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PubMed2004

Development of a homology model for clade A human immunodeficiency virus type 1 gp120 to localize temporal substitutions arising in recently infected women.

The virus population transmitted by a human immunodeficiency virus type 1 (HIV-1) infected individual undergoes restriction and subsequent diversification in the new host. However, in contrast to men, who have limited virus diversity at seroconversion, there is measurable diversity in viral envelope gene sequences in women infected with clade A HIV-1. In this study, virus sequence diversity in three unrelated, clade A infected women preceding and shortly after seroconversion was evaluated. It was demonstrated that there is measurable evolution of envelope gene sequences over this time interval. Furthermore, in each of the three individuals, amino acid substitutions arose at five or six positions in sequences derived at or shortly after seroconversion relative to sequences obtained from the seronegative sample. Presented here is a model of clade A gp120 to determine the location of substitutions that appeared as the virus population became established in three clade A HIV-1 infected women.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Molecular characterization of the segment 2 gene of epizootic hemorrhagic disease virus serotype 2: gene sequence and genetic diversity.

The complete nucleotide sequence of the gene encoding the major outer capsid protein VP2 from the Alberta isolate of epizootic hemorrhagic disease virus serotype 2 (EHDV-2) was determined. Complementary DNA (cDNA) corresponding to segment 2 was 3002 nucleotides in length with a single open reading frame that encoded a VP2 of 982 amino acids. Although the VP2 from EHDV-2 was only 34% homologous to the cognate protein from EHDV-1, their predicted hydropathic profiles were similar, suggesting that conservation of structure is important biologically to these capsid proteins. Sequence analysis of six North American EHDV-2 field isolates showed a high degree of comparative genetic identity (> 97%). Phylogenetic profiles constructed suggest that regionalization of the viruses within the North American continent has contributed to the genetic diversity.

Amino Acid Sequence↗
PubMed2005

Serological and molecular diversity in the cattle MHC class I region.

Information on major histocompatibility complex (MHC) diversity in cattle is important to aid our understanding of immune responses and may contribute to maintenance of healthy cattle populations. Equally, understanding the mechanisms involved in generating this diversity may shed light on the complex nature of mammalian MHC evolution. The aim of this study was to assess molecular and serological variation within cattle MHC class I molecules and to study the mechanisms generating diversity. To address this aim, sequence variation was examined in 12 serologically assigned alleles from three putative loci and correlated with monoclonal antibody (mAb) binding data. The results demonstrate that both alloantisera and mAbs often fail to distinguish gene products that differ by a significant number of amino acids. Conversely, some mAbs could distinguish alleles differing by only one or two amino acids. Examination of the sequences demonstrates sharing of motifs between alleles, some encoded at distinct loci, supporting the occurrence of interlocus recombination within the cattle MHC class I region. The implications of this for MHC sequence diversity, and functional capability, are discussed.

Amino Acid Sequence↗
PubMed2002

Orthologs of the vaccinia A13L and A36R virion membrane protein genes display diversity in species of the genus Orthopoxvirus.

Alignment of vaccinia and variola virus genomes has highlighted some targets that display diversity. We have investigated the sequence diversity of two viral membrane protein genes from 36 different orthopoxvirus (OPV) strains to evaluate the suitability of these loci to differentiate between OPV species. Orthologs of the vaccinia virus Copenhagen A13L gene were all predicted to have functional genes that ranged between 201-213 bps in length. Whereas the N- and C-termini of each protein were relatively well conserved within the genus, a central proline-rich domain displayed characteristic species-specific amino acid motifs. Orthologs of the A36R gene displayed considerable sequence variation between species and strains. The majority of variation was localised to the last 100 bps of the gene. Multiple-alignment of these sequences identified the presence of gaps, insertions or frame-shift mutations among the samples examined. Nearly all strains of cowpox virus contained different nucleotide sequences at this locus. Phylogenetic analysis of the aligned sequences showed that variola and camelpox viruses shared a common ancestry with cowpox virus, whereas ectromelia viruses were divergent from all the other OPVs examined. Phylogeny generated with A13L sequences distributed the OPV species in a manner that correlated to their known properties.

Acinonyx↗
PubMed2003

Relative roles of mutation and recombination in generating allelic polymorphism at an MHC class II locus in Peromyscus maniculatus.

The MHC class II loci encoding cell surface antigens exhibit extremely high allelic polymorphism. There is considerable uncertainty in the literature over the relative roles of recombination and de novo mutation in generating this diversity. We studied class II sequence diversity and allelic polymorphism in two populations of Peromyscus maniculatus, which are among the most widespread and abundant mammals of North America. We find that intragenic recombination (or gene conversion) has been the predominant mode for the generation of allelic polymorphism in this species, with the amount of population recombination per base pair exceeding mutation by at least an order of magnitude during the history of the sample. Despite this, patchwork motifs of sites with high linkage disequilibrium are observed. This does not appear to be consistent with the much larger amount of recombination versus mutation in the history of the sample, unless the recombination rate is highly non-uniform over the sequence or selection maintains certain sites in linkage disequilibrium. We conclude that selection is most likely to be responsible for preserving sequence motifs in the presence of abundant recombination.

Alleles↗
PubMed2004

Quality of alignment comparison by COMPASS improves with inclusion of diverse confident homologs.

MOTIVATION: Adding more distant homologs to a multiple alignment and thus increasing its diversity may eventually deteriorate the numerical profile constructed from this alignment. Here, we addressed the question whether such a diversity limit can be reached in the alignments of confident homologs found by PSI-BLAST, and we analyzed the dependence of the quality of the profile-profile comparison made by COMPASS on the sequence diversity within these alignments. RESULTS: Protein families that have a greater number of diverse confident homologs in the current sequence databases provide an increased quality of similarity detection in profile databases, but produce on average less accurate profile-profile alignments with their remote relatives. This lower alignment accuracy cannot be improved when the most distant members of these families are excluded from their profiles. On the contrary, the presence of more diverse members results in more accurate alignments. For families with a high diversity of confident homologs, the lower quality of profile alignments with their remote relatives seems to be an attribute of these families or their alignments, rather than to be caused by the large number of diverse sequences itself. Our results suggest that at any level of profile diversity, one should include in the multiple alignment as many confident sequence homologs as possible in order to produce the most accurate results.

Algorithms↗
PubMed1999

CRAWview: for viewing splicing variation, gene families, and polymorphism in clusters of ESTs and full-length sequences.

MOTIVATION: DNA sequence clustering has become a valuable method in support of gene discovery and gene expression analysis. Our interest lies in leveraging the sequence diversity within clusters of expressed sequence tags (ESTs) to model gene structure for the study of gene variants that arise from, among other things, alternative mRNA splicing, polymorphism, and divergence after gene duplication, fusion, and translocation events. In previous work, CRAW was developed to discover gene variants from assembled clusters of ESTs. Most importantly, novel gene features (the differing units between gene variants, for example alternative exons, polymorphisms, transposable elements, etc.) that are specialized to tissue, disease, population, or developmental states can be identified when these tools collate DNA source information with gene variant discrimination. While the goal is complete automation of novel feature and gene variant detection, current methods are far from perfect and hence the development of effective tools for visualization and exploratory data analysis are of paramount importance in the process of sifting through candidate genes and validating targets. RESULTS: We present CRAWview, a Java based visualization extension to CRAW. Features that vary between gene forms are displayed using an automatically generated color coded index. The reporting format of CRAWview gives a brief, high level summary report to display overlap and divergence within clusters of sequences as well as the ability to 'drill down' and see detailed information concerning regions of interest. Additionally, the alignment viewing and editing capabilities of CRAWview make it possible to interactively correct frame-shifts and otherwise edit cluster assemblies. We have implemented CRAWview as a Java application across windows NT/95 and UNIX platforms. AVAILABILITY: A beta version of CRAWview will be freely available to academic users from Pangea Systems (http://www.pangeasystems.com). Contact :

Alternative Splicing↗
PubMed2005

Ancient differentiation of the H and I haplomes in diploid Hordeum species based on 5S rDNA.

5S rDNA clones from 12 South American diploid Hordeum species containing the HH genome and 3 Eurasian diploid Hordeum species containing the II genome, including the cultivated barley Hordeum vulgare, were sequenced and their sequence diversity was analyzed. The 374 sequenced clones were assigned to "unit classes", which were further assigned to haplomes. Each haplome contained 2 unit classes. The naming of the unit classes reflected the haplomes, viz. both the long H1 and short I1 unit classes were identified with II genome diploids, and both the long H2 and long Y2 unit classes were recognized in South American HH genome diploids. Based upon an alignment of all sequences or alignments of representative sequences, we tested several evolutionary models, and then subjected the parameters of the models to a series of maximum likelihood (ML) analyses and various tests, including the molecular clock, and to a Bayesian evolutionary inference analysis using Markov chain Monte Carlo (MCMC). The best fitting model of nucleotide substitution was the HKY+G (Hasegawa, Kishino, Yano 1985 model with the Gamma distribution rates of nucleotide substitutions). Results from both ML and MCMC imply that the long H1 and short I unit classes found in the II genome diploids diverged from each other at the same rate as the long H2 and long Y2 unit classes found in the HH genome diploids. The divergence among the unit classes, estimated to be circa 7 million years, suggests that the genus Hordeum may be a paleopolyploid.

DNA, Plant↗
PubMed1991

Heavy chain variable region gene families evolved early in phylogeny. Ig complexity in fish.

The V regions of channel catfish H chain cDNA clones have been analyzed. Based upon sequence relationships and hybridization analyses, five different groups of VH genes are identified whose definition is consistent with that of five different VH families. Genomic Southern blots indicate that as many as 100 different germ-line VH genes are likely represented by these families. The sequence diversity between identified members of these different families is similar in magnitude to the divergence represented between members of different human or mouse VH families. The FR regions are the most conserved regions when members of different catfish VH families are compared; specific amino acid positions appear to be highly conserved in phylogeny. Equally important is that diversity is represented in complementarity-determining regions CDR1 and CDR2 in members of the different families as well as in members of the same VH family. These results suggest that an extensive repertoire of VH genes can contribute to antibody diversity in this lower vertebrate. Sequence comparisons indicate that one of the catfish VH families shares considerable structural similarity to several higher vertebrate VH gene families--a relationship which suggests that this VH family may be ancestral to some VH gene families of higher vertebrates. Characteristic of the genomic organization of higher vertebrate H chains, catfish appear to have different VH families wherein a VH gene likely undergoes functional recombination with putative DH gene segments and one of apparently several different JH segments. The recombined V region is expressed with the same C region gene. These combined results suggest that bony fishes are the earliest known phylogenetic representatives to have evolved extensive V region gene families.

Animals↗
PubMed1997

Mechanisms for variability in a member of the scavenger-receptor cysteine-rich superfamily.

This study reports a molecular analysis of pig WC1, a new member of the scavenger-receptor cysteine-rich (SRCR) superfamily. The pig WC1 contains up to six extra-cellular SRCR domains, highly homologous to other members of the family. However, the striking feature of the WC1 gene, as for its cattle and sheep homologues, is that it is present as a multigene family showing extensive sequence diversity, for both DNA and predicted protein sequence. The basis of this diversity was examined and was shown to be attributable to several different causes. These included single base-pair changes within SRCR domains, the optional usage of whole domains or exons, including a SRCR domain and the proximal "hinge" region, and alternative isoforms of the putative cytoplasmic tail. These results suggest that WC1 may code for a new, though more primitive type of antigen recognition structure specific for gamma/delta T cells.

Amino Acid Sequence↗
PubMed2004

Nitrous oxide reductase (nosZ) gene fragments differ between native and cultivated Michigan soils.

The effect of standard agricultural management on the genetic heterogeneity of nitrous oxide reductase (nosZ) fragments from denitrifying prokaryotes in native and cultivated soil was explored. Thirty-six soil cores were composited from each of the two soil management conditions. nosZ gene fragments were amplified from triplicate samples, and PCR products were cloned and screened by restriction fragment length polymorphism (RFLP). The total nosZ RFLP profiles increased in similarity with soil sample size until triplicate 3-g samples produced visually identical RFLP profiles for each treatment. Large differences in total nosZ profiles were observed between the native and cultivated soils. The fragments representing major groups of clones encountered at least twice and four randomly selected clones with unique RFLP patterns were sequenced to verify nosZ identity. The sequence diversity of nosZ clones from the cultivated field was higher, and only eight patterns were found in clone libraries from both soils among the 182 distinct nosZ RFLP patterns identified from the two soils. A group of clones that comprised 32% of all clones dominated the gene library of native soil, whereas many minor groups were observed in the gene library of cultivated soil. The 95% confidence intervals of the Chao1 nonparametric richness estimator for nosZ RFLP data did not overlap, indicating that the levels of species richness are significantly different in the two soils, the cultivated soil having higher diversity. Phylogenetic analysis of deduced amino acid sequences grouped the majority of nosZ clones into an interleaved Michigan soil cluster whose cultured members are alpha-Proteobacteria. Only four nosZ sequences from cultivated soil and one from the native soil were related to sequences found in gamma-Proteobacteria. Sequences from the native field formed a distinct, closely related cluster (D(mean) = 0.16) containing 91.6% of the native clones. Clones from the cultivated field were more distantly related to each other (D(mean) = 0.26), and 65% were found outside of the cluster from the native soil, further indicating a difference in the two communities. Overall, there appears to be a relationship between use and richness, diversity, and the phylogenetic position of nosZ sequences, indicating that agricultural use of soil caused a shift to a more diverse denitrifying community.

Agriculture↗
PubMedDate not supplied

Molecular genetics of anti-carbohydrate antibodies.

Antibodies directed against carbohydrate determinants provide useful model systems for understanding the structure and organisation of antibody genes and the generation of antibody diversity. We have used three such systems, PC, DEX and GAC, and have studied the heavy chains and VH gene segments of each. In two of these systems, PC and GAC, much of the diversity in heavy-chain protein sequences results from somatic mutation events superimposed on expression of a single VH gene. In the DEX system, it appears that germ-line sequence diversity may be an important contributor to the variability in heavy-chain sequence. Detailed structural analyses of this type will ultimately provide a complete picture of the mechanisms which underlie effective humoral immunity.

Animals↗
PubMed1998

Intervening sequences in 16S rRNA genes of Campylobacter sp.: diversity of nucleotide sequences and uniformity of location.

We found and sequenced intervening sequences (IVSs) in the PCR-amplicons of 16S rRNA genes of 3 strains of Campylobacter rectus, 2 strains of C. curvus and 2 strains of C. sputorum. The lengths of the IVSs were 140 to 233 bp. The IVSs of C. rectus were identical and had a sequence homology of 55 to 79% against those of C. curvus and C. helveticus. The IVSs of C. sputorum were 97.9-100% homologous but poorly homologous to the other IVSs. In spite of the diversities of the lengths and the nucleotide sequences, all of the IVSs were located at the same position in the 16S rRNA genes.

Base Sequence↗
PubMed1998

DNA sequence conservation and diversity in transposable element IS605 of Helicobacter pylori.

BACKGROUND: IS605, a transposable element-like sequence identified in the virulence-associated cag region of Helicobacter pylori reference strain NCTC11638, is unusual in containing two oppositely-oriented open reading frames whose products are homologues of the single transposases of the unrelated elements, IS200 and IS1341. METHODS: One hundred independent H. pylori isolates from different parts of the world were screened by PCR and dot blot hybridization to determine the presence of IS605. For some positive isolates, southern hybridizations and sequence analyses were done. RESULTS: Of the 100 isolates, 31 were found to contain sequences related to each ORF with orientation and spacing matching those in canonical IS605-hybridizing sequences. No isolate containing just one ORF and not the other was found. The frequencies of IS605 carriage were independent of geographical origin (U.S. vs. non-U.S.), and of the probable virulence of the isolate (cag status, toxin production or vacA alleles, patient symptoms). Southern blot hybridization of six IS605-containing strains revealed one to nine IS605 copies per genome. Two types of DNA sequence diversity were found: first, a specific 100 bp deletion in two isolates; second, base substitution divergence of 0.4% to 7.5% in pairwise comparisons among the eight isolates characterized, a level of divergence similar to that seen in other H. pylori chromosomal genes. CONCLUSIONS: Based on these findings, we speculate that IS605 is a relatively ancient component of the H. pylori gene pool that has proliferated in this species by horizontal gene transfer, homologous recombination, and transposition.

Base Sequence↗
PubMed1997

Abbreviated junctional sequences impoverish antibody diversity in urodele amphibians.

Of the six complementarity-determining regions (CDR) forming the structure of the Ab combining site, CDR3 of heavy chain is the most variable in length and sequence. Diversity of this loop is determined by the number of gene segments involved, extent of addition to or deletion from the joining genes, and imprecision of the site of recombination. In neonatal mice and Xenopus tadpoles, the last two factors occur less frequently than in adults, which in tadpoles result in low affinity Ab responses that do not mature. In contrast, adult urodele amphibians make larval-like responses and are notorious for lifelong poor immunocompetence. The mechanism for this is not known, and in this study we cloned germline VH genes from the axolotl and obtained rearrangements to these VH gene segments by reverse-transcriptase PCR. These sequences were analyzed for heavy chain junctional diversity and found to be even less variable than that in newborn mouse or Xenopus tadpoles, although for different reasons. Only 29% of the CDR3 loop in the axolotl consisted of somatically generated sequences, compared with 44% in tadpole, 39% in newborn mice, and 57% in both adult mice and Xenopus. This distinguishing feature of axolotl CDR3 results not only from shorter junctional sequences, but also unusually extensive integration of germline JH sequence. As the CDR3 loop is the most important portion of the Ig sequence for determining Ab combining site diversity, our data provide the molecular basis for a contributing factor in the deficient urodele amphibian Ab responses.

Aging↗
PubMed2004

The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.

While there is considerable appeal to the idea of selecting a few SNPs to represent all, or much, of the DNA sequence variability in a local chromosomal region, it is also important to quantify what detail is lost in adopting such an approach. To address this issue, we compared high- and low-resolution depictions of sequence diversity for the same genomic region, the APOA1/C3/A4/A5 gene cluster on chromosome 11. First, extensive re-sequencing identified all nucleotide and sequence haplotype variation of the linked apolipoprotein genes in 72 individuals from three populations: African-Americans from Jackson, Miss., Europeans from North Karelia, Finland, and European-Americans from Rochester, Minn. We identified 124 SNPs in 17.7 kb and significant differences in variation among genes. APOC3 gene diversity was particularly distinctive at high resolution, showing large allele frequency differences ( F(ST) values >0.250) between Jackson and the other two samples, and divergent population-specific haplotype lineages. Next, we selected haplotype-tagging SNPs (htSNPs) for each gene, at a density of approximately one SNP per kb, using an algorithm suggested by Stram et al. (2003). The 17 htSNPs identified were then used to reconstruct low-resolution haplotypes, from which inferences about the structure of variation were also drawn. This comparison showed that while the htSNPs successfully tagged common haplotype variation, they also left much underlying sequence diversity undetected and failed, in some cases, to co-classify groups of closely related haplotypes. The implications of these findings for other haplotype-based descriptions of human variation are discussed.

Apolipoprotein C-III↗
PubMed1995

LTR-retrotransposons and MITEs: important players in the evolution of plant genomes.

Retrotransposons are an abundant and ancient component of plant genomes, yet recent evidence indicates that element activity in many modern plants is restricted to times of stress. Stress activation of plant retrotransposons may be a significant factor in somaclonal variation, in addition to providing an important means to isolate new active elements. Long terminal repeat retrotransposons and a second class of elements we have called miniature inverted-repeat transposable elements (MITEs) have recently been found to be associated with the genes of diverse plants where some contribute regulatory sequences. Because of their sequence diversity and small size, MITEs may be a valuable evolutionary tool for altering patterns of gene expression.

Animals↗
PubMed1990

Use of oligonucleotide probes directed against T cell antigen receptor gamma delta variable-(diversity)-joining junctional sequences as a general method for detecting minimal residual disease in acute lymphoblastic leukemias.

To provide a sensitive and generally applicable method to detect clonal cells in acute lymphoblastic leukemias (ALL), we have designed a new strategy based on the polymerase chain reaction (PCR) amplification of the T cell receptor gamma delta gene rearrangements found in most T and B lineage ALLs. PCR allows rapid sequencing of variable-(diversity)-joining (V-[D]-J) junctions from tumor DNA and construction of anti-junctional oligonucleotides (AJOs) used as probes to detect clonal cells in the same patient. We have defined oligonucleotides suitable for all T cell receptor (TCR) rearrangements involving functional V gamma segments. Oligonucleotides corresponding to preferential TCR delta rearrangements in T and B lineage ALLs were also used. By analysis of the nucleotide sequence of 52 V gamma-V gamma junctions from 30 cases of B and T ALLs, we demonstrate that V-J junctional sequences are clone specific in both lineages and at all stages of differentiation examined despite the frequent presence of the recently described P nucleotides. Experiments performed with TCR gamma delta AJOs on DNA from tumor cells and polyclonal T cells show that AJOs can be used to differentiate clonal cells from polyclonal T cells, distinguish between different T cell clones, and detect residual clonal populations at 10(-4)/10(-5) dilution. AJOs were also used to detect residual disease in samples from patients in clinical and morphological complete remission. Finally, rearrangement patterns were studied by classical Southern analysis in selected cases at both presentation and subsequent relapse showing absence of clonal evolution in most cases. V-(D)-J nucleotide sequences of rearrangements with an identical pattern of rearrangement at presentation and relapse were identical in all cases analyzed. We therefore describe a new, specific, and clinically useful strategy for the detection of minor clonal populations applicable in the majority of cases of ALL.

Alleles↗