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Results for “nucleotide polymorphism patterns”

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PubMed2001

Allelic frequencies and patterns of single-nucleotide polymorphisms in candidate genes for asthma and atopy in Iceland.

Numerous asthma and atopy loci have been reported in studies demonstrating associations of the asthma-related phenotypes atopy, elevated IgE levels, and bronchial hyperresponsiveness with alleles of microsatellite markers and single-nucleotide polymorphisms (SNPs) within specific cytokine/chemokine and IgE-regulating genes. Although the studies reporting these observations are compelling, most of them lack statistical power. We assessed the nature, pattern, and frequency of SNPs in 24 candidate genes in Iceland and looked for associations with asthma and atopy. We identified 42 SNPs with an average minor allele frequency of 20.3% (asthma) and 20.7% (control). Twenty SNPs (48%) were within coding sequences and 90% of those led to a predicted change in protein sequence. No differences were detected in the allelic frequencies of SNPs in any of these candidate genes between control subjects and the patients with atopic asthma. Moreover, linkage analysis that included 269 patients with atopic asthma uncovered no evidence of linkage to markers associated with these genes. We conclude that this study has failed to produce evidence in support of the notion that variations within these 24 candidate atopy and asthma genes significantly influence the expression of the atopic asthmatic phenotype or contribute to the susceptibility of atopic asthma.

Adolescent↗

PubMed2003

Lineage-specific selection in human mtDNA: lack of polymorphisms in a segment of MTND5 gene in haplogroup J.

Human mitochondrial DNA (mtDNA) is a nonrecombining genome that codes for 13 subunits of the mitochondrial oxidative phosphorylation system, 2 rRNAs, and 22 tRNAs. Mutations have accumulated sequentially in mtDNA lineages that diverged tens of thousands of years ago. The genes in mtDNA are subject to different functional constraints and are therefore expected to evolve at different rates, but the rank order of these rates should be the same in all lineages of a phylogeny. Previous studies have indicated, however, that specific regions of mtDNA may have experienced different histories of selection in different lineages, possibly because of lineage-specific interactions or environmental factors such as climate. We report here on a survey for lineage-specific patterns of nucleotide polymorphism in human mtDNA. We calculated molecular polymorphism indices and neutrality tests for classes of functional sites and genes in 837 human mtDNA sequences, compared the results between continent-specific mtDNA lineages, and used two sliding window methods to identify differences in the patterns of polymorphism between haplogroups. A general correlation between nucleotide position and the level of nucleotide polymorphism was identified in the coding region of the mitochondrial genome. Nucleotide diversity in the protein-coding sequence of mtDNA was generally not much higher than that found for many genes in nuclear DNA. A comparison of nonsynonymous/synonymous rate ratios in the 13 protein-coding genes suggested differences in the relative levels of selection between haplogroups, including the European haplogroup clusters. Interestingly, a segment of the MTND5 gene was found to be almost void of segregating sites and nonsynonymous mutations in haplogroup J, which has been associated with susceptibility to certain complex diseases. Our results suggest that there are haplogroup-specific differences in the intensity of selection against particular regions of the mitochondrial genome, indicating that some mutations may be non-neutral within specific phylogenetic lineages but neutral within others.

DNA, Mitochondrial↗

PubMed2003

Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse.

The nature and organization of polymorphisms, or differences, between genomes of individuals are of great interest, because these variations can be associated with or even underlie phenotypic traits, including disease susceptibility. To gain insight into the genetic and evolutionary factors influencing such biological variation, we have examined the arrangement (haplotype) of single-nucleotide polymorphisms across the genomes of eight inbred strains of mice. These analyses define blocks of high or low diversity, often extending across tens of megabases that are delineated by abrupt transitions. These observations provide a striking contrast to the haplotype structure of the human genome.

Animals↗

PubMed1996

No evidence for mutations in the alpha- and beta-catenin genes in human gastric and breast carcinomas.

Disturbed function of E-cadherin and/or of one of its anchoring proteins, the catenins, is thought to destabilize E-cadherin-mediated cell-cell adhesion, which may enhance the invasiveness of epithelial cells and thus favor carcinoma progression. Reduced expression of E-cadherin and alpha-catenin, as well as mutations in the E-cadherin gene, have been found in various carcinomas, whereas mutations in the alpha- and beta-catenin genes have been described only in carcinoma cell lines. Using reverse transcription-PCR, followed by agarose gel electrophoresis and single-strand conformational polymorphism, we examined 16 diffuse- and 5 intestinal-type gastric carcinomas, as well as 9 lobular and 2 ductal breast carcinomas, for mutations of alpha- and beta-catenin cDNA. All of the investigated tumors were analyzed previously for E-cadherin mutations. Comparing tumorous and nontumorous samples, we detected neither deletions nor aberrant single-strand conformational polymorphism patterns. At nucleotide 2220 of the alpha-catenin gene, we identified one frequent polymorphism. Our findings suggest that, in contrast to E-cadherin, mutations of alpha- and beta-catenin do not contribute to the pathogenesis or the diffuse growth patterns of gastric or breast carcinomas.

Breast Neoplasms↗

PubMed1999

Molecular population genetics of floral homeotic loci. Departures from the equilibrium-neutral model at the APETALA3 and PISTILLATA genes of Arabidopsis thaliana.

Molecular variation in genes that regulate development provides insights into the evolutionary processes that shape the diversification of morphogenetic pathways. Intraspecific sequence variation at the APETALA3 and PISTILLATA floral homeotic genes of Arabidopsis thaliana was analyzed to infer the extent and nature of diversity at these regulatory loci. Comparison of AP3 and PI diversity with three previously studied genes revealed several features in the patterning of nucleotide polymorphisms common between Arabidopsis nuclear loci, including an excess of low-frequency nucleotide polymorphisms and significantly elevated levels of intraspecific replacement variation. This pattern suggests that A. thaliana has undergone recent, rapid population expansion and now exists in small, inbred subpopulations. The elevated intraspecific replacement levels may thus represent slightly deleterious polymorphisms that differentiate distinct ecotypes. The distribution of replacement and synonymous changes in AP3 and PI core and noncore functional domains also indicates differences in the patterns of molecular evolution between these interacting floral regulatory genes.

Alleles↗

PubMed2003

Unequal transmission of mitochondrial haplotypes in natural populations of field mice with XY females (genus Akodon).

In species with fertile XY females, such as South American field mice (genus Akodon), there are two types of mitochondrial DNA (mtDNA), one passing from XX females and one from XY females. The XX mothers pass their mtDNA to their XX daughters. The XY mothers, however, produce both XX and XY daughters. Because of this breeding scheme, the XY mtDNA remains isolated whereas the XX lineage is continuously invaded by XY mtDNA haplotypes. Using a set of recursion equations, I predicted that XY mtDNA haplotypes should rapidly spread through entire populations composed of both XX and XY females. I examined patterns of nucleotide polymorphism and divergence from the mtDNA control region as well as phylogenetic patterns for evidence of an mtDNA sweep. I compared patterns in two sister species, Akodon boliviensis and Akodon azarae, that are composed of 35% and 10% XY females, respectively. Akodon boliviensis XY females are found in all clades of a phylogenetic mtDNA tree consistent with the spread of mtDNA haplotypes. In addition, A. azarae mtDNA haplotypes showed no deviations from neutrality. These results, in combination with high levels of mtDNA nucleotide diversity in XY females, suggest an ancient origin (>10(4) generations) of XY females in both A. boliviensis and A. azarae.

Animals↗

PubMed2006

Thymidylate synthase expression pattern, expression level and single nucleotide polymorphism are predictors for disease-free survival in patients of colorectal cancer treated with 5-fluorouracil.

Several variables associated to thymidylate synthase (TS), the biological target of 5-fluorouracil (5FU) have been studied for their possible role as predictors of the clinical outcome and response to chemotherapy in colorectal cancer (CRC) patients. The level of protein expression and the number of variable tandem-repeats of a 28-bp sequence within the gene promoter have been proposed as predictive and/or prognostic factors with variable agreement, while consensus seems to be achieved with respect to the value of a single nucleotide polymorphism (SNP) described within this same region. More recently, an association between TS expression pattern and survival has been disclosed. Paraffin-embedded sections from 140 CRC patients were analyzed by immuno-histochemistry (Mab TS106) for TS levels and expression pattern. Also, VNTR and SNP were determined by polymerase-chain reaction (PCR) and restriction-length-fragment polymorphism (RFLP) in 123 and 112 patients, respectively. Cytoplasmic expression pattern tended to be associated to C SNP (p=0.06). Low TS expression levels, cytoplasmic expression pattern and C SNP arose as variables associated to longer progression-free survival (PFS) in patients treated with 5FU. Accordingly, patients having at least two favourable or unfavourable variables were classified respectively as 'low risk' and 'high risk', the former showing significantly longer PFS (p=0.0299). The possibility for designing a selection method for subsequent therapies is suggested on the basis of a probable combined effect of the above mentioned parameters but further studies in larger populations are needed to confirm these results.

Aged↗

PubMed1994

Concerted evolution and RAPping in mitochondrial VNTRs and the molecular geography of cricket populations.

In recent years, many animal species have been shown to exhibit a variable number of tandem repeats (VNTR) in the control region of their mitochondrial DNA. To characterize the nucleotide polymorphism of a VNTR system, this region was sequenced in individuals from two species of crickets (genus Gryllus) collected at a mainland locality and an island locality within each species. The data reveal a clear pattern of concerted evolution: homogeneity among repeats within individuals and populations, but heterogeneity among the tandem arrays from divergent populations, and between species. The patterns of nucleotide polymorphisms within the arrays show several instances of partial homogenization where derived nucleotides have not swept through all the repeats in the array. These serve as examples of concerted evolution "caught in the act". Additional repeat associated polymorphisms (RAPs) shed light on the molecular basis of the insertion and deletion of repeat units and, with the concerted evolution of VNTRs, provide phylogeographic resolution of island and mainland populations within and between species. The polymorphisms within VNTRs also provide a simple system in which to examine the balance of mutation and drift and offer a unique view of the histories of genomic and organismal phenomena in the patterns and processes of molecular evolution.

Animals↗

PubMed2003

Patterns of nucleotide variation in homoeologous regulatory genes in the allotetraploid Hawaiian silversword alliance (Asteraceae).

Genome-wide duplication (polyploidization) is prevalent in a large number of eukaryotic organisms and is particularly widespread in flowering plants. Polyploid species appear to vary from their diploid progenitors in a variety of ecologically important traits, suggesting that genome duplications provide a mechanism for ecological diversification. Studies of nucleotide variation at duplicate genes that arise via polyploidization allow us to infer the evolutionary forces that act on these polyploid loci. In an effort to examine the evolutionary dynamics of homoeologous loci, molecular population genetic analyses were undertaken for duplicate regulatory genes in the allopolyploid Hawaiian silversword alliance, a premier example of adaptive radiation. The levels and patterns of nucleotide variation for the floral homeotic genes ASAPETALA1 (ASAP1) and ASAPETALA3/TM6 (ASAP3/TM6) were studied in two species representing different lineages within the Hawaiian silversword alliance: Argyroxiphium sandwicense ssp. macrocephalum and Dubautia ciliolata ssp. glutinosa. Homoeologueous copies of ASAP1 and ASAP3/TM6 show differing levels and patterns of nucleotide polymorphism. Duplicate ASAP1 copies have similar levels of nucleotide diversity and haplotype structure in both species; by contrast, duplicate ASAP3/TM6 genes display different levels and patterns of variation in D. ciliolata ssp. glutinosa. Additionally, D. ciliolata ssp. glutinosa appears to be segregating for a moderate frequency null allele in one ASAP3/TM6 homoeologue. These results suggest that differing evolutionary forces can affect duplicate loci arising from allopolyploidization.

Asteraceae↗

PubMed2000

Nucleotide variation at the yellow gene region is not reduced in Drosophila subobscura: a study in relation to chromosomal polymorphism.

In contrast to Drosophila melanogaster and Drosophila simulans, the yellow (y) gene region of Drosophila subobscura is not located in a region with a strong reduction in recombination. In addition, this gene maps very close to the breakpoints of different inversions that segregate as polymorphic in natural populations of D. subobscura. Therefore, levels of variation at the y gene region in this species relative to those found in D. melanogaster and D. simulans may be affected not only by the change in the recombinational environment, but also by the presence of inversion polymorphism. To further investigate these aspects, an approximately 5.4-kb region of the A (=X) chromosome including the y gene was sequenced in 25 lines of D. subobscura and in the closely related species Drosophila madeirensis and Drosophila guanche. The D. subobscura lines studied differed in their A-chromosomal arrangements, A(st), A(2), and A(1). Unlike in D. melanogaster and D. simulans, levels of variation at the y gene region of D. subobscura are not reduced relative to those found at other genomic regions in the same species (rp49, Acp70A, and Acph-1). This result supports the effect of the change in the recombinational environment of a particular gene on the level of neutral variation. In addition, nucleotide variation is affected by chromosomal polymorphism. A strong genetic differentiation is detected between the A(1) arrangement and either A(st) or A(2), but not between A(st) and A(2). This result is consistent with the location of the y gene relative to the breakpoints of inversions A(1) and A(2). In addition, the pattern of nucleotide polymorphism in A(st)+A(2) and A(1) seems to point out that variation at the y gene region within these chromosomal classes is in the phase transient to equilibrium. The estimated ages of these arrangements assuming a star genealogy indicate that their origin cannot predate the D. madeirensis split. Therefore, the present results are consistent with a chromosomal phylogeny where Am(1), which is an arrangement present in D. madeirensis but absent in current populations of D. subobscura, would be the ancestral arrangement.

Animals↗

PubMed1999

The procedure of polymerase chain reaction-restriction fragment-single strand conformation polymorphism analysis by Hha I/Hinc II to detect mitochondrial DNA mutations.

We reported 56 mitochondrial DNA (mtDNA) mutations in Japanese compared with the Cambridge Sequence by polymerase chain reaction-restriction fragment-single strand conformation polymorphism (PCR-RF-SSCP) analysis. Here we report the principle and the detailed procedures of PCR-RF-SSCP analysis. Restriction map of the 15,673 bp PCR product of mtDNA was designed by MacMolly Tetra, and Hha I and Hinc II were selected. Restriction fragment length polymorphism (RFLP) analysis of 15,673 bp PCR products by Hha I/Hinc II revealed one common pattern and 10 polymorphic patterns compared with the prediction based on the Cambridge Sequence. When the samples were electrophoresed by SSCP analysis, DNA fragments of 912 bp, 772 bp, 761 bp, 634 bp, 431 bp, 327 bp, 226 bp and 171 bp showed 6, 4, 5, 4, 5, 7, 2 and 3 polymorphic patterns, respectively. The determinations of nucleotide sequence of these 46 polymorphic patterns revealed 56 mutations compared with the Cambridge Sequence and 7 of these mutations were common in Japanese. Among these, 20 mutations have not been reported before.

DNA, Mitochondrial↗

PubMed2006

Extensive introgression of mitochondrial DNA relative to nuclear genes in the Drosophila yakuba species group.

Studies of gene flow between recently diverged species can illuminate the role of natural selection in the formation of new species. Drosophila santomea and D. yakuba are recently diverged, partially reproductively isolated species that continue to hybridize in the wild, and appear to be reproductively isolated from the more distantly related species D. teissieri. We examine patterns of nucleotide polymorphism and divergence in these three species at multiple X-linked, Y-linked, and mitochondrial markers. All three species harbor drastically reduced variability on the Y chromosome relative to the X, as expected for a nonrecombining chromosome subject to variation-reducing selection. The three species are generally well differentiated at the nuclear markers, with little evidence for recent introgression for either the X- or Y-linked genes. Based on the nuclear genes, we estimate that D. santomea and D. yakuba diverged about one-half million years ago and split from D. teissieri about one million years ago. In contrast to the pattern at nuclear loci, all three species share a very similar mtDNA haplotype. We show that the mtDNA must have recently introgressed across species boundaries in the D. yakuba subgroup and that its fixation was driven by either selection on the mitochondria itself or other cytoplasmic factors. These results demonstrate that different regions of the genome can have distinct evolutionary dynamics in the context of species formation. Although natural selection is usually thought of as accentuating divergence between species, our results imply that it can also act as a homogenizing force.

Animals↗

PubMed2005

Genealogical footprints of speciation processes in wild tomatoes: demography and evidence for historical gene flow.

Multilocus studies assessing patterns of nucleotide polymorphism within and among closely related species provide access to genealogical information bearing on demographic and geographic aspects of their speciation history. However, the technical difficulties in obtaining sufficient sequence data have severely limited this approach thus far, especially in outbred plant taxa. We employ the analytical framework of divergence population genetics in testing the isolation model of speciation in three self-incompatible species of wild tomatoes (clade Lycopersicon), in particular the assumption of divergence without gene flow. Based on DNA sequence data for 13 nuclear loci, average levels of silent polymorphism vary more than three-fold among species. We estimate a large effective population size for the ancestral species, quite similar to that of the highly polymorphic L. peruvianum. The other two species, however, exhibit concordant signatures of population-size reduction. These demographic inferences are biologically plausible and consistent with results obtained from standard neutrality tests. While the isolation model cannot be rejected by goodness-of-fit criteria, patterns of intragenic linkage disequilibrium in L. peruvianum are indicative of historical introgression at least in some regions of the genome. Considered jointly with the geographic pattern of postzygotic reproductive isolation, our results suggest that speciation occurred under residual gene flow, implying natural selection as one of the evolutionary forces driving the diversification of tomato lineages.

Base Sequence↗

PubMed2003

Molecular population genetics of the beta-esterase gene cluster of Drosophila melanogaster.

We have investigated nucleotide polymorphism at the beta-esterase gene cluster including the Est-6 gene and psiEst-6 putative pseudogene in four samples of Drosophila melanogaster derived from natural populations of southern Africa (Zimbabwe), Europe (Spain), North America (USA: California), and South America (Venezuela). A complex haplotype structure is revealed in both Est-6 and psiEst-6. Total nucleotide diversity is twice in psiEst-6 as in Est-6; diversity is higher in the African sample than in the non-African ones. Strong linkage disequilibrium occurs within the beta-esterase gene cluster in non-African samples, but not in the African one. Intragenic gene conversion events are detected within Est-6 and, to a much greater extent, within psiEst-6; intergenic gene conversion events are rare. Tests of neutrality with recombination are significant for the beta-esterase gene cluster in the non-African samples but not significant in the African one. We suggest that the demographic history (bottleneck and admixture of genetically differentiated populations) is the major factor shaping the pattern of nucleotide polymorphism in the beta-esterase gene cluster. However there are some 'footprints' of directional and balancing selection shaping specific distribution of nucleotide polymorphism within the cluster. Intergenic epistatic selection between Est-6 and psiEst-6 may play an important role in the evolution of the beta-esterase gene cluster preserving the putative pseudogene from degenerative destruction and reflecting possible functional interaction between the functional gene and the putative pseudogene. Est-6 and psiEst-6 may represent an indivisible intergenic complex ('intergene') in which each single component (Est-6 or psiEst-6) cannot separately carry out the full functional role.

Animals↗

PubMed2004

Polymorphism analysis within the HLA-A locus by universal oligonucleotide array.

Human leukocyte antigen (HLA) class I genes present some of the most complex single nucleotide polymorphism (SNP) patterns in the human genome. HLA typing is therefore extremely challenging. In this article, we use the ligation detection reaction (LDR) combined with a universal array (UA) as a robust and efficient method to analyze SNPs within the HLA-A region that includes HLA-A alleles of interest for immunotherapy in tumor diseases. The LDR, combined with a UA platform, has been optimized for the detection of 27 alleles distributed within exons 2 and 3 of HLA-A. The assay involves the amplification by PCR of the HLA-A genomic region (1,900 bp), the cycled ligation reaction, followed by the capture of ligated products through hybridization onto a UA. Each slide was designed to allow the detection of up to eight samples in parallel. The PCR/LDR/UA HLA-A assay was evaluated by analyzing 62 individuals (31 homozygous and 31 heterozygous) previously typed by direct sequencing. We demonstrate that the microarray genotyping procedure described here is a robust and efficient method for unambiguous detection of HLA alleles. HLA genotyping by PCR/LDR/UA is in perfect agreement with typing obtained by direct sequencing. Our results clearly demonstrate that the combination of enzymatic processing (LDR) and a demultiplexing hybridization onto a UA is a robust tool for SNP discrimination within the highly polymorphic HLA region. We demonstrate the specificity and efficiency of such an approach, suggesting the feasibility of a PCR/LDR/UA low resolution HLA typing procedure.

Alleles↗

PubMed2005

Inter- and intralocus recombination drive MHC class IIB gene diversification in a teleost, the three-spined stickleback Gasterosteus aculeatus.

The mutational mechanism underlying the striking diversity in MHC (major histocompatibility complex) genes in vertebrates is still controversial. In order to evaluate the role of inter- and intragenic recombination in MHC gene diversification, we examined patterns of nucleotide polymorphism across an exon/intron boundary in a sample of 31 MHC class IIB sequences of three-spined stickleback (Gasterosteus aculeatus). MHC class IIB genes of G. aculeatus were previously shown to be under diversifying (positive) selection in mate choice and pathogen selection experiments. Based on recoding of alignment gaps, complete intron 2 sequences were grouped into three clusters using maximum-parsimony analysis. Two of these groups had >90% bootstrap support and were tentatively assigned single locus status. Intron nucleotide diversity within and among loci was low (p-distance within and among groups = 0.016 and 0.019, respectively) and fourfold lower than the rate of silent mutations in exon 2, suggesting that noncoding regions are homogenized by frequent interlocus recombination. A substitution analysis using GENECONV: revealed as many intergenic conversion events as intragenic ones. Recombination between loci may explain the occurrence of sequence variants that are particularly divergent, as is the case in three-spined stickleback, with nucleotide diversity attaining dN = 0.39 (peptide-binding residues only). For both MHC class II loci we also estimated the amount of intragenic recombination as population rate (4N(e)r) under the coalescent and found it to be approximately three times higher compared to point mutations (Watterson estimate per gene, 4N(e)mu). Nonindependence of molecular evolution across loci and frequent recombination suggest that MHC class II genes of bony fish may follow different evolutionary dynamics than those of mammals. Our finding of widespread recombination suggests that phylogenies of MHC genes should not be based on coding segments but rather on noncoding introns.

Animals↗

PubMed2004

Sarcocystis neurona major surface antigen gene 1 (SAG1) shows evidence of having evolved under positive selection pressure.

The major surface antigen gene 1 (SAG1) is conserved among members of Sarcocystidae and may play an important role in parasite pathogenesis. Additionally, generation and selection of different antigenic variants of SAG1 has the potential for inclusion in a subunit vaccine or in the development of a diagnostic assay. In this study, patterns of nucleotide polymorphism were used to test the hypothesis that natural selection promotes diversity in different parts of SAG1 of Sarcocystis neurona. Nucleotide and amino acid sequence analysis of SAG1 from multiple S. neurona isolates identified two alleles. Sequences were identical intra-allele and highly divergent inter-alleles. Also, phylogenetic reconstruction showed sequences clustering into two clades. Tajima's and Fu and Li's neutrality tests indicated that selection is more likely to be acting on SAG1. Moreover, a sliding window analysis based on the ratio of silent substitutions to amino acid replacements provided strong evidence that two short segments in the central and 3' domain of SAG1 have been under positive selection in the divergence of the two alleles, suggesting that it may be important for the evasion of host immune responses and would be a suitable target for vaccine development.

Animals↗

PubMed2002

Molecular evolution of FOXP2, a gene involved in speech and language.

Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution.

Alleles↗