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PubMed2004

Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations.

Recent studies have suggested that a significant fraction of the human genome is contained in blocks of strong linkage disequilibrium, ranging from ~5 to >100 kb in length, and that within these blocks a few common haplotypes may account for >90% of the observed haplotypes. Furthermore, previous studies have suggested that common haplotypes in candidate genes are generally shared across populations and represent the majority of chromosomes in each population. The conclusions drawn from these preliminary studies, however, are based on an incomplete knowledge of the variation in the regions examined. To bridge this gap in knowledge, we have completely resequenced 100 candidate genes in a population of African descent and one of European descent. Although these genes have been well studied because of their medical importance, we demonstrate that a large amount of sequence variation has not yet been described. We also report that the average number of inferred haplotypes per gene, when complete data is used, is higher than in previous reports and that the number and proportion of all haplotypes represented by common haplotypes per gene is variable. Furthermore, we demonstrate that haplotypes shared between the two populations constitute only a fraction of the total number of haplotypes observed and that these shared haplotypes represent fewer of the African-descent chromosomes than was expected from previous studies. Finally, we show that restricting variation discovery to coding regions does not adequately describe all common haplotypes or the true haplotype block structure observed when all common variation is used to infer haplotypes. These data, derived from complete knowledge of genetic variation in these genes, suggest that the haplotype architecture of candidate genes across the human genome is more complex than previously suggested, with important implications for candidate gene and genomewide association studies.

Africa↗
PubMed1995

Mitochondrial DNA variation in North American oedipodinae.

Restriction fragment analysis of mitochondrial DNA (mtDNA) was used to examine genetic variation and population structure in 13 species of banded-winged grasshoppers (subfamily Oedipodinae). Total DNA of 246 individuals was digested with 11 restriction enzymes and probed with three cloned EcoRI fragments representing the entire mitochondrial genome of Melanoplus sanguinipes. On average, members of this subfamily were five times more variable than those in another subfamily, Melanoplinae, previously examined. This would appear to lend support to Vickery's claim that the time of origin of Nearctic oedipodines is more ancient than that of melanoplines. With respect to population structure, a few different patterns were exhibited. Species such as Camnula pellucida had populations containing a mixture of haplotypes, some widespread and some geographically restricted. In contrast, Chortophaga viridifasciata populations were characterized by unique assemblages of diverse haplotypes. Phylogeographic hypotheses are advanced to account for these observations.

Animals↗
PubMed2005

A locus on chromosome 2 influences levels of tissue factor pathway inhibitor: results from the GAIT study.

OBJECTIVE: Levels of tissue factor pathway inhibitor (TFPI) have been associated with arteriosclerosis and thrombotic disease. Although a genetic component to variation in TFPI levels is well-documented, no systematic genome-wide screens have been conducted to localize genes influencing levels of TFPI. METHODS AND RESULTS: We studied TFPI levels in 397 individuals in 21 Spanish families participating in the Genetic Analysis of Idiopathic Thrombosis (GAIT) study. Twelve families were selected through a proband with idiopathic thrombosis and 9 were ascertained without regard to phenotype. A genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. Standard multipoint variance component linkage methods were used. The heritability of TFPI levels was 0.52 (P<0.0001), with no evidence for shared household effects. In the genome screen, only 1 LOD score >2 was observed. On chromosome 2q, the maximum multipoint LOD score was 3.52 near marker D2S1384. This is near the structural gene for TFPI, which is located at 2q32. In follow-up association analyses, marginal evidence of association (P=0.04) was observed with the TFPI promoter variant C-399T. CONCLUSIONS: These results suggest that polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels.

Adolescent↗
PubMed2004

Haplotype structure and phenotypic associations in the chromosomal regions surrounding two Arabidopsis thaliana flowering time loci.

The feasibility of using linkage disequilbrium (LD) to fine-map loci underlying natural variation in Arabidopsis thaliana was investigated by looking for associations between flowering time and marker polymorphism in the genomic regions containing two candidate genes, FRI and FLC, both of which are known to contribute to natural variation in flowering. A sample of 196 accessions was used, and polymorphism was assessed by sequencing a total of 17 roughly 500-bp fragments. Using a novel Bayesian algorithm based on haplotype similarity, we demonstrate that LD could have been used to fine-map the FRI gene to a roughly 30-kb region and to identify two common loss-of-function alleles. Interestingly, because of genetic heterogeneity, simple single-marker associations would not have been able to map FRI with nearly the same precision. No clear evidence for previously unknown alleles at either locus was found, but the effect of population structure in causing false positives was evident.

Arabidopsis↗
PubMed2004

Sequencing complex diseases With HapMap.

Determining the patterns of DNA sequence variation in the human genome is a useful first step toward identifying the genetic basis of a common disease. A haplotype map (HapMap), aimed at describing these variation patterns across the entire genome, has been recently developed by the International HapMap Consortium. In this article, we present a novel statistical model for directly characterizing specific sequence variants that are responsible for disease risk based on the haplotype structure provided by HapMap. Our model is developed in the maximum-likelihood context, implemented with the EM algorithm. We perform simulation studies to investigate the statistical properties of this disease-sequencing model. A worked example from a human obesity study with 155 patients was used to validate this model. In this example, we found that patients carrying a haplotype constituted by allele Gly16 at codon 16 and allele Gln27 at codon 27 genotyped within the beta2AR candidate gene display significantly lower body mass index than patients carrying the other haplotypes. The implications and extensions of our model are discussed.

Body Mass Index↗
PubMed1998

Structural analysis of the Spiroplasma virus, SpV4: implications for evolutionary variation to obtain host diversity among the Microviridae.

BACKGROUND: Spiroplasma virus, SpV4, is a small, non-enveloped virus that infects the helical mollicute Spiroplasma melliferum. SpV4 exhibits several similarities to the Chlamydia phage, Chp1, and the Coliphages alpha 3, phi K, G4 and phi X174. All of these viruses are members of the Microviridae. These viruses have isometric capsids with T = 1 icosahedral symmetry, cause lytic infections and are the only icosahedral phages that contain single-stranded circular DNA genomes. The aim of this comparative study on these phages was to understand the role of their capsid proteins during host receptor recognition. RESULTS: The three-dimensional structure of SpV4 was determined to 27 A resolution from images of frozen-hydrated particles. Cryo-electron microscopy (cryo-EM) revealed 20, approximately 54 A long, 'mushroom-like' protrusions on the surface of the capsid. Each protrusion comprises a trimeric structure that extends radially along the threefold icosahedral axes of the capsid. A 71 amino acid portion of VP1 (the SpV4 capsid protein) was shown, by structural alignment with the atomic structure of the F capsid protein of phi X174, to represent an insertion sequence between the E and F strands of the eight-stranded antiparallel beta-barrel. Secondary structure prediction of this insertion sequence provided the basis for a probable structural motif, consisting of a six-stranded antiparallel beta sheet connected by small turns. Three such motifs form the rigid stable trimeric structures (mushroom-like protrusions) at the threefold axes, with hydrophobic depressions at their distal surface. CONCLUSIONS: Sequence alignment and structural analysis indicate that distinct genera of the Microviridae might have evolved from a common primordial ancestor, with capsid surface variations, such as the SpV4 protrusions, resulting from gene fusion events that have enabled diverse host ranges. The hydrophobic nature of the cavity at the distal surface of the SpV4 protrusions suggests that this region may function as the receptor-recognition site during host infection.

Amino Acid Sequence↗
PubMed2002

Low genetic variation between isolates of Citrus leaf blotch virus from different host species and of different geographical origins.

The population structure and genetic diversity of Citrus leaf blotch virus (CLBV) were estimated by single-strand conformation polymorphism and nucleotide sequence analyses of two genomic regions located within the replicase (R) and the coat protein (C) genes. Analysis of 30 cDNA clones of each genomic region from two CLBV isolates showed that both isolates contained a predominant haplotype and others closely related. Analysis of 37 CLBV Spanish field isolates showed low genetic diversity (0.0041 and 0.0018 for genomic regions R and C, respectively). Comparison of 14 CLBV isolates from Spain, Japan, USA, France and Australia showed genetic diversities of 0.0318 (R) and 0.0209 (C), respectively. No correlation was found between genetic distance and geographical origin or host species of the isolates. The ratio between nonsynonymous and synonymous substitutions was the lowest found in a plant virus, indicating a strong negative selective pressure in both genomic regions.

Australia↗
PubMed2026

A Novel Complete F8 Tandem Duplication Causing Elevated Factor VIII Activity and Associated with Venous Thromboembolism.

Background Coagulation factor VIII (FVIII) is a critical component of the intrinsic coagulation pathway. While elevated FVIII levels are an established risk factor for venous thromboembolism (VTE), genetic variants in the F8 gene directly causing such elevations remain scarce. Here, we report a novel complete F8 tandem duplication identified in a female patient with splanchnic venous thrombosis (SVT). Methods We performed genetic testing using a thrombophilia panel targeting 35 genes involved in thrombosis and haemostasis to detect both point variants and copy number variations (CNVs). Family co-segregation analysis and phenotypic assays for FVIII and von Willebrand factor (VWF) were conducted. The structural basis of the identified F8 copy number gain was elucidated using optical genome mapping (OGM). Full-length F8 mRNA amplification, quantitative PCR, plasma FVIII Western blotting, and X-chromosome inactivation analysis were performed to assess the functional consequences of the duplication. Thrombin generation test (TGT) was employed to assess the hypercoagulable state. Results Genetic testing identified three copies of all 26 exons of the F8 gene in the proband, which was also detected in her mother (CNVs = 3) and son (CNVs = 2). One-stage clotting and chromogenic assays confirmed persistently elevated FVIII activity in the proband and her mother, accompanied by increased FVIII antigen levels. The OGM analysis confirmed a 229 kb tandem duplication including the F8 gene on one of the proband's X chromosomes. The junction regions exhibited high sequence homology and were rich in repetitive sequences, which precluded precise breakpoint mapping. Full-length F8 mRNA amplification revealed no aberrant transcripts, whereas quantitative PCR showed increased F8 mRNA expression in all carriers. Plasma FVIII Western blotting indicated FVIII heavy and light chains of expected molecular weights with increased band intensity in carriers. X-chromosome inactivation analysis in female carriers showed no significant skewing. TGT in two available carriers showed increased thrombin generation compared with a normal control at both low (1 pM) and high (5 pM) tissue factor concentrations. Conclusion We identified a novel complete F8 tandem duplication associated with increased FVIII expression and a hypercoagulable phenotype in a female patient with SVT. These findings support F8 gene dosage gain as a rare gain-of-function mechanism contributing to elevated FVIII levels and thrombophilia, while variation in VWF levels and acquired risk factors may modify thrombotic penetrance.

coagulation factor VIII↗
PubMed2004

The human genome project and the discovery of genetic determinants of cancer susceptibility.

The Human Genome Project has recently provided a great deal of information on the sequence that comprises the human genome. We are now in the process of structuring and deciphering the 3 x 10(9) base sequence in order to gain insights into its functional role. Several efforts are focusing on the search for DNA sequence variations underlying common/complex diseases that constitute a real burden in terms of public health measures. As expected, the genetic architecture of these complex traits, shows tremendous complexity, and the discovery and characterisation of susceptibility alleles constitute a real challenge for the geneticist. Conceptual and experimental genetic approaches aimed at dissecting the molecular features of susceptibility genes, in particular those predisposing to cancer, are outlined and discussed in this review.

Animals↗
PubMed2006

Gene conversion between direct noncoding repeats promotes genetic and phenotypic diversity at a regulatory locus of Zea mays (L.).

While evolution of coding sequences has been intensively studied, diversification of noncoding regulatory regions remains poorly understood. In this study, we investigated the molecular evolution of an enhancer region located 5 kb upstream of the transcription start site of the maize pericarp color1 (p1) gene. The p1 gene encodes an R2R3 Myb-like transcription factor that regulates the flavonoid biosynthetic pathway in maize floral organs. Distinct p1 alleles exhibit organ-specific expression patterns on kernel pericarp and cob glumes. A cob glume-specific regulatory region has been identified in the distal enhancer. Further characterization of 6 single-copy p1 alleles, including P1-rr (red pericarp/red cob) and P1-rw (red pericarp and white cob), reveals 3 distinct enhancer types. Sequence variations in the enhancer are correlated with the p1 gene expression patterns in cob glume. Structural comparisons and phylogenetic analyses suggest that evolution of the enhancer region is likely driven by gene conversion between long direct noncoding repeats (approximately 6 kb in length). Given that tandem and segmental duplications are common in both animal and plant genomes, our studies suggest that recombination between noncoding duplicated sequences could play an important role in creating genetic and phenotypic variations.

Alleles↗
PubMed1986

Resolution of linear minichromosomes with hairpin ends from circular plasmids containing vaccinia virus concatemer junctions.

The junctions, separating unit-length genomes in intracellular concatemeric forms of vaccinia virus DNA, are duplex copies of the hairpin loops that form the ends of mature DNA molecules present in infectious virus particles. Circular E. coli plasmids with palindromic junction fragments were replicated in vaccinia virus-infected cells and resolved into linear minichromosomes with vector DNA in the center and vaccinia virus DNA hairpins at the two ends. Resolution did not occur when the concatemer joint was less than 250 bp or when plasmids were transfected into uninfected cells, indicating requirements for a specific DNA structure and viral trans-acting factors. These studies indicate that concatemers can serve as replicative intermediates and account for the generation of flip-flop sequence variation of the hairpins at the ends of the mature vaccinia virus genome.

Animals↗
PubMed1990

Molecular analysis of structural protein genes of the Yamagata-1 strain of defective subacute sclerosing panencephalitis virus. III. Nucleotide sequence of the hemagglutinin gene.

The full-length cDNA corresponding to the mRNA for the hemagglutinin (H) protein of the Yamagata-1 strain of the subacute sclerosing panencephalitis (SSPE) virus was cloned and the nucleotide sequence was determined. The mRNA corresponding to the H protein was composed of 1952 nucleotides and contained a single large open reading frame, which encoded 620 amino acids with a predicted molecular weight of 69,723. This cDNA clone expressed the H protein in Cos 7 cells, and the transfected cells showed hemadsorption. The nucleotide and amino-acid sequence homology with the Edmonston strain of MV were 98.0% and 96.6%, respectively. The deduced amino acid sequence had a single hydrophobic domain near the N-terminus that was long enough to serve as an anchor in the membrane. Five potential glycosylation sites were found on the H protein at identical positions as in the H protein of MV. Cysteine and proline were located at almost identical positions as those of the H protein of MV. In addition, monoclonal antibody study revealed that three epitopes, including the domains that were involved in the biological activities of the H protein of MV, were conserved on the Yamagata-1 strain. These results suggested that the H protein of the Yamagata-1 strain of defective SSPE virus is structurally and functionally similar to that of the Edmonston strain of MV.

Amino Acid Sequence↗
PubMed2001

Microsatellite evolution in vertebrates: inference from AC dinucleotide repeats.

We analyze published data from 592 AC microsatellite loci from 98 species in five vertebrate classes including fish, reptiles, amphibians, birds, and mammals. We use these data to address nine major questions about microsatellite evolution. First, we find that larger genomes do not have more microsatellite loci and therefore reject the hypothesis that microsatellites function primarily to package DNA into chromosomes. Second, we confirm that microsatellite loci are relatively rare in avian genomes, but reject the hypothesis that this is due to physical constraints imposed by flight. Third, we find that microsatellite variation differs among species within classes, possibly relating to population dynamics. Fourth, we reject the hypothesis that microsatellite structure (length, number of alleles, allele dispersion, range in allele sizes) differs between poikilotherms and homeotherms. The difference is found only in fish, which have longer microsatellites and more alleles than the other classes. Fifth, we find that the range in microsatellite allele size at a locus is largely due to the number of alleles and secondarily to allele dispersion. Sixth, length is a major factor influencing mutation rate. Seventh, there is a directional mutation toward an increase in microsatellite length. Eighth, at the species level, microsatellite and allozyme heterozygosity covary and therefore inferences based on large-scale studies of allozyme variation may also reflect microsatellite genetic diversity. Finally, published microsatellite loci (isolated using conventional hybridization methods) provide a biased estimate of the actual mean repeat length of microsatellites in the genome.

Adenine↗
PubMed1997

[Mechanisms of antigenic variation in influenza virus].

Human influenza A viruses evolve rapidly by antigenic shift and antigenic drift. Antigenic shift occurs by gentic reassortment between currently circulating human viruses and influenza viruses of other origin and by re-emergence of a previously circulating virus. The segmental structure of the virus genome enables reassortment in multiply infected cells and also promotes multiple infection because it results in yielding noninfectious particles which randomly lack some genome segment and only become infectious by complementation with others. Antigenic drift is due to an accumulation of nonsynonymous substitutions in the genes encoding the HA and NA proteins. The limited nature of infection to the respiratory epithelium which is the border of the immune system capacitates the virus to reinfect and grow under the partial immune pressure which results in selecting and expanding antigenic mutants.

Antigenic Variation↗
PubMed2000

A novel FUS/CHOP chimera in myxoid liposarcoma.

The cytogenetic hallmark of myxoid liposarcoma is the chromosomal aberration t(12;16)(q13;p11), which is pathognomonic for this tumor type. The translocation results in the hybrid gene FUS/CHOP, where the central and C-terminal parts of FUS, coding for the RNA binding domain and the RGG triplet motif, are replaced by the full length CHOP protein. Thus, CHOP is under the control of the FUS promoter and the FUS/CHOP chimera contains the 5'-terminal part of FUS which provides a transcriptional activation function. Although different structural variations of the FUS/CHOP chimeric transcript have been reported, none of them contains the parts of FUS encoding the RNA binding properties. An explanation is the location of the genomic breakpoint in FUS, which frequently occurs in the region spanning exon 5 to intron 8. We describe here a case of myxoid liposarcoma containing two novel FUS/CHOP chimeric transcripts and with the breakpoint occurring in intron 14 of FUS. Reverse transcription-polymerase chain reaction, using FUS forward and CHOP reverse primers, amplified strongly a 2.1-kbp DNA fragment and weakly a 0.9-kbp DNA fragment. Direct sequencing showed that in the 2.1-kbp transcript nt 1474, which corresponds to the third nucleotide of exon 14 of FUS, was in-frame fused to exon 2 of CHOP. In the 0.9-kbp DNA fragment, exon 3 of FUS was in-frame fused to exon 2 of CHOP. Genomic analyses revealed that the breaks were located at the end of exon 14/beginning of intron 14 of FUS and in intron 1 of CHOP and that microdeletions had occurred in the close vicinity of the breakpoints.

Amino Acid Sequence↗
PubMed2002

A variable region on the chlorovirus CVK2 genome contains five copies of the gene for Vp260, a viral-surface glycoprotein.

A 22.2-kb variable region near the left end of the chlorovirus CVK2 genome that was previously supposed to be expanded compared to the PBCV-1 genome was characterized. This region contains a tandem array of five gene copies for the Vp260-like protein, a viral-surface glycoprotein. The authentic 104-kDa Vp260 was found to be encoded at another site on the genome and to contain 13 internal tandem repeats of 61-65 amino acids, similar to the prominent Rickettsia surface antigen. The extra copies were also found to retain 10 of the internal repeats, despite the C-terminal deletions or extensions. These extra copies are conserved among chloroviruses isolated in various areas of Japan. By Northern blot analysis, these genes were demonstrated to be expressed late in infection. The proteins are incorporated into virions, as revealed by comparing viral structural proteins between wild-type and deletion mutants. These results indicate that extra copies of Vp260-like proteins encoded in a variable region on the genome may give variations in the surface nature of the chloroviral particles.

Amino Acid Sequence↗
PubMed1989

Genetics and congenital heart disease: perspectives and prospects.

Elucidating the role of genes in the ontogenesis of the cardiovascular system is a task that involves many fields of inquiry. Recent dramatic advances in the molecular biology of transcription and its variations and the prospects for sequencing the entire human genome must not induce complacency; the major task of determining how a one-dimensional code specifies a three-dimensional structure demands an understanding of biologic systems considerably beyond the current level. The study of pathologic cardiovascular ontogeny is equally in need of new insight and fresh approaches. Although all clinicians might agree that genes are important contributors to both the etiology and the pathogenesis of congenital heart defects, with the exception of a few Mendelian conditions, this knowledge cannot be put to practice beyond crude statements of empirically determined probabilities. In this review, we selectively examine studies that are addressing what we perceive as provocative issues and suggest some areas, such as chaos theory, in which new ideas might be found.

Genetic Linkage↗