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PubMed2003

Induction of hepatic injury by hepatitis C virus-specific CD8+ murine cytotoxic T lymphocytes in transgenic mice expressing the viral structural genes.

In the present study, we generated killer cells specific for hepatitis C virus (HCV) structural protein by re-stimulation of immune spleen cells from H-2(d) haplotype transgenic (Tg) mice, expressing the core, E1, E2, and NS2 genes of HCV regulated by the Cre/loxP switching system. The generated killer cells were conventional CD8(+)L(d) class-I MHC molecule-restricted cytotoxic T lymphocytes (CTLs) and specific for the HCV E1 structural protein. Because the CTLs could also kill hepatocytes from the Tg mice expressing HCV structural proteins in vitro, we attempted to transfer those CTLs intravenously into interferon regulatory factor-1 (IRF-1) negative, CD8-deficient Tg mice representing the HCV structural genes on hepatocytes to examine whether the inoculated CD8(+) CTLs can eliminate hepatocytes expressing the HCV genes in vivo. We observed an elevation of serum ALT level as well as damage of the liver tissue histologically. To our knowledge, this is the first demonstration to show that HCV-specific CD8(+) CTLs specifically attack hepatocytes expressing the HCV structural proteins both in vitro and in vivo.

Adenoviridae↗
PubMed2004

Phylogenetic structure of Zacco platypus (Teleostei, Cyprinidae) populations on the upper and middle Chang Jiang (=Yangtze) drainage inferred from cytochrome b sequences.

We examined the genetic structure and phylogenetic relationships of some Chinese populations from the Chang Jiang (=Yangtze) drainage of the cyprinid Zacco platypus. We sequenced the complete mitochondrial cytochrome b gene of 64 individuals from 6 upper and middle tributaries of the Sichuan and Hunan Provinces to assess their population structure and systematics. The combined analyses of the phylogenetic information and the population structure suggested that Chinese Z. platypus consist of four distinct mtDNA lineages which exhibit high genetic variation and haplotypic diversity (Zacco A-D). The high molecular divergence observed among Zacco A-D mtDNA lineages (TrN+I (0.76) distance, mean 8.9%+/-1.7%) and their phylogeographic structure indicate that all four lineages have evolved independently. Analysis of molecular variance (AMOVA) indicates that most of the genetic variation observed is found among the four Zacco mtDNA lineages (thetaCT = 0.94) suggesting restricted gene flow among the Chang Jiang populations. Long-term interruption of gene flow was also evidenced by thetaST values higher than 0.9 that could be favoured by the discontinuous distributions of the lineages inhabiting upper (Sichuan Province) and middle (Hunan Province) Chang Jiang tributaries. The significant correlation between the geographic and genetic distances provide support for the importance of geographic discontinuity in shaping the Zacco genetic structure. Nested clade analysis (NCA) results were congruent with phylogenetic relationships recovered and confirm the genetic distinctiveness of four independent Zacco groups. These four groups correspond to the four Zacco A-D mtDNA lineages recovered in the phylogeny and were defined by nucleotide synapomorphies permitting bootstrapped and Bayesian confidence of 95% or greater. The high level of mitochondrial sequence divergence separating all Zacco mtDNA lineages suggested that the Z. platypus populations from the Chang Jiang drainage probably correspond to four different species.

Animals↗
PubMed1979

Structural studies on the murine Ia alloantigens. VI. Evidence that both subunits of the I-A alloantigen are encoded by the I-A subregion.

The alpha and beta subunits of the murine I-A alloantigens from several H-2 haplotypes were examined by comparative tryptic peptide mapping by using double label (3H and 14C) techniques. Significant structural variation between alleles was detected in both subunits. Tryptic digests of the alpha polypeptides from s, b, and d showed only 65% co-elution with k; beta-chains from s, b, d, and r were about 50% similar to the k beta subunit. Peptide analysis of the Ak subunits from intra-H-2 recombinant strains indicated that both the alpha and beta polypeptides are encoded within the I-A subregion.

Animals↗
PubMed2006

Population structure between environmentally transmitted vibrios and bobtail squids using nested clade analysis.

Squids from the genus Euprymna (Cephalopoda: Sepiolidae) and their symbiotic bacteria Vibrio fischeri form a mutualism in which vibrios inhabit a complex light organ within the squid host. A host-mediated daily expulsion event seeds surrounding seawater with symbiotically capable V. fischeri that environmentally colonize newly hatched axenic Euprymna juveniles. Competition experiments using native and non-native Vibrio have shown that this expulsion/re-colonization phenomenon has led to cospeciation in this system in the Pacific Ocean; however, the genetic architecture of these symbiotic populations has not been determined. Using genetic diversity and nested clade analyses we have examined the variation and history of three allopatric Euprymna squid species (E. scolopes of Hawaii, E. hyllebergi of Thailand, and E. tasmanica from Australia) and their respective Vibrio symbionts. Euprymna populations appear to be very genetically distinct from each other, exhibiting little or no migration over large geographical distances. In contrast, Vibrio symbiont populations contain more diverse haplotypes, suggesting both host presence and unidentified factors facilitating long-distance migration structure in Pacific Vibrio populations. Findings from this study highlight the importance of how interactions between symbiotic organisms can unexpectedly shape population structure in phylogeographical studies.

Animals↗
PubMed2001

Primary structure of alpha-globin chains from river buffalo (Bubalus bubalis L.) hemoglobins.

Primary structure analysis of the four river buffalo alpha-globin chains showed that haplotypes A and B differ from each other by a substitution at codon 64 that may encode Ala or Asn. The A haplotype encodes two alpha-globin chains, Ialpha1 and IIalpha3, which differ at positions 129 and 131: Ialpha1 has 64 Ala, 129 Phe, 131 Asn; IIalpha3 has 64 Ala, 129 Leu, 131 Ser. The B haplotype encodes two alpha-globin chains, Ialpha2 and IIalpha4, which differ at positions 10 and 11: Ialpha2 has 10 I1e, 11 Gln, 64 Asn; IIalpha4 has 10 Val, 11 Lys, 64 Asn. Apart from the Ala/Asn polymorphism at position 64, amino acid substitutions in allelic and nonallelic alpha-globin chains seem to have arisen by single point mutations. Detection of electrophoretically silent mutations due to neutral amino acid substitutions and their influence on the isoelectric point are discussed. Furthermore, primary structures of river buffalo alpha-globin chains are compared to other species of the Bovidae family to suggest evolutionary events that have characterized the amino acid substitutions of river buffalo hemoglobin.

Amino Acid Sequence↗
PubMed1989

Two genetic elements regulate murine beta-glucuronidase synthesis following transcript accumulation.

Mutant alleles of two genetic regulatory elements, which underlie a three- to sixfold reduction in beta-glucuronidase (GUS) activity levels, distinguish mice of the H haplotype from those of the other two common GUS haplotypes, A and B. Both elements are tightly linked to the GUS structural gene over which they exert control. One (Gus-u) exerts a cis-active effect upon GUS activity levels in all tissues at all times while the other (Gus-t) regulates GUS activity in trans after the 12th postnatal day in certain tissues. While previous studies show that differences in the rate of GUS synthesis account for the combined effects of these two elements in liver of adult mice, we demonstrate the separate effects of each on GUS synthesis at times during early postnatal development when their individual expressions can be distinguished. Assessments of the relative levels of S1 nuclease protection of a radiolabeled GUS antisense RNA probe after hybridization with total liver RNA preparations from adult mice of A and H haplotypes reveal no differences. These results argue that Gus-u and Gus-t exert their control of GUS expression subsequent to the accumulation of processed GUS transcripts.

Animals↗
PubMed2006

Vicariance and dispersal effects on phylogeographic structure and speciation in a widespread estuarine invertebrate.

Vicariance and dispersal can strongly influence population genetic structure and allopatric speciation, but their importance in the origin of marine biodiversity is unresolved. In transitional estuarine environments, habitat discreteness and dispersal barriers could enhance divergence and provide insight to evolutionary mechanisms underlying marine and freshwater biodiversity. We examined this by assessing phylogeographic structure in the widespread amphipod Gammarus tigrinus across 13 estuaries spanning its northwest Atlantic range from Quebec to Florida. Mitochondrial cytochrome c oxidase I and nuclear internal transcribed spacer 1 phylogenies supported deep genetic structure consistent with Pliocene separation and cryptic northern and southern species. This break occurred across the Virginian-Carolinian coastal biogeographic zone, where an oceanographic discontinuity may restrict gene flow. Ten estuarine populations of the northern species occurred in four distinct clades, supportive of Pleistocene separation. Glaciation effects on genetic structure of estuarine populations are largely unknown, but analysis of molecular variance (AMOVA) supported a phylogeographic break among clades in formerly glaciated versus nonglaciated areas across Cape Cod, Massachusetts. This finding was concordant with patterns in other coastal species, though there was no significant relationship between latitude and genetic diversity. This supports Pleistocene vicariance events and divergence of clades in different northern glacial refugia. AMOVA results and private haplotypes in most populations support an allopatric distribution across estuaries. Clade mixture zones are consistent with historical colonization and human-mediated transfer. An isolation-by-distance model of divergence was detected after we excluded a suspected invasive haplotype in the St. Lawrence estuary. The occurrence of cryptic species and divergent population structure support limited dispersal, dispersed habitat distribution, and historical factors as important determinants of estuarine speciation and diversification.

Amphipoda↗
PubMed2003

American marten (Martes americana) in the Pacific Northwest: population differentiation across a landscape fragmented in time and space.

American marten (Martes americana) have a close association with mature temperate forests, a habitat that expanded throughout the Pacific Northwest as glaciers receded at the end of the Pleistocene. Similar to several other forest-associated mammals in North America (e.g. black bear), genetic analysis of the marten shows a deep phylogeographical subdivision that reflects populations with distinctive evolutionary histories. Using a suite of 14 microsatellite markers, we explored the genetic structure of marten populations in two reciprocally monophyletic clades in the Pacific Northwest identified previously as M. caurina and M. americana by mitochondrial haplotypes and morphology. Microsatellite phylogeographical patterns were congruent with mitochondrial analyses. These independent data sets shed light upon hybridization patterns, population structure and evolutionary histories. Hybridization between M. caurina and M. americana individuals was documented in two regions of sympatry (Kuiu Island in southeastern Alaska and southern Montana). Northern insular populations of M. caurina exhibited higher differentiation and lower variability relative to northern populations of M. americana. Greater divergence among M. caurina populations may reflect longer isolation and persistence in coastal forest habitat that was fragmented by rising sea level in the early Holocene. Lower differentiation among northern M. americana populations and close relationship to other continental M. americana populations may reflect more recent expansion into the Pacific Northwest and/or continued gene flow among populations. Differentiation among M. caurina populations was attributed to habitat fragmentation (i.e. rising sea level), as opposed to isolation-by-distance; oceanic straits pose significant barriers to gene flow among M. caurina populations and between populations of M. caurina and M. americana.

Animal Population Groups↗
PubMed1989

BstEII restriction fragment alleles and haplotypes of the human IGHG genes with reference to the BamHI/SacI RFLPs and to the Gm polymorphism.

In previous studies, we have described, for each of the five human immunoglobulin IGHG (C gamma) genes, BamHI, SacI and BamHI/SacI allelic restriction fragments. Further, we have determined BS (BamHI/SacI) linkage groups of alleles for the whole of the IGHG loci and we have demonstrated correlation with the Gm alleles and haplotypes. In this paper we characterize more precisely the polymorphism of the IGHG genes and, consequently, the structure and evolution of this multigene family, using the restriction enzyme BstEII and two different probes, a IGHG (C gamma) probe and a G3 (C gamma 3) specific probe. Alleles and haplotypes of the BstEII restriction fragments have been defined with reference to the BS alleles and haplotypes. New RFLPs of the IGHG genes are described and unambiguous correlations have been established with most of the Gm alleles and haplotypes. Thus, the IGHG gene RFLPs strengthen the Gm polymorphisms as powerful tools for the characterization of populations, disease and genetic marker linkage analyses, forensic medicine and evolution of these IGHG genes.

Alleles↗
PubMed1999

Mutation screening of phenylketonuria in the Far East of Russia.

We analyzed mutant genotypes at the human phenylalanine hydroxylase (PAH) locus among phenylketonuria (PKU) patients in the Far East of Russia. A total of 60 variant alleles from 30 PKU families were analyzed for prevalent Caucasian mutations and restriction fragment length polymorphism/variable number of tandem repeats (RFLP/VNTR) haplotypes. Seventy-eight percent of all variant alleles carried six mutations. The most prevalent mutation was R408W (63%), with a haplotype background of 2.3. It also showed a very high degree of homozygosity (43%). The other five mutations (R158Q, R261Q, R252W, R261X, and IVS12nt-1) accounted for 1.7%-6.7% of all PKU alleles, and a single haplotype was associated with each genotype, except for R261Q. The genetic structure of PKU patients in the Far East of Russia seems to be relatively homogeneous, compared with that in the other Slavic and Oriental populations of surrounding countries. Prediction of a clinical phenotype and carrier detection will be feasible using DNA tests.

Child↗
PubMed2005

The 'involution' of mannose-binding lectin.

Mannose-binding lectin (MBL) acts as a serum opsonin in innate immune defense and induces complement activation by the lectin pathway. In humans, low levels of functional serum MBL are caused by the dominant action of three single nucleotide substitutions in exon 1 that disrupt the glycine-rich backbone structure of the protein. The presence of common MBL variant alleles is associated with both infectious and autoimmune diseases. Conversely, it has also been suggested that MBL variants are maintained because of selective advantages for the host. In man, the MBL genetic system comprises one functional gene (MBL2) and one expressed pseudogene (MBL1P1), whereas the lower primate, the rhesus monkey resembles rodents with two functional MBL genes. We have investigated the molecular mechanisms behind the evolutionary loss of MBL expression from lower primates to man, including silencing of the MBL1P1 gene and the generation of MBL2 variant structural alleles and promoter polymorphisms leading to the present human MBL2 haplotypes. We present data showing that the MBL1P1 gene has been repeatedly hit throughout evolution and silenced eventually by mutations in the glycine residues of the collagen-like region. Our results indicate that the MBL1P1 gene has been selectively turned off during evolution through the same molecular mechanisms causing the MBL2 variant alleles in man, suggesting an evolutionary selection for low-producing MBL genes.

Alleles↗
PubMed1995

Intraspecific phylogeography of the gopher tortoise, Gopherus polyphemus: RFLP analysis of amplified mtDNA segments.

The slow rate of mtDNA evolution in turtles poses a limitation on the levels of intraspecific variation detectable by conventional restriction fragment surveys. We examined mtDNA variation in the gopher tortoise (Gopherus polyphemus) using an alternative restriction assay, one in which PCR-amplified segments of the mitochondrial genome were digested with tetranucleotide-site endonucleases. Restriction fragment polymorphisms representing four amplified regions were analysed to evaluate population genetic structure among 112 tortoises throughout the species' range. Thirty-six haplotypes were identified, and three major geographical assemblages (Eastern, Western, and Mid-Florida) were resolved by UPGMA and parsimony analyses. Eastern and Western assemblages abut near the Apalachicola drainage, whereas the Mid-Florida assemblage appears restricted to the Brooksville Ridge. The Eastern/Western assemblage boundary is remarkably congruent with phylogeographic profiles for eight additional species from the south-eastern U.S., representing both freshwater and terrestrial realms.

Animals↗
PubMed1985

Structure and polymorphism of murine and human class II major histocompatibility antigens.

The molecular analysis of the Class II region of the MHC of mice and of humans has to date led to some important conclusions. These regions encode sizeable families of related loci, at least 2 alpha and 6 beta in mice and 6 alpha and 7 beta in man. In addition to the sizeable number of potential molecules that could be expressed by the loci of this region, all the beta chains and both A alpha and DC alpha have extensive amounts of polymorphism. This polymorphism is strikingly similar at Class II loci in mouse and man. The majority of the variability is found in the first domain and consists of discrete regions of variability. These variable regions appear to be important functionally in presenting antigen, as evidenced by the bm12 mutant. The allotypy of these molecules is complex and is presumably generated by a combination of gene conversion and point mutation followed by selection. Final definition of the range of allelic variability and further insights into the mechanism by which it was generated are still to be resolved, as in a complete map of all the Class II loci in both mouse and man. The data available at present pose certain questions that now need to be addressed. The precise functional role of individual regions or residues of the Class II molecules can now be analyzed using the available sequence data and site specific mutagenesis. Fine structural analysis of these molecules is impossible at present using only sequence data, and X-ray crystallography will be required to answer fundamental questions about 3-dimensional structure. Finally, disease-specific sequences may be uncovered on particular haplotypes which permit the production of disease-specific probes. The molecular revelations of the last few years have resolved many questions about the polymorphisms of Class II products, but many new questions need to be resolved before these molecules and their extensive polymorphism can be properly understood.

Animals↗
PubMed2000

Genetic diversity and dynamics of Sinorhizobium meliloti populations nodulating different alfalfa cultivars in Italian soils.

We analyzed the genetic diversity of 531 Sinorhizobium meliloti strains isolated from nodules of Medicago sativa cultivars in two different Italian soils during 4 years of plant growth. The isolates were analyzed for DNA polymorphism with the random amplified polymorphic DNA method. The populations showed a high level of genetic polymorphism distributed throughout all the isolates, with 440 different haplotypes. Analysis of molecular variance allowed us to relate the genetic structure of the symbiotic population to various factors, including soil type, alfalfa cultivar, individual plants within a cultivar, and time. Some of these factors significantly affected the genetic structure of the population, and their relative influence changed with time. At the beginning of the experiment, the soil of origin and, even more, the cultivar significantly influenced the distribution of genetic variability of S. meliloti. After 3 years, the rhizobium population was altered; it showed a genetic structure based mainly on differences among plants, while the effects of soil and cultivar were not significant.

DNA, Bacterial↗
PubMed2005

Cytochrome b polymorphisms and population structure of two species of Alouatta (Primates).

We carried out a phylogenetic and population study in Alouatta caraya and Alouatta belzebul based on cytochrome b DNA sequence data. Maximum Parsimony and Median-Joining analyses grouped A. caraya from different localities showing a population structure in accordance with geographic distribution. The relation between A. caraya haplotypes could be explained with respect to the species range in the Cerrado, one of the most ancient morphoclimatic domains of South America, and the Chaco. Conversely, A. belzebul from the Amazonas and Atlantic forests grouped in a paraphyletic arrangement without an evident geographic pattern. Recent geologic events resulting in the separation of A. belzebul might explain why these geographically distant groups shared similar haplotypes and why ancestral polymorphisms might have been maintained in this species. Time of divergence estimates indicated that the splitting of the Alouatta lineage leading to A. caraya occurred some 4.58 MYA while the lineage leading to A. belzebul emerged 4.14 MYA.

Alouatta↗
PubMed2025

Genetic structuring and estimation of reproductive adults in Onchocerca volvulus: A genome-wide analysis across hosts and regions.

Genomic analysis of parasites can deepen our understanding of their transmission, population structure, and important biological characteristics. Onchocerciasis (river blindness), caused by the parasitic nematode Onchocerca volvulus, involves adult worms residing in subcutaneous nodules that produce larval-stage microfilariae (mf), which are routinely detected in the skin for diagnosis. Whole-genome studies of mf are limited; most analyses have focused on the mitochondrial genome. We conducted a genome-wide analysis with 94% median nuclear genome coverage, analyzing 171, 37, and 98 mf from 16, 3, and 5 individuals from Ghana, Liberia, and the Democratic Republic of Congo, respectively. These data were used to investigate population differentiation, estimate the number of reproductive adult worms, and analyze genetic variation across chromosomes. Population genetic analyses across hosts and countries showed that nuclear genome diversity can reveal fine-scale genetic structure, even between geographically close countries, providing more resolution than mitochondrial haplotype data. By reconstructing maternal and paternal sibships, we estimated the number of reproductively active adult filariae. Comparisons between adult worm estimates from genetic data and nodule observations showed that genetics-based estimates were higher or equal to observed worm counts in 8 out of 9 hosts for female worms and 7 out of 9 hosts for male worms. Our analysis also revealed lower-than-expected X chromosome diversity, consistent with neo-X chromosome fusions in filarial species. This study represents an important step in using nuclear genome data from mf to support onchocerciasis elimination efforts and in developing genetic tools that could inform mass drug administration programs.

Onchocerca volvulus↗
PubMed1988

Hypotheses on the molecular basis of susceptibility to rheumatoid arthritis.

An interpretive summary of recent immunologic and molecular biologic data concerning the molecular basis of susceptibility of rheumatoid arthritis will be presented. The central point of view is taken that the MHC class II molecules encoding disease susceptibility function in a specific immune recognition event. This could involve an antigen "X" that currently eludes characterization or be directed to polymorphic determinants on the MHC molecule itself. The problem of understanding the meaning of the association of susceptibility to rheumatoid arthritis with diverse MHC alleles such as DR4 (Dw4 and Dw14) and DR1 is approached by detailed biochemical analysis that led to the identification of common stretches of amino acid sequence, presumably encoding conformationally equivalent structures. The sequence shared by the otherwise unrelated DR1 and DR4 haplotypes from residue 67 in the DR a chain that appears to confer susceptibility is Leu-X-X-Gln-Arg/Lys. Non-classic MHC polymorphisms related to disease susceptibility but not associated with particular alleles such as identified by Ab109d6 prove especially valuable in suggesting new directions for attempting to understand the significance of these associations. Consideration is given to the possibility that a family of either slightly different or identical conformations encoded in either cis or trans cumulatively confer the liability to develop rheumatoid arthritis. This implies a highly non-classic mode of inheritance. It seems reasonable to consider the pathogenesis of rheumatoid arthritis as evolving from a typical immune response based on a simple immune recognition event directed to a single antigen.

Antigens, Differentiation↗