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PubMed1995

Nucleotide diversity of mitochondrial DNAs between the swamp and the river types of domestic water buffaloes, Bubalus bubalis, based on restriction endonuclease cleavage patterns.

Cleavage patterns of mitochondrial DNAs (mtDNAs) by 15 restriction endonucleases were analyzed for 10 swamp and 13 river types of domestic water buffaloes. Digestions with nine enzymes exhibited polymorphisms giving two or three kinds of cleavage patterns. Five mtDNA types were identified, three types in the swamp buffaloes of the Philippines, Vietnam, and Indonesia (S-types) and two types in the river buffaloes of Bangladesh and Pakistan (R-types). Nucleotide diversities ranged from 0.2 to 0.6% within the S- and R-types and from 1.9 to 2.4% between the R-types and the S-types. These values indicated that R-type and S-type mtDNAs differentiated at the subspecific level of other mammalian species reported. The possibility of polyphyletic domestication in different places is discussed for the origin of two distinct types of domestic water buffaloes.

Animals↗

PubMed2005

Large-scale genomic correlations in Arabidopsis thaliana relate to chromosomal structure.

BACKGROUND: The chromosomes of the plant Arabidopsis thaliana contain various genomic elements, distributed with appreciable spatial heterogeneity. Clustering of and/or correlations between these elements presumably should reflect underlying functional or structural factors. We studied the positional density fluctuations and correlations between genes, indels, single nucleotide polymorphisms (SNPs), retrotransposons, 180 bp tandem repeats, and conserved centromeric sequences (CCSs) in Arabidopsis in order to elucidate any patterns and possible responsible factors for their genomic distributions. RESULTS: The spatial distributions of all these elements obeyed a common pattern: the density profiles of each element within chromosomes exhibited low-frequency fluctuations indicative of regional clustering, and the individual density profiles tended to correlate with each other at large measurement scales. This pattern could be attributed to the influence of major chromosomal structures, such as centromeres. At smaller scales the correlations tended to weaken -- evidence that localized cis-interactions between the different elements had a comparatively minor, if any, influence on their placement. CONCLUSION: The conventional notion that retrotransposon insertion sites are strongly influenced by cis-interactions was not supported by these observations. Moreover, we would propose that large-scale chromosomal structure has a dominant influence on the intrachromosomal distributions of genomic elements, and provides for an additional shared hierarchy of genomic organization within Arabidopsis.

Arabidopsis↗

PubMed2003

A survey of chromosomal and nucleotide sequence variation in Drosophila miranda.

There have recently been several studies of the evolution of Y chromosome degeneration and dosage compensation using the neo-sex chromosomes of Drosophila miranda as a model system. To understand these evolutionary processes more fully, it is necessary to document the general pattern of genetic variation in this species. Here we report a survey of chromosomal variation, as well as polymorphism and divergence data, for 12 nuclear genes of D. miranda. These genes exhibit varying levels of DNA sequence polymorphism. Compared to its well-studied sibling species D. pseudoobscura, D. miranda has much less nucleotide sequence variation, and the effective population size of this species is inferred to be several-fold lower. Nevertheless, it harbors a few inversion polymorphisms, one of which involves the neo-X chromosome. There is no convincing evidence for a recent population expansion in D. miranda, in contrast to D. pseudoobscura. The pattern of population subdivision previously observed for the X-linked gene period is not seen for the other loci, suggesting that there is no general population subdivision in D. miranda. However, data on an additional region of period confirm population subdivision for this gene, suggesting that local selection is operating at or near period to promote differentiation between populations.

Alleles↗

PubMed1998

Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1.

In at least 98% of fragile X syndrome cases, the disease results from expansion of the CGG repeat in the 5' end of FMR1. The use of microsatellite markers in the FMR1 region has revealed a disparity of risk between haplotypes for CGG repeat expansion. Although instability appears to depend on both the haplotype and the AGG interspersion pattern of the repeat, these factors alone do not completely describe the molecular basis for the linkage disequilibrium between normal and fragile X chromosomes, in part due to instability of the marker loci themselves. In an effort to better understand the mechanism of dynamic mutagenesis, we have searched for and discovered a single nucleotide polymorphism in intron 1 of FMR1 and characterized this marker, called ATL1, in 564 normal and 152 fragile X chromosomes. The G allele of this marker is found in 40% of normal chromosomes, in contrast to 83% of fragile X chromosomes. Not only is the G allele exclusively linked to haplotypes over-represented in fragile X syndrome, but G allele chromosomes also appear to transition to instability at a higher rate on haplotypes negatively associated with risk of expansion. The two alleles of ATL1 also reveal a highly significant linkage disequilibrium between unstable chromosomes and the 5' end of the CGG repeat itself, specifically the position of the first AGG interruption. The data expand the number of haplotypes associated with FMR1 and specifically allow discrimination, by ATL1 alleles, of single haplotypes with differing predispositions to expansion. Such haplotypes should prove useful in further defining the mechanism of dynamic mutagenesis.

Adenine Nucleotides↗

PubMed2003

Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region.

Recombination, demographic history, drift and selection influence the extent of linkage disequilibrium (LD) in the human genome, but their relative contributions remain unclear. To investigate the effect of meiotic recombination versus population history on LD, three populations with different demographic histories (UK north Europeans, Saami and Zimbabweans) were genotyped for high-frequency single-nucleotide polymorphisms (SNPs) across a 75 kb DNA segment of the MHC class II region. This region spans three well-characterized recombination hotspots and a 60 kb long LD block. Despite a high level of underlying haplotype diversity and considerable divergence in haplotype composition between populations, all three populations showed very similar patterns of LD. Surprisingly, the entire 60 kb LD block was present even in Africans, although it was relatively difficult to detect owing to a systematic deficiency of high frequency SNPs. In contrast, DNA within recombination hotspots did not show this low nucleotide diversity in Africans. Thus, while population history has some influence on LD, our findings suggest that recombination hotspots play a major global role in shaping LD patterns as well as helping to maintain localized SNP diversity in this region of the MHC.

Female↗

PubMed1996

Two novel missense mutations in the LDL receptor gene causing familial hypercholesterolemia.

We have employed analysis of single-strand conformation polymorphisms to identify mutations in the low density lipoprotein receptor gene causing familial hypercholesterolemia. Two familial hypercholesterolemia heterozygotes had abnormal single-strand conformation polymorphism patterns of exons 4 and 8. DNA sequencing revealed that the abnormal pattern of exon 4 was due to heterozygosity (G/T) at nucleotide 502. Nucleotide 502 is the first base of codon 147, and the G->T mutation (D147Y) changes this codon from AspGAC to TyrUAC. The abnormal pattern of exon 8 was due to heterozygosity (A/G) at nucleotide 1097. Nucleotide 1097 is the second base of codon 345, and the A->G mutation (Q345R) changes this codon from GlnCAG to ArgCGG. Based upon screening of 437 unrelated familial hypercholesterolemia heterozygotes, both D147Y and Q345R account for about 0.5% of the mutations causing familial hypercholesterolemia in Norway.

Base Sequence↗

PubMed1992

Nucleotide polymorphism at the xanthine dehydrogenase locus in Drosophila pseudoobscura.

Sequential polyacrylamide electrophoresis has revealed 20 allozymes of xanthine dehydrogenase (XDH) in Drosophila pseudoobscura. DNA sequence determination of seven isolates of the Xdh locus that represent six allozyme classes are presented here. Of the 5,456 sites examined, 180 are polymorphic, with 27 polymorphisms occurring at nonsynonymous, or replacement, sites. An average of nine amino acids differ between XDH allozyme classes, with 85% of the polymorphic amino acids singly represented. The level and pattern of variation observed at Xdh argue that the effective population size of the species is quite large--i.e., on the order of 2 x 10(6)--and that the populations sampled are quite ancient. In addition, as judged by two statistical tests, the levels of nucleotide polymorphism observed at Xdh are compatible with predictions from the neutral theory of molecular evolution.

Alleles↗

PubMed2003

5'-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients.

White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9-a critical enzyme in the drug's metabolism. Accordingly, analysis of the -2.1-kb 5'-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5'-flanking patterns linked with at least one CYP2C9*3 allele or CYP2C9*2/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wild-type promoter and coding sequences had significantly (P <.01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese.

Alleles↗

PubMed2004

The impact of SNP density on fine-scale patterns of linkage disequilibrium.

Linkage disequilibrium (LD) is a measure of the degree of association between alleles in a population. The detection of disease-causing variants by association with neighbouring single nucleotide polymorphisms (SNPs) depends on the existence of strong LD between them. Previous studies have indicated that the extent of LD is highly variable in different chromosome regions and different populations, demonstrating the importance of genome-wide accurate measurement of LD at high resolution throughout the human genome. A uniform feature of these studies has been the inability to detect LD in regions of low marker density. To investigate the dependence of LD patterns on marker selection we performed a high-resolution study in African-American, Asian and UK Caucasian populations. We selected over 5000 SNPs with an average spacing of approximately 1 SNP per 2 kb after validating ca 12 000 SNPs derived from a dense SNP collection (1 SNP per 0.3 kb on average). Applications of different statistical methods of LD assessment highlight similar areas of high and low LD. However, at high resolution, features such as overall sequence coverage in LD blocks and block boundaries vary substantially with respect to marker density. Model-based linkage disequilibrium unit (LDU) maps appear robust to marker density and consistently influenced by marker allele frequency. The results suggest that very dense marker sets will be required to yield stable views of fine-scale LD in the human genome.

Black or African American↗

PubMed2006

An artificial neural network approach to the drug efficacy of interferon treatments.

INTRODUCTION: Interferon taken alone or in combination with ribavirin can be used for the treatment of persons with chronic hepatitis C. It is highly desirable, both clinically and economically, to establish tools to distinguish responders from nonresponders and to predict possible outcomes of the treatments. In this work, our goal is to develop a prediction model resulting from the analysis of chronic hepatitis C patients' single nucleotide polymorphisms, viral genotype, viral load, age and gender, to predict the responsiveness of interferon combination treatment. MATERIALS AND METHODS: We collected blood samples from 523 chronic hepatitis C patients that had received interferon and ribavirin combination therapy. Based on the current treatment strategy for chronic hepatitis C patients, we focused our search for candidate genes involved in pathways related to interferon signaling and immunomodulation. With artificial neural network algorithms, we then developed pattern recognition methodologies to achieve predictions among the patients. The artificial neural network model was trained by an algorithm with an adaptive momentum and learning rate. RESULTS: There were seven single nucleotide polymorphisms selected from six candidate genes including adenosine deaminase-RNA-specific, caspase 5, interferon consensus sequence binding protein 1, interferon-induced protein 44, phosphoinositide-3-kinase catalytic gamma polypeptide and transporter 2 ATP-binding cassette subfamily B genes. We further applied the artificial neural network algorithms with these seven single nucleotide polymorphisms, viral genotype, viral load, age and gender information to build tools for predicting the responsiveness of interferon. Based on the fivefold cross-validation method to evaluate the performance, the model achieved a high success rate of prediction. CONCLUSION: We demonstrated that a trained artificial neural network model is a promising method for providing the inference from factors such as single nucleotide polymorphisms, viral genotype, viral load, age and gender to the responsiveness of interferon.

Aging↗

PubMed2006

Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation.

Meiotic crossovers in the human genome cluster into highly localized hotspots identifiable indirectly from patterns of DNA diversity and directly by high-resolution sperm typing. Little is known about factors that control hotspot activity and the apparently rapid turnover of hotspots during recent evolution. Clues can, however, be gained by characterizing variation in sperm crossover activity between men. Previous studies have identified single nucleotide polymorphisms within hotspots that appear to suppress crossover activity and which may be involved in hotspot attenuation/extinction. We now analyse a closely spaced pair of hotspots (MSTM1a, MSTM1b) on chromosome 1q42.3, the former being a candidate for a young hotspot that has failed to leave a significant mark on haplotype diversity. Extensive surveys of different men revealed substantial polymorphism in sperm crossover frequencies at both hotspots, but with very different patterns of variation. Hotspot MSTM1b was active in all men tested but with widely differing crossover frequencies. In contrast, MSTM1a was active in only a few men and appeared to be recombinationally inert in the remainder, providing the first example of presence/absence polymorphism of a human hotspot. Haplotype analysis around both hotspots identified active and suppressed men sharing identical haplotypes, establishing that these major variations in the presence/absence of a hotspot and in quantitative activity are not caused by local DNA sequence variation. These findings suggest a role for distal regulators or epigenetic factors in hotspot activity and provide the first direct evidence for the rapid evolution of recombination hotspots in humans.

Chromosome Mapping↗

PubMed1993

Polymorphism of human complement component C6: an amino acid substitution (Glu/Ala) within the second thrombospondin repeat differentiates between the two common allotypes C6 A and C6 B.

Component C6 of the human complement system exhibits a genetic polymorphism in all populations tested so far. Using isoelectric focusing two common allotypes, C6 A ('acidic') and C6 B ('basic') and a number of rare variants have been described. A comparison of the two published cDNA sequences of C6 suggests a polymorphism in codon 98. Using polymerase chain reaction (PCR) we amplified a segment of the human C6 gene encompassing the presumably polymorphic codon. According to the restriction fragment patterns obtained after DdeI digestion of the PCR product, three genotypes were distinguished. The polymorphism is caused by a nucleotide substitution (C-->A) in the second position of codon 98; allele 1 (GCG) codes for Ala, allele 2 (GAG) for Glu. Sequencing of PCR products confirmed the mutation. For 46 unrelated individuals genotyped by this PCR-based method we also determined C6 protein phenotype. Three phenotypes were observed (C6 A, C6 AB, C6 B). There was an absolute concordance between C6 protein typing and DNA typing. We thus conclude that the C6 A allotype is characterized by a Glu and the C6 B allotype by an Ala residue in position 98 of the C6 polypeptide chain.

Alanine↗

PubMed2004

New method of differentiating wild-type varicella-zoster virus (VZV) strains from Oka varicella vaccine strain by VZV ORF 6-based PCR and restriction fragment length polymorphism analysis.

A new method was developed to distinguish accurately wild-type varicella-zoster virus (VZV) strains from the Oka vaccine strain. Several DNA fragments covering open reading frame (ORF) 1-37 were amplified from wild-type VZV strains including the Oka parent strain and from the Oka vaccine strain. Restriction fragment length polymorphisms of these regions were compared, and nucleotide differences between the vaccine virus and other wild-type VZV strains were noted in ORFs 6, 10, and 35. In addition, variations of the R2 and R4 reiterated structures of the vaccine and its parent strains were examined. The Oka vaccine strain used in Japan was shown to be a mixture of viruses with different nucleotide sequences that had variations in at least three nucleotide positions in ORF 1-37 and had variable polymorphisms at R2 and R4 repeat regions (two and three patterns, respectively). The Oka parent strain on the other hand showed a single sequence and had only one reiterated structure at these regions. When VZV ORF 6 was amplified and its product was digested with AluI, the Oka vaccine strain could be precisely differentiated from its parent and from 56 other Japanese clinical isolates.

Chickenpox Vaccine↗

PubMed2005

Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.

Cell Line, Tumor↗

PubMed2025

Epigenome-wide association study of placental co-methylated regions in newborns for prenatal opioid exposure.

The increasing incidence of opioid use during pregnancy has led to a rise in the number of infants exposed to opioids in utero. Prenatal opioid exposure may have consequences for health and (neuro)development, including neonatal opioid withdrawal syndrome (NOWS). It is unknown which infants are at greatest risk for NOWS. DNA methylation (DNAm) is an epigenetic mark reflecting both allelic variation and environmental exposures, which may provide biomarkers for prenatal opioid exposure and infant NOWS. The placenta is an accessible, biologically relevant tissue in which to directly investigate the epigenetic effects of prenatal opioid exposure. Therefore, the aims of this study were to examine whether prenatal opioid exposure is associated with differential DNAm, including epigenetic age acceleration (EAA) in the placenta. We performed an epigenome-wide association study based on co-methylated regions and single CpG sites in placental samples from in utero opioid-exposed (n = 19) and nonexposed infants (n = 143), correcting for potential confounders. We did not identify statistically significant differential DNAm profiles, but the strongest associations were found for cg06621211; cg18688392 (ZMIZ1, adjusted P = .068) and cg04460738 (KCNMA1, adjusted P = .068), although effect sizes were very small. One of these DNAm patterns (cg06621211) was in part under control of genetic variants through methylation quantitative trait loci. The involved single nucleotide polymorphism did not show significant associations in recent genome-wide association studies for phenotypes related to substance use, and the finding was not driven by potential co-occurring substance use based on sensitivity analyses. There was also no association between placental EAA and in utero opioid exposure. In conclusion, placental DNAm showed limited associations with in utero opioid exposure and NOWS diagnosis.

DNA methylation↗

PubMed2003

Estimating the time since the fixation of a beneficial allele.

The fixation of a beneficial allele in a population leaves a well-characterized signature in patterns of nucleotide variation at linked sites. This signature can be used to estimate the time since fixation from patterns of polymorphism in extant individuals. I introduce a method to assess the support in polymorphism data for a recent episode of directional positive selection and to estimate the time since fixation. I summarize the polymorphism data by three statistics that carry information about levels of diversity, the allele frequency spectrum, and the extent of allelic associations. Simulations are then used to obtain a sample from the posterior distribution of the time since fixation, conditional on the observed summaries. I test the performance of the approach on simulated data and apply it to the gene tb1 in maize. The data support the recent fixation of a favored allele, consistent with what is known about the importance of tb1 in the domestication process of maize.

Algorithms↗

PubMed2006

Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools.

The vast amount of protein sequence data now available, together with accumulating experimental knowledge of protein function, enables modeling of protein sequence and function evolution. The PANTHER database was designed to model evolutionary sequence-function relationships on a large scale. There are a number of applications for these data, and we have implemented web services that address three of them. The first is a protein classification service. Proteins can be classified, using only their amino acid sequences, to evolutionary groups at both the family and subfamily levels. Specific subfamilies, and often families, are further classified when possible according to their functions, including molecular function and the biological processes and pathways they participate in. The second application, then, is an expression data analysis service, where functional classification information can help find biological patterns in the data obtained from genome-wide experiments. The third application is a coding single-nucleotide polymorphism scoring service. In this case, information about evolutionarily related proteins is used to assess the likelihood of a deleterious effect on protein function arising from a single substitution at a specific amino acid position in the protein. All three web services are available at http://www.pantherdb.org/tools.

Amino Acid Substitution↗

PubMed1992

Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene.

Human piebald trait is an autosomal dominant defect in melanocyte development characterized by patches of hypopigmented skin and hair. Although the molecular basis of piebaldism has been unclear, a phenotypically similar "dominant spotting" of mice is caused by mutations in the murine c-kit protooncogene. In this regard, one piebald case with a point mutation and another with a deletion of c-kit have been reported, although a polymorphism or the involvement of a closely linked gene could not be excluded. To confirm the hypothesis that piebaldism results from mutations in the human gene, c-kit exons were amplified by polymerase chain reaction from the DNA of 10 affected subjects and screened for nucleotide changes by single-stranded conformation polymorphism analysis. In one subject with a variant single-stranded conformation polymorphism pattern for the first exon encoding the kinase domain, DNA sequencing demonstrated a missense mutation (Glu583----Lys). This mutation is identical to the mouse W37 mutation which abolishes autophosphorylation of the protein product and causes more extensive depigmentation than "null" mutations. In accord with this "dominant negative" effect, the identical mutation in this human kindred is associated with unusually extensive depigmentation. Thus, the finding of a piebald subject with a mutation that impairs receptor activity strongly implicates the c-kit gene in the molecular pathogenesis of this human developmental defect.

Alleles↗