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PubMed2006

The speciation history of the Drosophila nasuta complex.

The Drosophila nasuta subgroup of the immigrans species group is widely distributed throughout the South-East Asian region, consisting of morphologically similar species with varying degrees of reproductive isolation. Here, I report nucleotide variability data for five X-linked and two mtDNA loci in eight taxa from the nasuta subgroup, with deeper sampling from D. albomicans and its sister species D. nasuta. Phylogenetic relationships among these species vary among different genomic regions, and levels of genetic differentiation suggest that this species group diversified only about one million years ago. D. albomicans and D. nasuta share nucleotide polymorphisms and are distinguished by relatively few fixed differences. Patterns of genetic differentiation between this species pair are compatible with a simple isolation model with no gene flow. Nucleotide variability levels of species in the nasuta group are comparable to those in members of the melanogaster and pseudoobscura species groups, indicating effective population sizes on the order of several million. Population genetic analyses reveal that summaries of the frequency distribution of neutral polymorphisms in both D. albomicans and D. nasuta generally fit the assumptions of the standard neutral model. D. albomicans is of particular interest for evolutionary studies because of its recently formed neo-sex chromosomes, and our phylogenetic and population genetic analyses suggest that it might be an ideal model to study the very early stages of Y chromosome evolution.

Animals↗

PubMed2006

A scan statistic for identifying chromosomal patterns of SNP association.

We have developed a single nucleotide polymorphism (SNP) association scan statistic that takes into account the complex distribution of the human genome variation in the identification of chromosomal regions with significant SNP associations. This scan statistic has wide applicability for genetic analysis, whether to identify important chromosomal regions associated with common diseases based on whole-genome SNP association studies or to identify disease susceptibility genes based on dense SNP positional candidate studies. To illustrate this method, we analyzed patterns of SNP associations on chromosome 19 in a large cohort study. Among 2,944 SNPs, we found seven regions that contained clusters of significantly associated SNPs. The average width of these regions was 35 kb with a range of 10-72 kb. We compared the scan statistic results to Fisher's product method using a sliding window approach, and detected 22 regions with significant clusters of SNP associations. The average width of these regions was 131 kb with a range of 10.1-615 kb. Given that the distances between SNPs are not taken into consideration in the sliding window approach, it is likely that a large fraction of these regions represents false positives. However, all seven regions detected by the scan statistic were also detected by the sliding window approach. The linkage disequilibrium (LD) patterns within the seven regions were highly variable indicating that the clusters of SNP associations were not due to LD alone. The scan statistic developed here can be used to make gene-based or region-based SNP inferences about disease association.

Chromosome Mapping↗

PubMed2005

Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing.

Aberrant or modified splicing patterns of genes are causative for many human diseases. Therefore, the identification of genetic variations that cause changes in the splicing pattern of a gene is important. Elsewhere, we described the widespread occurrence of alternative splicing at NAGNAG acceptors. Here, we report a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, we extracted 64 SNPs that most likely affect alternative NAGNAG splicing. We demonstrate that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. The evolutionarily young NAGNAG alleles, as determined by the comparison with the chimpanzee genome, exhibit the same biases toward intron phase 1 and single-amino acid insertion/deletions that were already observed for all human NAGNAG acceptors. Since 28% of the NAGNAG SNPs occur in known disease genes, they represent preferable candidates for a more-detailed functional analysis, especially since the splice relevance for some of the coding SNPs is overlooked. Against the background of a general lack of methods for identifying splice-relevant SNPs, the presented approach is highly effective in the prediction of polymorphisms that are causal for variations in alternative splicing.

Alleles↗

PubMed2002

Strains of Escherichia coli O157:H7 differ primarily by insertions or deletions, not single-nucleotide polymorphisms.

Escherichia coli O157:H7 (O157) strains demonstrate varied pulsed-field gel electrophoresis patterns following XbaI digestion, which enable epidemiological surveillance of this important human pathogen. The genetic events underlying PFGE differences between strains, however, are not defined. We investigated the mechanisms for strain variation in O157 by recovering and examining nucleotide sequences flanking each of the XbaI restriction enzyme sites in the genome. Our analysis demonstrated that differences between O157 strains were due to discrete insertions or deletions that contained the XbaI sites polymorphic between strains rather than single-nucleotide polymorphisms in the XbaI sites themselves. These insertions and deletions were found to be uniquely localized within the regions of the genome that are specific to O157 compared to E. coli K-12 (O islands), suggesting that strain-to-strain variation occurs in these O islands. These results may be utilized to devise novel strain-typing tools for this pathogen.

Chromosomes, Bacterial↗

PubMed2003

Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism.

CCND1 mRNA is alternatively spliced to produce 2 transcripts, and the splicing pattern may be modulated by a frequent A870G single-nucleotide polymorphism within the conserved splice donor site of exon 4. Several studies have suggested a significant association between the CCND1 genotype and onset or progression of various cancers. To investigate the correlation of the polymorphism with genetic susceptibility to PCa and its disease status, we examined the polymorphism in 214 cases of PCa, 234 cases of BPH and 254 male controls. The CCND1 A allele was more frequently observed in the PCa group (p = 0.015) and the BPH group (p = 0.018) than the control group. Men with the AA genotype had an increased risk of PCa (aOR = 1.93, 95% CI 1.13-3.30, p = 0.016) and BPH (aOR = 1.84, 95% CI 1.09-3.09, p = 0.023) compared to those with the GG genotype. No significant association was observed when men with the AG genotype were compared to those with the GG genotype (PCa: aOR = 1.00, 95% CI 0.65-1.54, BPH: aOR = 0.91, 95% CI 0.60-1.39). The risk of PCa associated with the AA genotype appeared to be stronger in men aged 73 years or younger (aOR = 2.89, 95% CI 1.38-6.01, p = 0.005), whereas no association was found in men older than 73 years (aOR = 1.02, 95% CI 0.44-2.34). No significant difference in genotype frequency was found among patients with low-, intermediate- and high-grade tumors (p = 0.730) or between patients with localized and metastatic PCa (p = 0.679). However, in patients with high-grade or metastatic PCa, a significantly increased risk associated with the AA genotype compared to controls was observed, while no significant results were found in those with low/intermediate or localized PCa. The A allele of the CCND1 A870G polymorphism was recessively associated with susceptibility to PCa and BPH in a Japanese population, giving a 2-fold increased risk of PCa and BPH in men with the AA genotype compared to those with the GG genotype. Although the risk of PCa associated with the AA genotype appeared to contribute especially to men aged 73 years or younger and the A allele may be associated with disease status of PCa, these conjectures require validation in future studies on a larger number of subjects.

Adenocarcinoma↗

PubMed2006

Genotypic analysis of Mycobacterium leprae isolates from Japan and other Asian countries reveals a global transmission pattern of leprosy.

The genotype of single-nucleotide polymorphism type 3, CTC, at positions 14676, 164275, and 2935685, along with four copies of 6 bp repeats in the rpoT gene, was predominant for isolates originating in the Japanese mainland. Type 1, CGA, type 2, CTA, and type 3 were detected from Korea, Indonesia, and Myanmar. No isolates with four copies of 6 bp were detected from Myanmar, Okinawa, and Japanese Brazilian patients. Type 4, TTC, with three copies of 6 bp, was detected only from Japanese Brazilians. The results indicate that infection occurred in Brazil and the disease developed later in Japan.

Adolescent↗

PubMed2003

Using denaturing HPLC for SNP discovery and genotyping, and establishing the linkage disequilibrium pattern for the all-trans-retinol dehydrogenase (RDH8) gene.

All-trans-retinol dehydrogenase (RDH8) is a visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol. As part of an on-going effort to map genes involved in complex eye diseases, myopia in particular, using association studies, single nucleotide polymorphisms (SNPs) were identified and linkage disequilibrium (LD) pattern was established within and around the RDH8 gene. We used denaturing high-performance liquid chromatography (DHPLC) to screen SNPs in four DNA pools each consisting of DNA from five individuals and genotyped the identified SNPs in 150 Chinese subjects from Hong Kong. Fifteen SNPs were identified: seven were common with the minor allele frequency >0.05 and ten were novel. Common SNPs were included in LD and haplotype analysis using the ASSOCIATE and EH programmes. Four SNPs in the 3' region exhibited significant LD and formed a haplotype block, while three common SNPs in the 5' region did not exhibit useful LD. The LD pattern around the RDH8 gene suggested that one SNP from the 3'region and two to three SNPs from the 5' region were needed in association studies involving RDH8. Our results demonstrated the efficiency of DHPLC in screening SNPs when coupled with DNA pooling strategy and in genotyping SNPs.

Alcohol Oxidoreductases↗

PubMed2001

A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity.

CD14 is a pattern recognition receptor that plays a central role in innate immunity through recognition of bacterial lipoglycans, primarily LPS. Recently, our group has identified a common single nucleotide polymorphism, -159C-->T, in the CD14 proximal promoter. Homozygous carriers of the T allele have a significant increase in soluble CD14, but a decreased total serum IgE. This epidemiologic evidence led us to investigate the molecular basis for the effects of CD14/-159C-->T on CD14 regulation in monocytes and hepatocytes, the two major cell types known to express this gene in vivo. EMSA analysis showed that the T allele results in decreased affinity of DNA/protein interactions at a GC box that contains a binding site for Sp1, Sp2, and Sp3 transcription factors. In reporter assays, the transcriptional activity of the T allele was increased in monocytic Mono Mac 6 cells, which express low levels of Sp3, a member of the Sp family with inhibitory potential relative to activating Sp1 and Sp2. By contrast, both alleles were transcribed equivalently in Sp3-rich hepatocytic HepG2 cells. Our data indicate that the interplay between CD14 promoter affinity and the [Sp3]:[Sp1 + Sp2] ratio plays a critical mechanistic role in regulating transcription of the two CD14 alleles. Variation in a key gene of innate immunity may be important for the pathogenesis of allergy and inflammatory disease through gene-by-gene and/or gene-by-environment interactions.

Base Sequence↗

PubMed2000

Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays.

Most human cancers are characterized by genomic instability, the accumulation of multiple genetic alterations and allelic imbalance throughout the genome. Loss of heterozygosity (LOH) is a common form of allelic imbalance and the detection of LOH has been used to identify genomic regions that harbor tumor suppressor genes and to characterize tumor stages and progression. Here we describe the use of high-density oligonucleotide arrays for genome-wide scans for LOH and allelic imbalance in human tumors. The arrays contain redundant sets of probes for 600 genetic loci that are distributed across all human chromosomes. The arrays were used to detect allelic imbalance in two types of human tumors, and a subset of the results was confirmed using conventional gel-based methods. We also tested the ability to study heterogeneous cell populations and found that allelic imbalance can be detected in the presence of a substantial background of normal cells. The detection of LOH and other chromosomal changes using large numbers of single nucleotide polymorphism (SNP) markers should enable identification of patterns of allelic imbalance with potential prognostic and diagnostic utility.

Adenocarcinoma↗

PubMed2004

The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis.

Ankylosing spondylitis (AS) is a common and highly heritable inflammatory arthropathy. Although the gene HLA-B27 is almost essential for the inheritance of the condition, it alone is not sufficient to explain the pattern of familial recurrence of the disease. We have previously demonstrated suggestive linkage of AS to chromosome 2q13, a region containing the interleukin 1 (IL-1) family gene cluster, which includes several strong candidates for involvement in the disease. In the current study, we describe strong association and transmission of IL-1 family gene cluster single-nucleotide polymorphisms and haplotypes with AS.

Chromosomes, Human, Pair 2↗

PubMed2005

Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma.

RATIONALE: Allergic diseases are influenced by both genes and environment. A 70-kb haplotype block in the G protein-coupled receptor for asthma susceptibility gene (GPR154; alias GPRA) on chromosome 7p was recently identified to influence susceptibility to asthma and elevated total serum IgE levels in adults. OBJECTIVES: To assess the impact of GPR154 on childhood allergic disease, including allergic sensitization, asthma, and rhinoconjunctivitis, in study populations with diverse environmental backgrounds. METHODS: We studied farm children, Steiner school children, and two reference groups from five Western European countries in the cross-sectional PARSIFAL (Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle) study and a sample of children from the Swedish birth cohort study BAMSE. DNA samples from 3,113 PARSIFAL and 800 BAMSE children were genotyped for 7 GPR154 polymorphisms and haplotypes were inferred. The proportions of alleles and haplotypes (H1-H7) were compared in affected children with their healthy counterparts. RESULTS: Data indicate a global association of the haplotype block to sensitization (allergen-specific serum IgE > or = 0.35 kU/L, p = 0.022), with significant haplotype-specific associations for H1, H5, and H6. Haplotypes H1 and H5 were also significantly associated with childhood allergic asthma (p = 0.045 and p = 0.023, respectively), and H5 to asthma regardless of sensitization. A broader involvement of GPR154 in allergic diseases was further supported in allergic rhinoconjunctivitis (H3: p = 0.046). The associated haplotypes could be allocated into risk (H5/H6) and nonrisk (H1/H3) groups, a pattern supported by allelic association of single nucleotide polymorphisms (SNPs) rs324384 and rs324396. CONCLUSIONS: Our results indicate that polymorphisms and haplotypes in the haplotype block of GPR154 are associated with asthma, rhinoconjunctivitis, and sensitization in European children.

Adolescent↗

PubMed2002

Single nucleotide polymorphisms and disease gene mapping.

Single nucleotide polymorphisms are the most important and basic form of variation in the genome, and they are responsible for genetic effects that produce susceptibility to most autoimmune diseases. The rapid development of databases containing very large numbers of single nucleotide polymorphisms, and the characterization of haplotypes and patterns of linkage disequilibrium throughout the genome, provide a unique opportunity to advance association strategies in common disease rapidly over the next few years. Only the careful use of these strategies and a clear understanding of their statistical limits will allow novel genetic determinants for many of the common autoimmune diseases to be determined.

Autoimmune Diseases↗

PubMed2001

Contrasting patterns of X-linked and autosomal nucleotide variation in Drosophila melanogaster and Drosophila simulans.

Surveys of molecular variation in Drosophila melanogaster and Drosophila simulans have suggested that diversity outside of Africa is a subset of that within Africa. It has been argued that reduced levels of diversity in non-African populations reflect a population bottleneck, adaptation to temperate climates, or both. Here, I summarize the available single-nucleotide polymorphism data for both species. A simple "out of Africa" bottleneck scenario is consistent with geographic patterns for loci on the X chromosome but not with loci on the autosomes. Interestingly, there is a trend toward lower nucleotide diversity on the X chromosome relative to autosomes in non-African populations of D. melanogaster, but the opposite trend is seen in African populations. In African populations, autosomal inversion polymorphisms in D. melanogaster may contribute to reduced autosome diversity relative to the X chromosome. To elucidate the role that selection might play in shaping patterns of variability, I present a summary of within- and between-species patterns of synonymous and replacement variation in both species. Overall, D. melanogaster autosomes harbor an excess of amino acid replacement polymorphisms relative to D. simulans. Interestingly, range expansion from Africa appears to have had little effect on synonymous-to-replacement polymorphism ratios.

Animals↗

PubMed2006

Challenges in the phenotypic characterisation of patients in genetic studies of coronary artery disease.

Coronary artery disease and acute myocardial infarction are complex traits in which there has been recent research to identify the principal genes that engender susceptibility or provide protection. Although there has been exceptional progress in the technology, which now allows genotyping of hundreds of thousands of single-nucleotide polymorphisms in each individual, there remains a pattern of inconsistency in the studies performed to date, in part owing to the difficulties in defining cases and controls. In this paper, salient issues to facilitate research in this important field are reviewed.

Adolescent↗

PubMed2002

The canine Phosducin gene: characterization of the exon-intron structure and exclusion as a candidate gene for generalized progressive retinal atrophy in 11 dog breeds.

PURPOSE: The exon-intron structure of the canine Phosducin (PDC) gene was identified and the gene evaluated as a candidate for generalized progressive retinal atrophy (gPRA) in 20 dog breeds. METHODS: Intronic sequences of the PDC gene were analyzed after amplification using polymerase chain reaction (PCR) and following sequencing from clones isolated from a canine genomic library. Mutation screening was performed by PCR with single strand conformation polymorphism (SSCP) analysis. Conspicuous banding patterns were analyzed via sequence analyses to detect the underlying nucleotide variations. RESULTS: No polymorphisms were identified after PCR-SSCP analysis within the entire coding region of the PDC gene. A 3 bp deletion in intron intervening sequence (IVS) 3 (position -16 to -18) was observed in 9 breeds, a T->A transversion (position IVS3 -63) in 10 breeds and an A->T transversion (position IVS3 -64) in 2 dog breeds. CONCLUSIONS PDC was excluded as a candidate gene for autosomal recessively (ar) transmitted gPRA in 11 of the 20 dog breeds investigated.

Animals↗

PubMed2005

A multilocus sequence survey in Arabidopsis thaliana reveals a genome-wide departure from a neutral model of DNA sequence polymorphism.

The simultaneous analysis of multiple genomic loci is a powerful approach to studying the effects of population history and natural selection on patterns of genetic variation of a species. By surveying nucleotide sequence polymorphism at 334 randomly distributed genomic regions in 12 accessions of Arabidopsis thaliana, we examined whether a standard neutral model of nucleotide sequence polymorphism is consistent with observed data. The average nucleotide diversity was 0.0071 for total sites and 0.0083 for silent sites. Although levels of diversity are variable among loci, no correlation with local recombination rate was observed, but polymorphism levels were correlated for physically linked loci (<250 kb). We found that observed distributions of Tajima's D- and D/D(min)- and of Fu and Li's D-, D*- and F-, F*-statistics differed significantly from the expected distributions under a standard neutral model due to an excess of rare polymorphisms and high variances. Observed and expected distributions of Fay and Wu's H were not different, suggesting that demographic processes and not selection at multiple loci are responsible for the deviation from a neutral model. Maximum-likelihood comparisons of alternative demographic models like logistic population growth, glacial refugia, or past bottlenecks did not produce parameter estimates that were more consistent with observed patterns. However, exclusion of highly polymorphic "outlier loci" resulted in a fit to the logistic growth model. Various tests of neutrality revealed a set of candidate loci that may evolve under selection.

Arabidopsis↗

PubMed2006

Evolutionary anatomies of positions and types of disease-associated and neutral amino acid mutations in the human genome.

BACKGROUND: Amino acid mutations in a large number of human proteins are known to be associated with heritable genetic disease. These disease-associated mutations (DAMs) are known to occur predominantly in positions essential to the structure and function of the proteins. Here, we examine how the relative perpetuation and conservation of amino acid positions modulate the genome-wide patterns of 8,627 human disease-associated mutations (DAMs) reported in 541 genes. We compare these patterns with 5,308 non-synonymous Single Nucleotide Polymorphisms (nSNPs) in 2,592 genes from primary SNP resources. RESULTS: The abundance of DAMs shows a negative relationship with the evolutionary rate of the amino acid positions harboring them. An opposite trend describes the distribution of nSNPs. DAMs are also preferentially found in the amino acid positions that are retained (or present) in multiple vertebrate species, whereas the nSNPs are over-abundant in the positions that have been lost (or absent) in the non-human vertebrates. These observations are consistent with the effect of purifying selection on natural variation, which also explains the existence of lower minor nSNP allele frequencies at highly-conserved amino acid positions. The biochemical severity of the inter-specific amino acid changes is also modulated by natural selection, with the fast-evolving positions containing more radical amino acid differences among species. Similarly, DAMs associated with early-onset diseases are more radical than those associated with the late-onset diseases. A small fraction of DAMs (10%) overlap with the amino acid differences between species within the same position, but are biochemically the most conservative group of amino acid differences in our datasets. Overlapping DAMs are found disproportionately in fast-evolving amino acid positions, which, along with the conservative nature of the amino acid changes, may have allowed some of them to escape natural selection until compensatory changes occur. CONCLUSION: The consistency and predictability of genome-wide patterns of disease- associated and neutral amino acid variants reported here underscores the importance of the consideration of evolutionary rates of amino acid positions in clinical and population genetic analyses aimed at understanding the nature and fate of disease-associated and neutral population variation. Establishing such general patterns is an early step in efforts to diagnose the pathogenic potentials of novel amino acid mutations.

Amino Acid Substitution↗

PubMed2004

HapBlock: haplotype block partitioning and tag SNP selection software using a set of dynamic programming algorithms.

UNLABELLED: Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed with regions of low LD. Such LD patterns make it possible to select a set of single nucleotide polymorphism (SNPs; tag SNPs) for genome-wide association studies. We have developed a suite of computer programs to analyze the block-like LD patterns and to select the corresponding tag SNPs. Compared to other programs for haplotype block partitioning and tag SNP selection, our program has several notable features. First, the dynamic programming algorithms implemented are guaranteed to find the block partition with minimum number of tag SNPs for the given criteria of blocks and tag SNPs. Second, both haplotype data and genotype data from unrelated individuals and/or from general pedigrees can be analyzed. Third, several existing measures/criteria for haplotype block partitioning and tag SNP selection have been implemented in the program. Finally, the programs provide flexibility to include specific SNPs (e.g. non-synonymous SNPs) as tag SNPs. AVAILABILITY: The HapBlock program and its supplemental documents can be downloaded from the website http://www.cmb.usc.edu/~msms/HapBlock.

Algorithms↗