DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis.
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DnaSP is a Windows integrated software package for the analysis of the DNA polymorphism from nucleotide sequence data. DnaSP version 3 incorporates several methods for estimating the amount and pattern of DNA polymorphism and divergence, and for conducting neutrality tests. AVAILABILITY: For academic uses, DnaSP is available free of charge from: http://www.bio.ub.es/julio/DnaSP.html CONTACT: [email protected] (+info)
N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk.
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N-Acetyltransferase 1 (NAT1), encoded by the polymorphic NAT1 gene, has been shown to be one of the major enzymes in human breast tissue that activates aromatic and heterocyclic amines. Humans are mainly exposed to these carcinogens through cigarette smoking and consumption of well-done meat. To test the hypothesis that variations in the NAT1 gene are related to breast cancer risk, particularly among women who smoke or consume high levels of well-done meat, a nested case-control study was conducted in a prospective cohort study of 41,837 postmenopausal Iowa women. Information on cigarette smoking and other breast cancer risk factors was obtained at the baseline survey conducted in 1986. DNA samples and information on the consumption of well-done meat were obtained, in the case-control study, from breast cancer cases diagnosed from 1992 to 1994 and a random sample of cancer-free cohort members. Genomic DNA samples obtained from 154 cases and 330 controls were assayed for 11 NAT1 alleles (NAT1*3, *4, *5, *10, *11, *14, *15, *16, *17, *19, and *22). The NAT1*4 allele was the predominant allele observed in this study population, accounting for 73.2% (72.4% in cases versus 73.8% in controls) of the total alleles analyzed. Compared to controls, breast cancer cases had a slightly higher frequency of the NAT1*10 allele (18.8% in cases versus 17.3% in controls) and a substantially higher frequency of the NAT1*11 allele (3.6% versus 1.2%). In multivariate analyses, we found a 30% [95% confidence interval (CI) = 0.8-1.9] elevated risk of breast cancer associated with the NAT1*10 allele and a nearly 4-fold (95% CI = 1.5-10.5) elevated risk associated with the NAT1*11 allele. The positive association of breast cancer with the NAT1*11 allele was more evident among smokers [odds ratio (OR) = 13.2, 95% CI = 1.5-116.0] and those who consumed a high level of red meat (OR = 6.1, 95% CI = 1.1-33.2) or consistently consumed their red meat well done (OR = 5.6, 95% CI = 0.5-62.7). The association of the NAT1*10 allele with breast cancer was mainly confined to former smokers (OR = 3.3, 95% CI = 1.2-9.5). These findings are consistent with a role for the NAT1 gene in the etiology of human breast cancer. (+info)
Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.
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Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS. (+info)
The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.
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In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. (+info)
COL9A3: A third locus for multiple epiphyseal dysplasia.
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Multiple epiphyseal dysplasia (MED), an autosomal dominant osteochondrodysplasia, is a clinically and genetically heterogeneous disorder characterized by mild short stature and early-onset osteoarthritis. The phenotypic spectrum includes the mild Ribbing type, the more severe Fairbank type, and some unclassified forms. Linkage studies have identified two loci for MED. One of these, EDM1, is on chromosome 19, in a region that contains the cartilage oligomeric matrix protein (COMP) gene. Mutations have been identified in this gene in patients with the Ribbing type, the Fairbank type, and unclassified forms of MED. The second locus, EDM2, maps to chromosome 1, in a region spanning COL9A2. Recently, a splice-site mutation was found in COL9A2, causing skipping of exon 3 in one family with MED. Because of the exclusion of the EDM1 and EDM2 loci in some families, the existence of a third locus has been postulated. We report here one family with MED, evaluated clinically and radiologically and tested for linkage with candidate genes, including COMP, COL9A1, COL9A2, and COL9A3. No linkage was found with COMP, COL9A1, or COL9A2, but an inheritance pattern consistent with linkage was observed with COL9A3. Mutation analysis of COL9A3 identified an A-->T transversion in the acceptor splice site of intron 2 in affected family members. The mutation led to skipping of exon 3 and an in-frame deletion of 12 amino acid residues in the COL3 domain of the alpha3(IX) chain and thus appeared to be similar to that reported for COL9A2. This is the first disease-causing mutation identified in COL9A3. Our results also show that COL9A3, located on chromosome 20, is a third locus for MED. (+info)
Multicentric origin of hemochromatosis gene (HFE) mutations.
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Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends +info)
Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer.
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One hundred fifty-two families with prostate cancer were analyzed for linkage to markers spanning a 20-cM region of 1q42.2-43, the location of a putative prostate cancer-susceptibility locus (PCAP). No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in our total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, pedigrees were stratified into homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although LOD scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least five affected men (nonparametric linkage score of 1.2; P=.1). If heterogeneity is assumed, an estimated 4%-9% of these 152 families may show linkage in this region. We conclude that the putative PCAP locus does not account for a large proportion of these families with prostate cancer, although the linkage of a small subset is compatible with these data. (+info)
Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.
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Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype. (+info)