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PubMed2005

Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes.

BACKGROUND: Characterization of the linkage disequilibrium (LD) structure of candidate genes is the basis for an effective association study of complex diseases such as cancer. In this study, we report the LD and haplotype architecture and tagging-single nucleotide polymorphisms (tSNPs) for five DNA repair genes: ATM, MRE11A, XRCC4, NBS1 and RAD50. METHODS: The genes ATM, MRE11A, and XRCC4 were characterized using a panel of 94 unrelated female subjects (47 breast cancer cases, 47 controls) obtained from high-risk breast cancer families. A similar LD structure and tSNP analysis was performed for NBS1 and RAD50, using publicly available genotyping data. We studied a total of 61 SNPs at an average marker density of 10 kb. Using a matrix decomposition algorithm, based on principal component analysis, we captured >90% of the intragenetic variation for each gene. RESULTS: Our results revealed that three of the five genes did not conform to a haplotype block structure (MRE11A, RAD50 and XRCC4). Instead, the data fit a more flexible LD group paradigm, where SNPs in high LD are not required to be contiguous. Traditional haplotype blocks assume recombination is the only dynamic at work. For ATM, MRE11A and XRCC4 we repeated the analysis in cases and controls separately to determine whether LD structure was consistent across breast cancer cases and controls. No substantial difference in LD structures was found. CONCLUSION: This study suggests that appropriate SNP selection for an association study involving candidate genes should allow for both mutation and recombination, which shape the population-level genomic structure. Furthermore, LD structure characterization in either breast cancer cases or controls appears to be sufficient for future cancer studies utilizing these genes.

Acid Anhydride Hydrolases↗
PubMed2006

Restricted gene flow in the Caribbean staghorn coral Acropora cervicornis: implications for the recovery of endangered reefs.

Coral reef conservation requires information about the distance over which healthy reefs can rescue damaged reefs through input of coral larvae. This information is desperately needed in the Caribbean where the 2 dominant shallow water corals Acropora cervicornis and Acropora palmata have suffered unprecedented declines. Here we compare the population genetic structure in the staghorn coral A. cervicornis across the greater Caribbean using DNA sequence data from 1 mitochondrial and 3 nuclear genes. Data from 160 individuals from 22 populations and 9 regions show that A. cervicornis exhibits significant population genetic structure across the greater Caribbean in both the mitochondrial (Phi(st) = 0.130) and nuclear data (Phi(st) = 0.067). The highest population structure was observed in the species' own, native mtDNA haplotypes (Phi(st) = 0.235). Introgressed alleles from A. palmata tempered higher population structure in A. cervicornis over regional scales but in some cases generated highly localized "introgression hot spots" and fine-scale genetic structure among reefs separated by as few as 2 km. These data show that larval dispersal over moderate or long distances (>500 km) is limited for this threatened species and in some cases locally limited as well. Thus, the endangered Caribbean staghorn corals require local source populations for their recovery and targeted conservation efforts over spatial scales much smaller than the hundreds to thousands of kilometers usually proposed for marine reserves.

Animal Migration↗
PubMed2003

Beta(2)-adrenergic receptor gene polymorphism, age, and cardiovascular phenotypes.

Previous studies suggest that variants of the beta(2)-adrenergic receptor (ADRB2) may differently affect functional responses to adrenergic stimulation, thereby possibly modulating cardiovascular and metabolic phenotypes. We examined the hypothesis that G/R16 and Q/E27 polymorphism of ADRB2, or their haplotypes, may modulate blood pressure, cardiovascular structure, and function or metabolic cardiovascular risk factors in the general population. We examined a random sample of the general population (n=571; age, 35 to 64 years). Neither clinic nor 24-hour ambulatory blood pressure was significantly associated with ADRB2 genotypes in the overall population. Cardiac structure and function were also not influenced by ADRB2 polymorphism. After adjustment for potential confounders, association of the R16 allele with higher systolic blood pressure was observed in the subgroup of younger people (below age of 50 years). Haplotype analysis showed that higher blood pressure values were more specifically associated with the presence of R16-Q27. Younger people carrying the R16-Q27 haplotype also showed a trend toward lower heart rate, higher BMI, lower glycemia, and higher trygliceridemia, which is consistent with the hypothesis of a genetic predisposition to reduced cardiovascular and metabolic response to ADRB2 stimulation. This study does not provide evidence of a major role of ADRB2 gene variability in blood pressure modulation. However, association of ADRB2 polymorphism with cardiovascular and metabolic effects can be observed in younger subjects, before the development of age-related decline of ADRB2-mediated activity. Our study emphasizes the necessity of taking into account (patho)-physiological changes related to aging (in this case, decreased efficiency of ADRB2 signaling) when analyzing phenotypic effects of genetic variants.

Adult↗
PubMed2003

Population genetic structure of the toad Bufo woodhousii: an empirical assessment of the effects of haplotype extinction on nested cladistic analysis.

Nested cladistic analysis (NCA) is increasingly being used to infer historical population-level processes, including population fragmentation, range expansion and long-distance colonization. However, the effects on interpretation of NCA inferences of stochastic extinction of haplotypes due to genetic drift (lineage sorting), or of haplotype loss via localized biotic or climatic influences, have not been thoroughly explored. We provide empirical evidence suggesting that NCA may misinterpret population history when haplotypes or haplotype groups from one clade are replaced by those of another clade. We do so by using NCA to analyse mitochondrial sequences from the toad Bufo woodhousii from 45 locations spanning the Great Plains and southwestern USA. Portions of this region were glaciated and/or desertified in the late Pleistocene and early Holocene, and hence uninhabitable for plains-dwelling organisms. Although NCA inferences of isolation-by-distance and gradual range expansion in B. woodhousii are compatible with expectations based on climatic data and toad biology, NCA also detected several instances of long-distance movement. Such movement seems unlikely, given the low vagility of this species. We conclude that inferences of long-distance colonization likely result from extinction of haplotypes in intervening areas. We suggest using additional methods to look for congruent inferences, and amending the NCA inference key, to help avoid misinterpretations resulting from haplotype extinction.

Animals↗
PubMed2003

Rangewide phylogeography of a bird-dispersed Eurasian shrub: contrasting Mediterranean and temperate glacial refugia.

We studied the phylogeography of alder buckthorn (Frangula alnus), a bird-dispersed shrub or small tree distributed over most of Europe and West Asia and present in three of the four main refugia of West Palaearctic temperate woody plants: the Iberian Peninsula, the Balkans and Anatolia. A total of 78 populations from 21 countries were analysed for chloroplast DNA variation using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and 21 different haplotypes were distinguished. We found a very strong overall population differentiation (GST = 0.81) and phylogeographical structure, and a sharp contrast between the haplotype-rich refugia and the almost completely uniform area of postglacial colonization. The haplotype network comprises three lineages made up of haplotypes from the Iberian Peninsula, Anatolia with the Caucasus, and temperate Europe. The Iberian and the Anatolian branches represent parts of a major lineage that spans over the whole northern Mediterranean Basin and some neighbouring areas and probably dates back to the Tertiary. Many haplotypes of this lineage are distributed locally and most populations are fixed for a single haplotype; these populations have apparently been very stable since their establishment, experiencing negligible gene flow and few mutations. The temperate European lineage consists of one very widespread and abundant plus six locally distributed haplotypes. Four of them are located in Southeast Europe, the putative refugium of all extant temperate European populations. Contrary to populations from Iberia and Anatolia, F. alnus populations from the southeastern European refugium have most genetic variation within populations. Bird-mediated seed dispersal has apparently allowed not only a very rapid postglacial expansion of F. alnus but also subsequent regular seed exchanges between populations of the largely continuous species range in temperate Europe. In contrast, the disjunct F. alnus populations persisting in Mediterranean mountain ranges seem to have experienced little gene flow and have therefore accumulated a high degree of differentiation, even at short distances. Populations from the southern parts of the glacial refugia have contributed little to the postglacial recolonization of Europe, but their long-term historical continuity has allowed them to maintain a unique store of genetic variation.

DNA, Chloroplast↗
PubMed2000

Enhancement of experimental autoimmune encephalomyelitis severity by ultrasound emulsification of antigen/adjuvant in distinct strains of mice.

Susceptibility to experimental autoimmune encephalomyelitis (EAE) is associated with the major histocompatibility complex (MHC) haplotype. In this study EAE could be induced in six out of ten mice of the resistant DBA/2 (H-2d) strain by ultrasound emulsified antigen/adjuvant, whereas none of the mice immunized with the conventional adjuvant developed the disease. Similar results were previously obtained for the MHC identical BALB/c mice. Further, while only few T cells were present in the central nervous systems (CNS) of the diseased DBA/2 mice, macrophages formed the majority of the infiltrates. In congenic BALB.B (H-2b) and BALB.K (H-2 k) mice, EAE could be induced with both sonicated and extruded antigen/adjuvant emulsion. The results indicate that the EAE resistance in mice carrying the H-2d MHC haplotype is dependent on the physical structure of the immunogen.

Animals↗
PubMed1987

DNA sequence variation within the beta-glucuronidase gene complex among inbred strains of mice.

Tightly linked to the gene that encodes murine beta-glucuronidase (GUS) are three GUS-specific regulatory elements. Together, these elements define the GUS gene complex. Specific alleles of each regulatory element are associated with a specific GUS structural allele. These associations define the three common forms (haplotypes) of the GUS gene complex, designated A, B, and H. As an initial step in defining the DNA determinants of each regulatory element and to develop DNA markers for the common haplotypes, we have identified several DNA variants by blot hybridization analysis of restricted genomic DNA using GUS-specific cDNA probes. Of 30 tested restriction endonucleases, 24 reveal DNA polymorphisms that distinguish B- and H-haplotype DNA from that of the A haplotype. Of these 24, 18 uncover a restriction fragment length polymorphism in which the polymorphic fragment of A-haplotype DNA is 200-300 bp larger than the corresponding fragment of B- or H-haplotype DNA. DNA sequence analysis of this polymorphic region reveals the presence of a short, interspersed repetitive element of the B2 family within A-haplotype DNA which is absent in DNAs of B- or H-haplotype mice. None of the DNA variations revealed by these analyses can be associated at this time with variation in the regulatory or structural properties of GUS among the common haplotypes. Nevertheless, they do provide useful haplotype-specific markers within the GUS gene complex which are of critical importance for DNA transfer experiments in transgenic mice and in cultured cells.

Animals↗
PubMed2026

Haplotype-resolved reconstruction and functional interrogation of cancer karyotypes.

Complex karyotype changes are widespread in cancer genomes. A major gap in cancer genome characterization is the resolution of rearranged chromosomes with chromosome-length continuity. Here, we describe a two-tiered approach to determine the segmental composition of rearranged chromosomes with haplotype resolution. First, we present refLinker, a bioinformatic method for robust determination of chromosomal haplotypes using cancer Hi-C data. By contrast with existing methods, refLinker is insensitive to the presence of large-scale DNA deletions, duplications, and high-level amplification in cancer genomes. Second, we demonstrate a computational strategy to determine the segmental structure of rearranged chromosomes using haplotype-specific Hi-C contacts. We apply these methods to breast cancer genomes and provide direct evidence for long-range transcriptional changes associated with rearrangements of the inactive X chromosome. Together, these results highlight refLinker's broad utility for studying the functional consequences of chromosomal rearrangements.

Humans↗
PubMed2000

The comparative phylogeography of neotropical mammals: patterns of intraspecific mitochondrial DNA variation among bats contrasted to nonvolant small mammals.

The major aim of this study was to compare the phylogeographic patterns of codistributed bats and small nonvolant Neotropical mammals. Cytochrome b sequences (mitochondrial DNA) were obtained for a total of 275 bats representing 17 species. The tissue samples were collected in coastal Brazil, and were available from Mexico and the Guyana. The study concentrates on four species (Artibeus lituratus, Carollia perspicillata, Sturnira lilium and Glossophaga soricina) which were well represented. The other 13 species were sequenced to test the generality of the patterns observed. In general, sequence divergence values within species were low, with most bat species presenting less than 4% average sequence divergence, and usually between 1 and 2.5%. Clades of highly similar haplotypes enjoyed broad distribution on a continental scale. These clades were not usually geographically structured, and at a given locality the number of haplotypes was high (8-10). As distance increased, some moderately divergent clades were found, although the levels of divergence were low. This suggests a geographical effect that varied depending on species and scale. Small nonvolant mammals almost invariably have high levels of sequence divergence (> 10%) for cytochrome b over much shorter distances (< 1000 km). The grain of intraspecific variation found in small nonvolant mammals is much finer than in bats. Low levels of geographical structuring cannot be attributed to a slower evolutionary rate of bat DNA in relation to other mammalian taxa. The phylogeographic pattern of bats contrasts sharply with the pattern found for Neotropical rodents and marsupials.

Animals↗
PubMed2000

Determining the physical limits of the Brassica S locus by recombinational analysis.

A genetic analysis was performed to study the frequency of recombination for intervals across the Brassica S locus region. No recombination was observed between the S locus glycoprotein gene and the S receptor kinase gene in the segregating populations that we analyzed. However, a number of recombination breakpoints in regions flanking these genes were identified, allowing the construction of an integrated genetic and physical map of the genomic region encompassing one S haplotype. We identified, based on the pollination phenotype of plants homozygous for recombinant S haplotypes, a 50-kb region that encompasses all specificity functions in the S haplotype that we analyzed. Mechanisms that might operate to preserve the tight linkage of self-incompatibility specificity genes within the S locus complex are discussed in light of the relatively uniform recombination frequencies that we observed across the S locus region and of the structural heteromorphisms that characterize different S haplotypes.

Brassica↗
PubMed2000

Clinal variation of YAP+ Y-chromosome frequencies in Western Iberia.

The potential of Y-chromosome biallelic marker haplotypes to infer population affiliations and structures was exploited to analyze four populations from the southwestern edge of Europe, namely north, central, and south Portugal and Galicia. Three markers subdividing the YAP+ lineage were analyzed: the YAP Alu element insertion itself and the SRY8299 and sY81 base substitutions; these respectively define three haplotypes known as 4, 21, and 8. Only haplotype 21 was detected presenting an increasing north-to-south frequency gradient, from 9.6% (Galicia) to 24.5% (South Portugal). This clinal distribution most likely reflects the genetic input associated with the Neolithic spread of agriculture, but we cannot exclude other movements as potential contributors to the distribution. In this context, it is interesting to note the consistency between the clinal variation and the population movement associated with Islamic rule in Iberia. The absence of haplotype 8, a marker of sub-Saharan populations, suggests that, despite the massive introductions of African slaves in historical times, there was little admixture between the African males and Western Iberian populations.

Gene Frequency↗
PubMedDate not supplied

Molecular genetics of the S region of the murine H-2 major histocompatibility complex.

The mouse H-2S region has been conventionally identified by the functional, serological and electrophoretic variations of two plasma proteins which constitute its primary genetic markers, C4 (the fourth component of complement) and C4-Slp (sex-limited protein). Recently, recombinant DNA procedures applied in our laboratory as well as in several others have made available molecular clones corresponding to these two nonallelic genes. This paper focuses on the progress provided by the study of C4 and C4-Slp cDNA and genomic clones, as well as by the application of such clones to the probing of the S region structure in conventional and special H-2 haplotypes. At variance with the K, I and D regions of H-2, the S region contains genes which have no obvious structural interrelationship, although in some cases they display a functional interaction. The heterogeneity of S region products is emphasized by the recent detection of steroid 21-hydroxylase genes associated with each of the C4 gene copies.

Alleles↗
PubMed2001

Molecular phylogeography, reticulation, and lineage sorting in Mediterranean Senecio sect. Senecio (Asteraceae).

The Mediterranean species complex of Senecio serves to illustrate evolutionary processes that are likely to confound phylogenetic inference, including rapid diversification, gene tree-species tree discordance, reticulation, interlocus concerted evolution, and lack of complete lineage sorting. Phylogeographic patterns of chloroplast DNA (cpDNA) haplotype variation were studied by sampling 156 populations (502 individuals) across 18 species of the complex, and a species phylogeny was reconstructed based on sequences from the internal transcribed spacer (ITS) regions of nuclear ribosomal DNA. For a subset of species, randomly amplified polymorphic DNAs (RAPDs) provided reference points for comparison with the cpDNA and ITS datasets. Two classes of cpDNA haplotypes were identified, with each predominating in certain parts of the Mediterranean region. However, with the exception of S. gallicus, intraspecific phylogeographic structure is limited, and only a few haplotypes detected were species-specific. Nuclear sequence divergence is low, and several unresolved phylogenetic groupings are suggestive of near simultaneous diversification. Two well-supported ITS clades contain the majority of species, amongst which there is a pronounced sharing of cpDNA haplotypes. Our data are not capable of diagnosing the relative impact of reticulation versus insufficient lineage sorting for the entire complex. However, there is firm evidence that S. flavus subsp. breviflorus and S. rupestris have acquired cpDNA haplotypes and ITS sequences from co-occurring species by reticulation. In contrast, insufficient lineage sorting is a viable hypothesis for cpDNA haplotypes shared between S. gallicus and its close relatives. We estimated the minimum coalescent times for these haplotypes by utilizing the inferred species phylogeny and associated divergence times. Our data suggest that ancestral cpDNA polymorphisms may have survived for ca. 0.4-1.0 million years, depending on molecular clock calibrations.

Biological Evolution↗
PubMed2003

Pedigree disequilibrium tests for multilocus haplotypes.

Association tests of multilocus haplotypes are of interest both in linkage disequilibrium mapping and in candidate gene studies. For case-parent trios, I discuss the extension of existing multilocus methods to include ambiguous haplotypes in tests of models which distinguish between the cis and trans phase. A likelihood-ratio test is proposed, using the expectation-maximization (E-M) algorithm to account for haplotype ambiguities. Assumptions about the population structure are required, but realistic situations, including population stratification, which violate the assumptions lead to conservative tests. I describe a permutation procedure for the null hypothesis of interest, which controls for violation of the assumptions. For general pedigrees, I describe extensions of the pedigree disequilibrium test to include uncertain haplotypes. The summary statistics are replaced by their expected values over prior distributions of haplotype frequencies. If prior distributions are not available, a valid test is possible by using the E-M algorithm to estimate the null distribution of haplotype frequencies. Similar methods are available for quantitative traits. Exact permutation tests are difficult to construct in small samples, but an approximate procedure is appropriate in large samples, and can be used to account for dependencies between tests of multiple haplotypes and loci.

Algorithms↗
PubMed1998

[Effect of an increased radiation background on mice, carrying lethal t-haplotypes].

To study the effect of a high radiation background on the structure and function of the T-complex, we used laboratory mice carrying t-haplotypes of four complementation groups (t0, t12, tw1, and tw5). In 1987-1989, the animals were kept each year for a month within a 30-kilometer zone of Chernobyl Nuclear Power Station in regions with different degrees of pollution. Subsequent genetic analysis revealed a decrease in fertility, fecundity, and the index of preferable transmission of t-carrying chromosomes in radiated animals and some of their progeny. The effect of different radiation doses on these parameters was different in animals with various t-haplotypes. A lack of complementation or a decrease in the complementation effect was revealed in a number of crosses involving the progeny of irradiated animals. The frequency of complementation distortion was about 8 x 10(-2), which is more than an order higher than the usual recombination frequency characteristic of these t-haplotypes.

Animals↗
PubMed2004

Deriving haplotypes through recombination and gene conversion pathways.

Retracing the trajectories of past genetic events is crucial to understand the structure of the genome, both in individuals and across populations. A haplotype describes a string of polymorphic sites along a DNA segment. Haplotype diversity is due to mutations creating new variants, and to recombinations and gene conversions that mix and redistribute these variants among individual chromosomes in populations. A number of studies have revealed a relatively simple pattern of haplotype diversity in the human genome, dominated by a few common haplotypes representing founder ancestral ones. New haplotypes are usually rare and have a limited geographic distribution. We propose a method to derive a new haplotype from a set of putative ancestral haplotypes, once mutations in place, through minimal recombination and gene conversion pathways. We describe classes of pathways that represent the whole set of minimal pathways leading to a new haplotype. We show that obtaining this set of pathways can be represented as a problem of finding "secondary structures" of minimum energy. We present a polynomial algorithm solving this folding problem.

Algorithms↗
PubMed1989

Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype.

Celiac disease is strongly associated with the HLA class II D-region serologic markers DR3 (DRw17) and DQw2. Moreover, by restriction fragment length polymorphism analysis, greater than 90% of DR3 (DRw17), DQw2 celiac disease patients have a polymorphic 4.0-kilobase Rsa I DP B gene DNA fragment. The present study sought to determine if there is a unique HLA class II D-region A or B gene structural variant on the DR3 (DRw17) haplotype found in celiac disease. The polymorphic second exons of the coding DRB, DQA and DQB, and DPA and DPB genes in celiac disease patients with the DR3 (DRw17) haplotype were sequenced after amplification by the polymerase chain reaction. To define the DP B genes associated with celiac disease, the second exons of the coding DP B genes from 27 celiac disease patients were amplified similarly and probed by using a panel of sequence specific oligonucleotides. The HLA-DR, -DQ, and -DP A and B gene second exon sequences of celiac disease patients were noted to be identical to sequences that can be found also, although at a significantly lower frequency, in unaffected individuals. This is compatible with a disease model wherein the HLA class II genes on the DR3 (DRw17) haplotype are necessary, but not sufficient, for the phenotypic expression of celiac disease. Analysis of the DP B genes revealed a significant increase in the frequency of the alleles DPB1 and DPB3 in celiac disease. Furthermore, the increased frequency of the 4.0-kilobase Rsa I DP B gene restriction fragment length polymorphism in celiac disease can be accounted for by the overrepresentation in disease of the alleles DPB1 and DPB3. The HLA-associated susceptibility to celiac disease appears to be multigenic, with specific, but structurally normal, allelic variants in the DP and DQ/DR subregions contributing to disease susceptibility.

Alleles↗