structure of 3 mammalian major histocompatibility complexes (MHCs), human HLA, canine DLA, and feline FLA revealed remarkable structural differences between HLA and the other 2 MHCs. The 4.6-Mb HLA sequence was compared with the 3.9-Mb DLA sequence from 2 supercontigs generated by 7x whole-genome shotgun assembly and 3.3-Mb FLA draft sequence. For FLA, we confirm that 1) feline FLA was split into 2 pieces within the TRIM (member of the tripartite motif) gene family found in human HLA, 2) class II, III, and I regions were placed in the pericentromeric region of the long arm of chromosome B2, and 3) the remaining FLA was located in subtelomeric region of the short arm of chromosome B2. The exact same chromosome break was found in canine DLA structure, where class II, III, and I regions were placed in a pericentromeric region of chromosome 12 whereas the remaining region was located in a subtelomeric region of chromosome 35, suggesting that this chromosome break occurred once before the split of felid and canid more than 55 million years ago. However, significant differences were found in the content of genes in both pericentromeric and subtelomeric regions in DLA and FLA, the gene number, and amplicon structure of class I genes plus 2 other class I genes found on 2 additional chromosomes; canine chromosomes 7 and 18 suggest the dynamic nature in the evolution of MHC class I genes.
Journal Article•
TL;DR: The results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV- 1 pathogenesis.
Abstract: Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4+ T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5′ UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.
TL;DR: Genomic paw prints in the DNA of the world’s wild cats have clarified the cat family tree and uncovered several remarkable migrations in their past.
Abstract: Ju ly 20 07 Elegant and enigmatic, cats tantalize not only those of us who share our sofas with the smaller versions but scientists who have tried to puzzle out the origin and evolution of their larger cousins. Where did the modern cat family evolve? Why and when did they leave their homes and migrate across continents? How many species actually exist, and which ones are closely related? Experts generally agree that there are 37 species in the family Felidae, but they have offered dozens of classification schemes, ordering cat species in as few as two to as many as 23 genera. Who could argue? Under the skin, one cat species appears pretty similar to another. They look like big cats, midsize cats and small cats. Distinguishing a lion’s skull from a tiger’s can be a challenge even for an expert, and genetic investigations that we have tried over the past two decades have failed to sort the cats into definitive groupings. In recent years, however, a revolution in sequencing the genomes of various creatures, spearheaded by the Human Genome Project and by powerful technologies to probe DNA, has provided some extremely valuable new tools for inquiry. Drawing on Genomic paw prints in the DNA of the world’s wild cats have clarified the cat family tree and uncovered several remarkable migrations in their past
Journal Article•
TL;DR: DNA evidence shows that all living cats trace back to a pantherlike predator that lived in Southeast Asia nearly 11 million years ago and has clarified the cat family tree and uncovered remarkable migrations in their past.
Abstract: This article examines genomic findings in the DNA of the world's wild cats and says the information has clarified the cat family tree and uncovered remarkable migrations in their past. DNA evidence shows that all living cats trace back to a pantherlike predator that lived in Southeast Asia nearly 11 million years ago. The big roaring cats were the first to branch off and seven other lineages followed. As the sea levels rose and fell, the cats migrated and developed into new species. INSETS: KEY CONCEPTS;SOLVING THE CAT PUZZLE.
TL;DR: Strong support is found for the distinction between N. nebulosa and N. diardi based on three fragments of mtDNA and 18 microsatellites, equivalent to the genetic divergence among recognized species in the genus Panthera.
Abstract: The clouded leopard (Neofelis nebulosa) is one of the least known cat species and depletion of their forested habitats puts it under heavy pressure. Recently reclassification of Bornean clouded leopards (N. nebulosa diardi) to species level (N.diardi) was suggested based on molecular and morphological evidence. Since the genetic results were based solely on three Bornean samples we re-evaluated this partition using additional samples of Bornean clouded leopards (N = 7) and we were also able to include specimens from Sumatra (N = 3), which were lacking in previous analysis. We found strong support for the distinction between N. nebulosa and N. diardi based on three fragments of mtDNA (900 bp) and 18 microsatellites. Forty-one fixed mitochondrial nucleotide differences and non-overlapping allele sizes in 8 of 18 microsatellite loci distinguished N. nebulosa and N. diardi. This is equivalent to the genetic divergence among recognized species in the genus Panthera. Sumatran clouded leopards clustered with specimens from Borneo, suggesting that Sumatran individuals also belong to N. diardi. Additionally, a significant population subdivision was apparent among N. diardi from Sumatra and Borneo based on mtDNA and microsatellite data. Referring to their origin on two Sunda Islands we propose to give N. diardi the common name "Sundaland clouded leopard". The reduced gene flow between Borneo and Sumatra might suggest the recognition of two subspecies of N. diardi. Based on this reclassification of clouded leopards not only species, but also the populations on Borneo and Sumatra should be managed separately and a higher priority should be placed to protect the different populations from extinction.
TL;DR: In this paper, the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts was examined.
Abstract: Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (Apobec3) antiretroviral factors cause hypermutation of proviral DNA leading to degradation or replication-incompetent HIV-1. However, HIV-1 viral infectivity factor (Vif) suppresses Apobec3 activity through the Cullin 5-Elongin B-Elongin C E3 ubiquitin ligase complex. We examined the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts. A total of 12 single nucleotide polymorphisms (SNPs) spanning 93 kb in the CUL5 locus were genotyped and their haplotypes inferred. A phylogenetic network analysis revealed that CUL5 haplotypes were grouped into two clusters of evolutionarily related haplotypes. Cox survival analysis and mixed effects models were used to assess time to AIDS outcomes and CD4+ T cell trajectories, respectively. Relative to cluster I haplotypes, the collective cluster II haplotypes were associated with more rapid CD4+ T cell loss (relative hazards [RH] = 1.47 and p = 0.009), in a dose-dependent fashion. This effect was mainly attributable to a single cluster II haplotype (Hap10) (RH = 2.49 and p = 0.00001), possibly due to differential nuclear protein–binding efficiencies of a Hap10-specifying SNP as indicated by a gel shift assay. Consistent effects were observed for CD4+ T cell counts and HIV-1 viral load trajectories over time. The findings of both functional and genetic epidemiologic consequences of CUL5 polymorphism on CD4+ T cell and HIV-1 levels point to a role for Cullin 5 in HIV-1 pathogenesis and suggest interference with the Vif-Cullin 5 pathway as a possible anti-HIV-1 therapeutic strategy.
Journal Article•
TL;DR: The findings of both functional and genetic epidemiologic consequences of CUL5 polymorphism point to a role for Cullin 5 in HIV-1 pathogenesis and suggest interference with the Vif-Cullin 5 pathway as a possible anti-HIV-1 therapeutic strategy.
Abstract: Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (Apobec3) antiretroviral factors cause hypermutation of proviral DNA leading to degradation or replication-incompetent HIV-1. However, HIV-1 viral infectivity factor (Vif) suppresses Apobec3 activity through the Cullin 5-Elongin B-Elongin C E3 ubiquitin ligase complex. We examined the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts. A total of 12 single nucleotide polymorphisms (SNPs) spanning 93 kb in the CUL5 locus were genotyped and their haplotypes inferred. A phylogenetic network analysis revealed that CUL5 haplotypes were grouped into two clusters of evolutionarily related haplotypes. Cox survival analysis and mixed effects models were used to assess time to AIDS outcomes and CD4+ T cell trajectories, respectively. Relative to cluster I haplotypes, the collective cluster II haplotypes were associated with more rapid CD4+ T cell loss (relative hazards [RH] = 1.47 and p = 0.009), in a dose-dependent fashion. This effect was mainly attributable to a single cluster II haplotype (Hap10) (RH = 2.49 and p = 0.00001), possibly due to differential nuclear protein–binding efficiencies of a Hap10-specifying SNP as indicated by a gel shift assay. Consistent effects were observed for CD4+ T cell counts and HIV-1 viral load trajectories over time. The findings of both functional and genetic epidemiologic consequences of CUL5 polymorphism on CD4+ T cell and HIV-1 levels point to a role for Cullin 5 in HIV-1 pathogenesis and suggest interference with the Vif-Cullin 5 pathway as a possible anti-HIV-1 therapeutic strategy.
TL;DR: Describing nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF.
Abstract: Background. Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry. Methodology/Principal findings. Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages. Conclusions/significance. Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF.
TL;DR: It is shown that the eight African elephant continent-wide datasets compared, including that of Debruyne (2005), together support a two-species model with cyto-nuclear genomic dissociation rather than a one- species model, and together indicate that Africa harbors two species of elephant.
TL;DR: Logistic regression analysis showed a significant probability of a favorable outcome at 12 weeks in patients who received HD-CAP (OR 3.066, 95% CI, 1.092–8.61; P=0.033), and further studies are needed to evaluate efficacy of HD- CAP in severely immunosuppressed cancer patients with invasive fungal infections.
Abstract: High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation
TL;DR: Annotation features from the 1.9-fold whole-genome shotgun sequences of domestic cat have been organized into an interactive web application, Genome Annotation Resource Fields (GARFIELD), which allows the user to view annotations on a per chromosome basis with unplaced contigs provided on placeholder chromosomes.
Abstract: Annotation features from the 1.9-fold whole-genome shotgun (WGS) sequences of domestic cat have been organized into an interactive web application, Genome Annotation Resource Fields (GARFIELD) (http://lgd.abcc.ncifcrf.gov) at the Laboratory of Genomic Diversity and Advanced Biomedical Computing Center (ABCC) at The National Cancer Institute (NCI). The GARFIELD browser allows the user to view annotations on a per chromosome basis with unplaced contigs provided on placeholder chromosomes. Various tracks on the browser allow display of annotations. A Genes track on the browser includes 20 285 regions that align to genes annotated in other mammalian genomes: Homo sapiens, Pan troglodytes, Mus musculus, Rattus norvegicus, Bos taurus, and Canis familiaris. Also available are tracks that display the contigs that make up the chromosomes and representations of their GC content and repetitive elements as detected using the RepeatMasker (http://www.repeatmasker.org). Data from the browser can be downloaded in FASTA and GFF format, and users can upload their own data to the display. The Felis catus sequences and their chromosome assignments and additional annotations incorporate data analyzed and produced by a multicenter collaboration between NCI, ABCC, Agencourt Biosciences Corporation, Broad Institute of Harvard and Massachusetts Institute of Technology, National Human Genome Research Institute, National Center for Biotechnology and Information, and Texas A&M.
TL;DR: The results suggest that ongoing parallel gene conversion between CCR2 and CCR5 promotes receptor heterodimerization in independent evolutionary lineages and offers an effective adaptive strategy for gene editing and coevolution among interactive immune response genes in mammals.
TL;DR: The catalog of cat numts provides a valuable resource for future studies in Felidae species, including its use as a tool to avoid numt contaminations that may confound population genetics and phylogenetic studies.
Abstract: Translocation of mtDNA into the nuclear genome, also referred to as numt, was first reported in the domestic cat (Felis catus) by Lopez et al. (1994). The Lopez-numt consisted of a translocation of 7.9 kbp of mtDNA that inserted into the domestic cat chromosome D2 around 1.8 million years ago. More than a decade later, the release of the domestic cat whole-genome shotgun sequences (1.9� coverage) provides the resource to obtain more comprehensive insight into the extent of mtDNA transfer over time in the domestic cat genome. MegaBLAST searches revealed that the cat genome harbors a wide variety of numts (298 320 bp), one-third of which likely correspond to the Lopez-numt tandem repeat, whereas the remaining numts are probably derived from multiple independent insertions, which in some cases were followed by segmental duplication after insertion in the nucleus. Numts were detected across most cat chromosomes, but the number of numts assigned to chromosomes is underestimated due to the relatively high number of numt sequences with insufficient flanking sequence to map. The catalog of cat numts provides a valuable resource for future studies in Felidae species, including its use as a tool to avoid numt contaminations that may confound population genetics and phylogenetic studies.
TL;DR: The presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-2 transmission, which suggests that these alleles reduce infectivity for HIV- 1.
Abstract: Background: Genetic factors may play a role in the transmission of HIV-1 Because HLA-B alleles influence HIV-1 disease progression and viral levels, they might also influence HIV-1 transmission Objective: To investigate if the presence of HLA-B alleles with the Bw4 epitope in HIV1-infected men decreased the risk of transmission to their female sex partners Methods: The study comprised 304 HIV-1-infected men with hemophilia and 325 female sex partners HLA class I genes were amplified using sequence-specific primers Products of the polymerase chain reaction were blotted on nylon membranes and hybridized with sequence-specific oligonucleotide probes Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for HIV-1 infection among the women Results: Among the 325 women, 44 (135%) were infected with HIV-1 HIV-1 infection in the women was associated with the HLA-B genotype of their male partner [Bw6/Bw6, 22/118 (186%); Bw4/Bw6, 18/154 (117%); Bw4/Bw4, 4/53 (76%)] Compared with men who were homozygous for Bw6, men who carried Bw4 were about half as likely to have transmitted HIV-1 to their female partner (OR, 052; 95% CI, 027‐098; P ¼ 004) Transmission was higher among couples in which the man’s ethnicity was other than White (OR, 260; 95% CI, 125‐540; P ¼ 001), but the association between HIV-1 transmission and HLA-B genotype was not confounded by race Conclusion: The presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission, which suggests that these alleles reduce infectivity for HIV-1
TL;DR: Protocols for designing, optimizing and implementing conserved anchor primers for use in genome mapping or phylogenetic applications, with particular emphasis on homologous gene sequences among mammals are described.
Abstract: Designing and optimizing comparative anchor primers for comparative gene mapping and phylogenetic inference
TL;DR: The Y haplotyping system described here, consisting of 4 introns and 1 polymorphic microsatellite (SMCY-STR), represents the first available markers for tracking intraspecific male lineage polymorphisms in Felidae species and promises to provide significant insights to evolutionary and population genetic studies of the species.
Abstract: Y chromosome haplotyping based on microsatellites and single nucleotide polymorphisms (SNPs) has proved to be a powerful tool for population genetic studies of humans. However, the promise of the approach is hampered in the majority of nonhuman mammals by the lack of Y-specific polymorphic markers. We were able to identify new male-specific polymorphisms in the domestic cat Felis catus and 6 additional Felidae species with a combination of molecular genetic and cytogenetic approaches including 1) identifying domestic cat male-specific microsatellites from markers generated from a male cat microsatellite-enriched genomic library, a flow-sorted Y cosmid library, or a Y-specific cat bacteria artificial chromosome (BAC) clone, (2) constructing microsatellite-enriched libraries from flow-sorted Y chromosomes isolated directly from focal wildcat species, and (3) screening Y chromosome conserved anchored tagged sequences primers in Felidae species. Forty-one male-specific microsatellites were identified, but only 6 were single-copy loci, consistent with the repetitive nature of the Y chromosome. Nucleotide diversity (p) of Y-linked intron sequences (2.1 kbp) was in the range of 0 (tiger) to 9.95 � 10 � 4 (marbled cat), and the number of SNPs ranged from none in the tiger to 7 in the Asian leopard cat. The Y haplotyping system described here, consisting of 4 introns (SMCY3, SMCY7, UTY11, and DBY7) and 1 polymorphic microsatellite (SMCY-STR), represents the first available markers for tracking intraspecific male lineage polymorphisms in Felidae species and promises to provide significant insights to evolutionary and population genetic studies of the species.