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PubMed2000

Joint effects of natural selection and recombination on gene flow between Drosophila ananassae populations.

We estimated DNA sequence variation in a 5.7-kb fragment of the furrowed (fw) gene region within and between four populations of Drosophila ananassae; fw is located in a chromosomal region of very low recombination. We analyzed gene flow between these four populations along a latitudinal transect on the Indian subcontinent: two populations from southern, subtropical areas (Hyderabad, India, and Sri Lanka) and two from more temperate zones in the north (Nepal and Burma). Furthermore, we compared the pattern of differentiation at fw with published data from Om(1D), a gene located in a region of normal recombination. While differentiation at Om(1D) shows an isolation-by-distance effect, at fw the pattern of differentiation is quite different such that the frequencies of single nucleotide polymorphisms are homogenized over extended geographic regions (i.e., among the two populations of the northern species range from Burma and Nepal as well as among the two southern populations from India and Sri Lanka), but strongly differentiated between the northern and southern populations. To examine these differences in the patterns of variation and differentiation between the Om(1D) and fw gene regions, we determine the critical values of our previously proposed test of the background selection hypothesis (henceforth called F(ST) test). Using these results, we show that the pattern of differentiation at fw may be inconsistent with the background selection model. The data depart from this model in a direction that is compatible with the occurrence of recent selective sweeps in the northern as well as southern populations.

Animals↗
PubMed2006

Ethnic differences in key candidate genes for spontaneous preterm birth: TNF-alpha and its receptors.

OBJECTIVES: Spontaneous preterm birth (PTB) has a significant ethnic disparity with people of African descent having an almost 2-fold higher incidence than those of European descent in the United States. This disparity may be caused by differences in the distribution of genetic risk factors. The objective of this study is to examine genetic differences between African-Americans and European Americans for single nucleotide polymorphisms (SNPs) in candidate genes for PTB. METHODS: We examined patterns of variation in 19 SNPs in 3 candidate genes for preterm birth: TNF-alpha, TNF-receptor 1 and TNF-receptor 2. Allele, genotype and haplotype frequencies were compared between African-Americans (AA) and European-Americans (EA) in cases and controls separately. Both maternal and fetal genotypes were studied, as it is unclear whether one or both of these are important in the etiology of PTB. RESULTS: The vast majority of the SNPs differed significantly between ethnic groups, although there are only a few suggestive results comparing cases and controls within an ethnic group. For TNF-alpha, four of six SNPs; for TNF-R1, 5/6; and for TNF-R2, 6/7 showed significant differences between ethnic groups in either allele and/or genotype frequency. CONCLUSIONS: Our data demonstrate highly significant genetic differences between ethnic groups in genes that may play a role in the risk of PTB.

Adolescent↗
PubMed2005

A haplotype-based case-control study of BRCA1 and sporadic breast cancer risk.

Rare, highly penetrant germ line mutations in BRCA1 strongly predispose women to a familial form of breast and ovarian cancer. Whether common variants (either coding or noncoding) at this locus contribute to the more common form of the disease is not yet known. We tested common variation across the BRCA1 locus in African American, Native Hawaiian, Japanese, Latino, and White women in the Multiethnic Cohort Study. Specifically, 28 single nucleotide polymorphisms (SNPs) spanning the BRCA1 gene were used to define patterns of common variation in these populations. The majority of SNPs were in strong linkage disequilibrium with one another, indicating that our survey captured most of the common inherited variation across this gene. Nine tagging SNPs, including five missense SNPs, were selected to predict the common BRCA1 variants and haplotypes among the non-African American groups (five additional SNPs were required for African Americans) and genotyped in a breast cancer case-control study nested in the Multiethnic Cohort Study (cases, n = 1,715; controls, n = 2,502). We found no evidence for significant associations between common variation in BRCA1 and risk of breast cancer. Given the large size of our study population and detailed analysis of the locus, this result indicates either that common variants in BRCA1 do not substantially influence sporadic breast cancer risk, or that unmeasured heterogeneity in the breast cancer phenotype or unmeasured interactions with genetic or environmental exposures obscure our ability to detect any influence that may be present.

Aged↗
PubMed1993

Single-strand conformation polymorphism analysis is a rapid and effective method for the identification of mutations and polymorphisms in the gene for glycoprotein IIIa.

Glanzmann thrombasthenia (GT) is the most common inherited disorder of platelets. Most of the molecular defects previously identified in GT have been caused by point (or other small) mutations in the genes for glycoprotein (GP) IIb or GPIIIa. We have used single-strand conformation polymorphism (SSCP) analysis to rapidly identify single-base changes in the GPIIIa gene. Using genomic DNA from normal individuals and patients with GT, each GPIIIa exon and a short stretch of flanking intronic sequence was amplified, heat-denatured, and separated in nondenaturing acrylamide gels. Only those fragments with an abnormal migration pattern were isolated and the nucleotide sequence determined. Using SSCP, we detected the polymorphism in the HPA-1 (P1A) system and all three known silent polymorphisms in the GPIIIa gene. Screening 14 GPIIIa exons from 5 patients with GT, one mutant allele was identified. The nucleotide sequence of the abnormal 240-bp SSCP fragment was determined and a G-->A substitution in the splice donor site of exon iv was identified. Analysis of platelet RNA resulting from this mutation showed two mRNA species: one contained a deletion of exon iv, whereas the other had a 27-bp addition to exon iv due to the use of a cryptic splice site in the downstream intron. Single-base substitutions are the most common mutation in GT and often result in abnormal mRNA splicing. SSCP is a rapid and sensitive technique for identifying mutations or polymorphisms in the GPIIIa gene.

Base Sequence↗
PubMed2003

Molecular population genetics of the Arabidopsis CLAVATA2 region. The genomic scale of variation and selection in a selfing species.

The Arabidopsis thaliana CLAVATA2 (CLV2) gene encodes a leucine-rich repeat protein that regulates the development of the shoot meristem. The levels and patterns of nucleotide variation were assessed for CLV2 and 10 flanking genes that together span a 40-kb region of chromosome I. A total of 296 out of 7959 sequenced nucleotide sites were polymorphic. The mean levels of sequence diversity of the contiguous genes in this region are approximately twofold higher than those of other typical Arabidopsis nuclear loci. There is, however, wide variation in the levels and patterns of sequence variation among the 11 linked genes in this region, and adjacent genes appear to be subject to contrasting evolutionary forces. CLV2 has the highest levels of nucleotide variation in this region, a significant excess of intermediate frequency polymorphisms, and significant levels of intragenic linkage disequilibrium. Most alleles at CLV2 are found in one of three haplotype groups of moderate (>15%) frequency. These features suggest that CLV2 may harbor a balanced polymorphism.

Alleles↗
PubMed1998

Tandemly repeated sequences in the mitochondrial DNA control region and phylogeography of the Pike-Perches Stizostedion.

DNA sequences from the mitochondrial DNA control region are used to test the phylogeographic relationships among the pike-perches, Stizostedion (Teleostei: Percidae) and to examine patterns of variation. Sequences reveal two types of variability: single nucleotide polymorphisms and 6 to 14 copies of 10- to 11-base-pair tandemly repeated sequences. Numbers of copies of the tandem repeats are found to evolve too rapidly to detect phylogenetic signal at any taxonomic level, even among populations. Sequence similarities of the tandem repeats among Stizostedion and other percids suggest concerted evolutionary processes. Predicted folding of the tandem repeats and their proximity to termination-associated sequences indicate that secondary structure mediates slipped-strand mispairing among the d-loop, heavy, and light strands. Neighbor-joining and maximum parsimony analyses of sequences indicate that the genus is divided into clades on the continents of North America and Eurasia. Calibrating genetic distances with divergence times supports the hypothesis that Stizostedion dispersed from Eurasia to North America across a North Pacific Beringial land bridge approximately 4 million years before present, near the beginning of the Pliocene Epoch. The North American S. vitreum and S. canadense appear separated by about 2.75 million years, and the Eurasian S. lucioperca and S. volgensis are diverged by about 1.8 million years, suggesting that speciation occurred during the late Pliocene Epoch.

Animals↗
PubMed2000

Identification of phylogenetic footprints in primate tumor necrosis factor-alpha promoters.

The human tumor necrosis factor-alpha (TNF-alpha) gene encodes a pleiotropic cytokine that plays a critical role in basic immunologic processes. To investigate the TNF-alpha regulatory region in the primate lineage, we isolated TNF-alpha promoters from representative great apes, Old World monkeys, and New World monkeys. We demonstrate that there is a nonuniform distribution of fixed human differences in the TNF-alpha promoter. We define a "fixed human difference" as a site that is not polymorphic in humans, but which differs in at least one of the seven primate sequences examined. Furthermore, we identify two human TNF-alpha promoter single nucleotide polymorphisms that are putative ancestral polymorphisms, because each of the human polymorphic nucleotides was found at the identical site in at least one of the other primate sequences. Strikingly, the largest conserved region among the primate species, a 69-nt "phylogenetic footprint," corresponds to a region of the human TNF-alpha promoter that forms the transcriptionally active nucleoprotein-DNA complex, essential for gene regulation. By contrast, other regions of the TNF-alpha promoter, which exhibit a high density of variable sites, are nonessential for gene expression, indicating that distinct TNF-alpha promoter regions have been subjected to different evolutionary constraints depending on their function. TNF-alpha is the first case in which a promoter region dissected by functional analyses can be correlated with nucleotide polymorphism and variability in primate lineages. The results suggest that patterns of polymorphism and divergence are likely to be useful in identifying candidate regions important for gene regulation in other immune-response genes.

Animals↗
PubMed2006

The alpha-synuclein gene in multiple system atrophy.

BACKGROUND: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. METHOD: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. RESULTS AND CONCLUSION: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Gene Expression↗
PubMed2006

Expression of receptor for advanced glycation end products in sarcoid granulomas.

RATIONALE: The receptor for advanced glycation end products (RAGE) engages a number of ligands implicated in inflammatory processes. The RAGE coding gene maps to the 6p21.32 region, close to the genes DRB1 and BTNL2, which are associated with sarcoidosis. OBJECTIVES: We investigated a possible implication of RAGE in sarcoid granulomas. METHODS: RAGE and major ligands (N-epsilon-carboxy-methyl-lysine [CML], S100A12, and S100B) expression was investigated by immunostaining of 99 paraffin-embedded biopsies of sarcoid tissues, and expression patterns were determined. Among the three RAGE gene single-nucleotide polymorphisms investigated, -374 T/A was selected, characterized in terms of transcriptional effect (immunocytochemistry and real-time polymerase chain reaction), and its frequency was determined in DNA extracted from biopsies. MEASUREMENTS AND RESULTS: RAGE, CML, S100A12, and S100B immunoreactivity was observed in all sarcoid granulomas, although at different intensities. The degree of RAGE expression significantly correlated with the degree of S100A12 expression. The -374 TT/AT genotypes, associated with higher RAGE transcriptional activity, were more frequent in the sarcoidosis biopsy group than in control subjects, and the association was confirmed in a second, independent series of 101 patients with sarcoidosis. CONCLUSIONS: We showed the association of RAGE and its ligands with sarcoidosis and suggest that an intrinsic genetic factor could be in part involved in its expression. In Italian patients, the -374 T/A polymorphism seems to be significantly associated with this disease.

Adolescent↗
PubMed2005

Comparison of genotype- and haplotype-based approaches for fine-mapping of alcohol dependence using COGA data.

It is generally assumed that the detection of disease susceptibility genes via fine-mapping association study is facilitated by consideration of marker haplotypes. In this study, we compared the performance of genotype-based and haplotype-based association studies using the Collaborative Study of Genetics of Alcoholism dataset, on several chromosomal regions showing evidence for linkage with ALDX1. After correction for multiple testing, the most significant results were observed with the genotype-based analyses on two regions of chromosomes 2 and 7. Interestingly, the analyses results from this dataset showed that there was no advantage of the haplotype-based analyses over genotype-based (single-locus) analyses. However, caution should be taken when generalizing these results to other chromosomal regions or to other populations.

Alcoholism↗
PubMed2006

Scale invariant correlations between genes and SNPs on Human chromosome 1 reveal potential evolutionary mechanisms.

The local density of gene structures and single nucleotide polymorphisms (SNPs) along human chromosomes appears inhomogeneous. In chromosome 1, the density patterns from both these elements are shown here to exhibit similar scale invariant clustering, as well as long-ranged and scale invariant auto- and cross-correlations. The local densities of these elements sites can be accurately represented by the scale invariant exponential dispersion models, a group of stochastic models that act as limiting distributions for a wide range of generalized linear models. The scale invariant Poisson-gamma (PG) distribution is the most applicable of these models, since it describes the above findings and it lends itself to a stochastic mechanism for the accumulation of segmental chromosomal changes. This PG model describes the summation of neutral chromosomal mutations, deletions, rearrangements and recombinations, within chromosomal segments that are distinguished by their evolutionary genealogies. Scale invariance is a necessary property if such a description is to remain valid at different measurement scales. The observed density patterns, and proposed model, presumably represent the convergent summation of multiple stochastic processes within the evolutionary history of the chromosome.

Chromosomes, Human, Pair 1↗
PubMed2003

Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r(2) linkage disequilibrium (LD) statistic, because r(2) is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r(2) threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene, analysis of the tagSNP set can comprehensively interrogate for main effects from common functional variation. We demonstrate that, although common variation tends to be shared between populations, tagSNPs should be selected separately for populations with different ancestries.

Algorithms↗
PubMed1995

A recent common ancestry for human Y chromosomes.

The male-specific portion of the Y chromosome is especially useful for studies of human origins. Patterns of nucleotide variation that are neutral with respect to fitness should permit estimates of when and where ancestral Y chromosomes existed. However, variation on the human Y chromosome has been observed to be greatly reduced relative to the autosomes and the X chromosome. One explanation is that selection for a favourable mutation on the non-recombining portion of the Y chromosome has resulted in the recent fixation of a single Y haplotype. A 2.6-kilobase fragment encompassing a polymorphic Alu insertion was sequenced from 16 human and four chimpanzee Y chromosomes. Patterns of nucleotide sequence diversity and divergence provide no evidence for a recent, strong selective sweep on the human Y chromosome. The time back to a common ancestral human Y chromosome is estimated to be 188,000 years, with a 95% confidence interval from 51,000 to 411,000 years. These results are consistent with autosomal and mitochondrial DNA studies that suggest a long-term human effective population size of 10,000 and a sex ratio of 1 (ref. 7). These inferences contradict predictions of the multiregional hypothesis positing a widespread transformation of Homo erectus populations into Homo sapiens.

Animals↗
PubMed2005

Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure.

Thromboxane synthase (TBXAS1), a cytochrome P450 enzyme, converts prostaglandin H2 into thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. Thromboxane A2 has been implicated in modulating cell cytotoxicity and in tumor growth and metastasis. Twelve coding-region variants were identified in the human TBXAS1 gene in 48 African-American and 46 Caucasian individuals, of which eight were amino-acid substitutions. The latter were confirmed in an independent Caucasian population (n=94 unrelated individuals). We performed an evolutionary analysis of patterns of nucleotide diversity and identified patterns of amino acid replacement in human-mouse comparisons consistent with purifying selection on an inter-species time scale using the McDonald-Kreitman test. We also observed patterns of nucleotide diversity within humans consistent with purifying selection acting on existing polymorphism using Tajima's D within coding regions. These evolutionary tests suggest that some of the rare coding variations observed in the human population are deleterious. We used two sequence-homology-based software programs and molecular modeling to predict the potential impact of these polymorphisms on TBXAS1 function. The c.772C>T (p.Lys258Glu), c.1249C>G (p.Gln417Glu), and c.1348G>A (p.Glu450Lys) substitutions are predicted as most likely to alter protein function; another, c.1352C>A (p.Thr451Asn), may also affect function. Given the evolutionary evidence, these variants may be functional and therefore of relevance for disease endpoints related to inflammation and angiogenesis, as well as for the pharmacogenetics of non-steroidal anti-inflammatory drugs.

Black or African American↗
PubMed2004

Patterns of linkage disequilibrium in the MHC region on human chromosome 6p.

Single nucleotide polymorphisms (SNPs) in the human genome are thought to be organised into blocks of high internal linkage disequilibrium (LD), separated by intermittent recombination hotspots. Since understanding haplotype structure is critical for an accurate assessment of inter-individual genetic differences, we investigated up to 968 SNPs from a 10-Mb region on chromosome 6p21, including the human major histocompatibility complex (MHC), in five different population samples (45-550 individuals). Regions of well-defined block structure were found to coexist alongside large areas lacking any clear structure; occasional long-range LD was observed in all five samples. The four white populations analysed were remarkably similar in terms of the extend and spatial distribution of local LD. In US African Americans, the distribution of LD was similar to that in the white populations but the observed haplotype diversity was higher. The existence of large regions without any clear block structure renders the systematic and thorough construction of SNP haplotype maps a crucial prerequisite for disease-association studies.

Black or African American↗
PubMed2005

Corticosteroid receptor genetic polymorphisms and stress responsivity.

A fundamental question in the neuroendocrinology of stress-related psychopathology is why some individuals flourish and others perish under similar adverse conditions. In this contribution we focus on the variants of mineralocorticorticoid (MR) and glucocorticoid receptors (GR) that operate in balance and coordinate behavioral, autonomic, and neuroendocrine response patterns involved in homeostasis and health. In the GR-gene, three single nucleotide polymorphism (SNPs) have been associated with changes in metabolic profile and cardiovascular parameters: the ER22/23EK with a favorable and the N363S and the Bcl1 with a more adverse profile. Importantly, the N363S and the Bcl1 are found to increase cortisol responses to a psychosocial stressor. As a result, the whole body will suffer from overexposure with possible adverse effects on metabolism, cardiovascular control, immune function, and behavior. Also in the MR gene, variants are being identified that are associated with dysregulated autonomic, behavioral, and neuroendocrine responses. The data suggest that these MR and GR variants contribute to individual differences in resilience and vulnerability to stressors, and that these receptors therefore are potential drug targets for recovery of homeostasis and health.

Adaptation, Physiological↗
PubMed1996

Historical selection, amino acid polymorphism and lineage-specific divergence at the G6pd locus in Drosophila melanogaster and D. simulans.

The nucleotide diversity across 1705 bp of the G6pd gene is studied in 50 Drosophila melanogaster and 12 D. simulans lines. Our earlier report contrasted intraspecific polymorphism and interspecific differences at silent and replacement sites in these species. This report expands the number of European and African lines and examines the pattern of polymorphism with respect to the common A/B allozymes. In D. melanogaster the silent nucleotide diversity varies 2.8-fold across localities. The B allele sequences are two-to fourfold more variable than the derived A allele, and differences between allozymes are twice as among B alleles. There is strong linkage disequilibrium across the G6pd region. In both species the level of silent polymorphism increases from the 5' to 3' ends, while there is no comparable pattern in level of silent site divergence or fixation. The neutral model is not rejected in either species. Using D. yakuba as an outgroup, the D. melanogaster lineage shows a twofold greater rate of silent fixation, but less than half the rate of amino acid replacement. Lineage-specific differences in mutation fixation are inconsistent with neutral expectations and suggest the interaction of species-specific population size differences with both weakly advantageous and deleterious selection.

Animals↗
PubMed2004

Haplotype frequencies and linkage disequilibrium analysis of four frequent polymorphisms at the PTH/PTH-related peptide receptor gene locus.

The parathyroid hormone (PTH)/PTH-related peptide receptor is a critical component in the control of mineral ion metabolism and in bone development. This receptor is encoded by a single gene (PTHR1) on chromosome 3p21.1-p24.2, and mutations in this gene have been found in several clinical disorders of bone and mineral metabolism. To facilitate future genetic studies of this important gene, we determined haplotype frequencies and performed linkage disequilibrium (LD) analysis of four different polymorphisms at the PTHR1 locus. Combined analysis of Caucasian, African-American and Asian individuals indicated that LD exists between all but one pair of the four polymorphisms. However, the pattern of LD differed substantially among the three subpopulations; for example, LD between two closely spaced (154-bp apart) single nucleotide polymorphisms appeared to be present only in Asians. Depending on the population under study, genetic association studies may need to test even more closely spaced polymorphic markers when screening the PTHR1 locus. These findings may thus affect the design and interpretation of future genetic studies involving PTHR1.

Black or African American↗