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Results for “Genetic Variation”

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PubMed2006

Patterns of genetic variation in the adaptive radiation of New World crossbills (Aves: Loxia).

Incipient species groups or young adaptive radiations such as crossbills (Aves: Loxia) present the opportunity to investigate directly the processes occurring during speciation. New World crossbills include white-winged crossbills (Loxia leucoptera), Hispaniolan crossbills (Loxia megaplaga), and red crossbills (Loxia curvirostra complex), the last of which is comprised of at least nine morphologically and vocally differentiated forms ('call types') where divergent natural selection for specialization on different conifer resources has been strongly implicated as driving diversification. Here we use amplified fragment length polymorphism (AFLP) markers to investigate patterns of genetic variation across populations, call types, and species of New World crossbills. Tree-based analyses using 440 AFLP loci reveal strongly supported clustering of the formally recognized species, but did not separate individuals from the eight call types in the red crossbill complex, consistent with recent divergence and ongoing gene flow. Analyses of genetic differentiation based on inferred allele frequency variation however, reveal subtle but significant levels of genetic differentiation among the different call types of the complex and indicate that between call-type differentiation is greater than that found among different geographic locations within call types. Interpreted in light of evidence of divergent natural selection and strong premating reproductive isolation, the observed genetic differentiation suggests restricted gene flow among sympatric call types consistent with the early stages of ecological speciation.

Adaptation, Biological↗
PubMed2005

Genetic variation in the sand fly salivary protein, SP-15, a potential vaccine candidate against Leishmania major.

SP-15 is a sandfly salivary protein that provides strong protection against cutaneous leishmaniasis, caused by Leishmania major, and has been proposed as a potential vaccine against this disease. To investigate possible antigenic variation in this protein, we examined genetic polymorphism of SP-15 in 100 Phlebotomus papatasi sandflies, from a natural population from Sudan and four laboratory colonies from Egypt, Jordan, Israel and Saudi Arabia. We found that although many variants of SP-15 may be found in nature, differences among them are minimal (mean+/-SD pairwise differences=1.69+/-0.83% for forty nucleotide sequences and 3.06+/-1.13% for thirty amino acid sequence variants). Analysis of proportions of synonymous and non-synonymous substitutions indicated that SP-15 is not under diversifying selection. Our results suggest that a vaccine based on SP-15 protein should result in a uniform immune response.

Amino Acid Sequence↗
PubMed2006

Natural genetic variation for improving crop quality.

The narrow genetic basis of many crops combined with restrictions on the commercial use of genetically modified plants, has led to a surge of interest in exploring natural biodiversity as a source of novel alleles to improve the productivity, adaptation, quality and nutritional value of crops. Genetic methodologies have been applied to natural variation to improve quality aspects that are associated with the chemical composition of agricultural products. A future challenge in this emerging field is to integrate metabolic, phenotypic and genomic databases to allow a wider view of the plant metabolome and the application of this knowledge within genomics-assisted breeding.

Biodiversity↗
PubMed2004

The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept.

OBJECTIVE: To examine the roles of specific genetic polymorphisms as predictors of response to treatment of early rheumatoid arthritis (RA). METHODS: Subjects included 457 patients with early RA (duration of < or =3 years) who participated in a randomized controlled trial comparing weekly methotrexate and 2 dosages of etanercept (10 mg twice weekly and 25 mg twice weekly). Our primary outcome measure was achievement of 50% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR50 response) after 12 months of treatment. Subjects were genotyped for HLA-DRB1 alleles and polymorphisms in the following genes: TNF, LTA, TNFRSF1A, TNFRSF1B, FCGR2A, FCGR3A, and FCGR3B. Univariate and multivariate analyses were performed to define the impact of specific polymorphisms and haplotypes on response to treatment. Covariates for the multivariate analyses included sex, ethnicity, age, disease duration, and baseline values for rheumatoid factor and the tender and swollen joint counts. RESULTS: The presence of 2 HLA-DRB1 alleles encoding the shared epitope (SE) (compared with 1 or 0 copies) was associated with response to treatment with standard-dose etanercept (odds ratio [OR] 4.3, 95% confidence interval [95% CI] 1.8-10.3). Among Caucasian patients, 2 extended haplotypes that included the HLA-DRB1 alleles *0404 and *0101 (both of which encode the SE) and 6 single-nucleotide polymorphisms in the LTA-TNF region were associated with response to treatment. In a multivariate model that included treatment received and the aforementioned covariates, the ORs for the association of these haplotypes with achievement of an ACR50 response at 12 months were 2.5 (95% CI 0.8-7.3) and 4.9 (95% CI 1.5-16.1) for the *0404- and *0101-containing haplotypes, respectively. CONCLUSION: Genetic variation in the HLA-DRB1 and the LTA-TNF regions is significantly associated with response to treatment of early RA. These findings may have clinical application through the identification of patients who are most likely to benefit from treatment with methotrexate or etanercept.

Antirheumatic Agents↗
PubMed2006

Impact of genetic variations in the WRN gene on age related pathologies and mortality.

Mutations in the WRN gene lead to the Werner syndrome (WS), which resembles premature aging. Here, we hypothesize that genetic variations in the WRN gene may also influence aging-trajectories in the population at large. To test this hypothesis, we assessed the impact of the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene on the occurrence of cardiovascular pathologies, on cognitive performance and on the risks of all-cause, cardiovascular and cancer mortalities in the population-based Leiden 85-plus Study. This prospective follow-up study includes 1,245 participants aged 85 years and older, with a total follow-up of 5,164 person-years. At baseline the risks of myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke dependent on the i1-C/T, L1074F and C1367R polymorphisms, did not vary between the different genotypes. Also no differences in cognitive functioning were observed, except for attention, where carriers of the 1367R allele performed worse compared to the 1367C homozygotes (94.2 (4.35) versus 84.8 (1.84), p=0.04). Mortality risks, calculated separately for all SNPs, were similar between the different genotype carriers of the i1-C/T, L1074F and C1367R polymorphisms, showing no evidence of altered survival. In conclusion, the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene do not influence the aging-trajectories and survival in the population at large.

Adult↗
PubMed2001

Genetic variations and polymorphisms of G protein-coupled receptors: functional and therapeutic implications.

G protein-coupled receptors (GPCRs) represent a major class of proteins in the genome of many species, including humans. In addition to the mapping of a number of human disorders to regions of the genome containing GPCRs, a growing body of literature has documented frequently occurring variations (i.e. polymorphisms) in GPCR loci. In this article, we use a domain-based approach to systematically examine examples of genetic variation in the coding and noncoding regions of GPCR loci. Data to date indicate that residues in GPCRs are involved in ligand binding and coupling to G proteins and that regulation can be altered by polymorphisms. Studies of GPCR polymorphisms have also uncovered the functional importance of residues not previously implicated from other approaches that are involved in the function of GPCRs. We predict that studies of GPCR polymorphisms will have a significant impact on medicine and pharmacology, in particular, by providing new means to subclassify patients in terms of both diagnosis and treatment.

Animals↗
PubMed2006

Comprehensive assessment of genetic variation of catechol-O-methyltransferase and breast cancer risk.

Because catechol-O-methyltransferase (COMT) catalyzes the addition of methyl groups to stabilize catechol estrogens that may induce DNA damage, genetic variants could influence breast cancer risk. To comprehensively characterize genetic variation in this gene, we selected haplotype-tagging single nucleotide polymorphisms (htSNP) in COMT. A total of 11 htSNPs (including COMT Val(158)Met) were selected based on the resequencing and dense genotyping approach of the Breast and Prostate Cancer Cohort Consortium. htSNPs were genotyped in a population-based, case-control study in Poland (1,995 cases and 2,296 controls). Individual SNPs were not significantly associated with risk. Haplotypes were estimated using the expectation-maximization algorithm. Overall differences in the haplotype distribution between cases and controls were assessed using a global score test. The TGAG haplotype (frequent in 4.3% of controls), in a linkage disequilibrium (LD) block that included the 3' untranslated region (UTR) of COMT, was associated with breast cancer risk (odds ratio, 1.29; 95% confidence interval, 1.06-1.58) compared with the most common haplotype TGAA; however, the global test for haplotype associations was not significant (P = 0.09). Haplotypes in another LD block, which included COMT Val(158)Met, were not associated with breast cancer risk (global P = 0.76). Haplotype-breast cancer risk associations were not significantly modified by hormonally related risk factors, family history of breast cancer, or tumor characteristics. In summary, our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3' UTR of COMT needs to be confirmed in independent study populations.

3' Untranslated Regions↗
PubMed2006

Transferability of tag SNPs to capture common genetic variation in DNA repair genes across multiple populations.

Genetic association studies can be made more cost-effective by exploiting linkage disequilibrium patterns between nearby single-nucleotide polymorphisms (SNPs). The International HapMap Project now offers a dense SNP map across the human genome in four population samples. One question is how well tag SNPs chosen from a resource like HapMap can capture common variation in independent disease samples. To address the issue of tag SNP transferability, we genotyped 2,783 SNPs across 61 genes (with a total span of 6 Mb) involved in DNA repair in 466 individuals from multiple populations. We picked tag SNPs in samples with European ancestry from the Centre d'Etude du Polymorphisme Humain, and evaluated coverage of common variation in the other samples. Our comparative analysis shows that common variation in non-African samples can be captured robustly with only marginal loss in terms of the maximum r2. We also evaluated the transferability of specified multi-marker haplotypes as predictors for untyped SNPs, and demonstrate that they provide equivalent coverage compared to single-marker tests (pairwise tags) while requiring fewer SNPs for genotyping. The efficacy of a tagging-based approach in studying genotype-phenotype correlations in complex traits is strongly supported by our empirical results.

Computational Biology↗
PubMed2006

Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort.

BACKGROUND: Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk. METHODS: We sequenced IGF1 exons in germline DNA from 95 men with advanced prostate cancer to identify missense variants. IGF1 linkage disequilibrium patterns and common haplotypes were characterized by genotyping 64 single-nucleotide polymorphisms (SNPs) spanning 156 kilobases in 349 control subjects. Associations between IGF1 haplotypes and genotypes were investigated among 2320 patients with prostate cancer and 2290 control subjects from the Multiethnic Cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression to determine the association between prostate cancer and IGF1 haplotypes and genotypes. We used permutation testing to correct for multiple hypothesis testing. All statistical tests were two-sided. RESULTS: No IGF1 missense variants were observed. We identified four blocks of strong linkage disequilibrium and selected a subset of 29 tagging SNPs that could accurately predict both the common IGF1 haplotypes and the remaining SNPs. Haplotype analysis revealed nominally statistically significant associations with prostate cancer risk in each of the four haplotype blocks: haplotype 1B (OR = 1.21, 95% CI = 1.04 to 1.40), haplotype 2C (OR = 1.24, 95% CI = 1.06 to 1.44), haplotype 3C (OR = 1.25, 95% CI = 1.03 to 1.50), and haplotype 4D (OR = 1.19, 95% CI = 1.02 to 1.39). Two SNPs--rs7978742 (Ptrend = .002) and rs7965399 (Ptrend = .002)--were perfectly correlated (correlation coefficient = 1.0) with one another and also associated with prostate cancer risk. These two SNPs were strong proxies for haplotypes 1B, 2C, 3C, and 4D and could account for the haplotype findings. Permutation testing revealed that a similarly strong result would be observed by chance only 5.6% of the time. CONCLUSION: Inherited variation in IGF1 may play a role in the risk of prostate cancer.

Black or African American↗