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PubMed2005

Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts.

BACKGROUND: Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke. METHODS: Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1. RESULTS: If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1. CONCLUSIONS: Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

Adult↗
PubMed2006

AFLP analysis of genetic variation within the two economically important Anatolian grapevine (Vitis vinifera L.) varietal groups.

The Anatolian region of modern-day Turkey is believed to have played an important role in the history of grapevine (Vitis vinifera L.) domestication and spread. Despite this, the rich grape germplasm of this region is virtually uncharacterized genetically. In this study, the amplified fragment length polymorphisms (AFLP)-based genetic relations of the grapevine accessions belonging to the 2 economically important Anatolian table grape varietal groups known as V. vinifera 'Misket' (Muscat) and V. vinifera 'Parmak' were studied. Thirteen AFLP primer combinations used in the analyses revealed a total of 1495 (35.5% polymorphic) and 1567 (34.6% polymorphic) DNA fragments for the 'Misket' and 'Parmak' varietal groups, respectively. The unweighted pair-group method with arthimetic averaging (UPGMA) cluster analysis and principal coordinate analysis (PCA) conducted on polymorphic AFLP markers showed that both varietal groups contain a number of synonymous (similar genotypes known by different names) as well as homony mous (genetically different genotypes known by the same name) accessions. Our results also showed that 6 of the Anatolian 'Misket' genotypes were genetically very similar to V. vinifera 'Muscat of Alexandria', implying that these genotypes might have played some role in the formation of this universally known grape cultivar. Finally, the close genetic similarities found here between 'Muscat of Alexandria' and V. vinifera 'Muscat of Hamburg' support the recent suggestion that 'Muscat of Hamburg' probably originated from 'Muscat of Alexandria' through spontaneous hybridizations. Overall, the results of this study have implications for not only preservation and use of the Anatolian grape germplasm, but also better understanding of the historical role that this region has played during the domestication of grapes.

Cluster Analysis↗
PubMed1990

Genetic variation at the apolipoprotein gene loci contribute to response of plasma lipids to dietary change.

Dietary intervention studies (from a low polyunsaturated/saturated fatty acid ratio P/S diet to a high P/S diet), carried out on a group of healthy individuals from North Karelia, Eastern Finland between 1981-1984, provided evidence that there may be a genetic component contributing to variation in response to dietary change. We have resampled blood from 107 individuals involved in the original studies and used Restriction Fragment Length Polymorphisms (RFLPs) to study the genetic contribution of variation at a number of candidate gene loci to the response to dietary change. The genes investigated in this study were the apolipoprotein (apo) genes: apo B, apo AII, apo E (protein polymorphism), apo AI-CIII-AIV gene cluster, and the LDL-receptor gene. On the basal diet the major effect of genotype on lipid traits was due to variation at the apo E gene locus; this protein polymorphism explained 14.6% of the phenotypic variance in LDL cholesterol levels and 12.7% of the phenotypic variance in total cholesterol levels. When switched to low fat high P/S diet, these effects of variation at the apo E gene locus on the phenotypic variation of LDL and total cholesterol levels disappeared. The major effect on the response to dietary change, delta, was seen on the difference in apo AI levels mediated by variation at the apo B gene locus (MspI RFLP) explaining 6.3% of the phenotypic variance in apo AI change. For the RFLPs of the apo AI-CII-AIV gene cluster, small but not significant differences on delta were found. Our results indicate that within the limits of the candidate genes studied, the major effects in response to dietary change was on apo AI levels mediated through variation at the apo B gene locus.

Adult↗
PubMed1990

Hierarchical analysis of population genetic variation in mitochondrial and nuclear genes of Daphnia pulex.

The geographic structure of Daphnia pulex populations from the central United States is analyzed with respect to isozyme and mitochondrial DNA variation. The species complex consists of cyclic and obligate parthenogens. A hierarchical analysis of population structure in the cyclic parthenogens by using a fixation-index approach indicates that this is one of the most extremely subdivided species yet studied. This genetic structure, much of which accrues within 100 km, is certainly due in part to the limited dispersal ability of Daphnia. However, previous work has shown that fluctuating selection can account for the spatial heterogeneity in isozyme frequencies in these populations. This may explain why the population subdivision for the mitochondrial genome increases approximately three times as rapidly with distance as does that for nuclear genes, which is slower than the neutral expectation. The obligate parthenogens are shown to be polyphyletic in origin, evolutionarily young, and, in some cases, geographically widespread.

Animals↗
PubMed1989

Genetic variation in liver tumor susceptibility, plasma testosterone levels, and androgen receptor binding in six inbred strains of mice.

We compared six inbred mouse strains for their relative susceptibilities to liver and lung tumor induction. Male and female mice were treated at 12 days of age with a single i.p. injection of N-ethyl-N-nitrosourea (ENU; 0.25 mumol/g), and tumor multiplicity was analyzed at 32 weeks of age (males) or 44 weeks of age (females). Male mice of the SWR/J and C57BL/6J strains were relatively resistant to hepatocarcinogenesis, averaging 0 and 0.3 tumors per animal, respectively. Male C57BR/cdJ, P/J, and SM/J mice had intermediate susceptibilities, averaging seven to 17 tumors per animal, and male CBA/J mice were the most susceptible, averaging 45 tumors per animal. Female mice were more resistant than male mice: no liver tumors were observed for SWR/J females; C57BL/6J, SM/J, P/J, and CBA/J females averaged less than one tumor per animal and C57BR/cdJ females averaged five tumors per animal. In contrast to the results for liver tumor induction, there was no difference between the sexes in lung tumor susceptibility. Male and female SWR/J mice were the most susceptible, averaging 14 lung tumors per animal; male and female CBA/J mice were moderately susceptible, averaging six tumors per animal and the C57BR/cdJ, C57BL/6J, P/J, and SM/J strains were relatively resistant, averaging less than three tumors per animal. To determine if levels of testosterone, a potent liver tumor promoter in mice, or its receptor contribute to the strain variation in liver tumor susceptibility, we measured levels of plasma testosterone as well as binding properties of the hepatic androgen receptor for the six inbred strains. Plasma testosterone in male mice ranged from 1.8 to 7.4 ng/ml and in females ranged from 0.21 to 0.42 ng/ml, which is consistent with the greater susceptibility of male mice to liver tumor development. However, variation in testosterone levels among the different strains of mice was not correlated with liver tumor susceptibility. We also demonstrated the presence of high affinity androgen receptors in mouse hepatic cytosol. The amounts of this receptor for the six strains tested ranged from 24 to 34 fmol/mg cytosolic protein. The apparent KD of the receptor for [3H]mibolerone (a synthetic androgen) differed between the strains: SWR/J, C57BL/6J, and C57BR/cdJ mice had the highest affinity (KD = 0.22 nM), P/J and CBA/J strains had an intermediate affinity (KD = 0.36 nM), and the SM/J strain had the lowest affinity receptor (KD = 0.45 nM). The strain variation in the affinity or abundance of the androgen receptor was not related to the strain variation in liver tumor induction.

Animals↗
PubMed2003

Evaluation of genetic variation and association in the matrix metalloproteinase 9 (MMP9) gene in ESRD patients.

BACKGROUND: Matrix metalloproteinases are Zn2+- and Ca2+-dependent endopeptidases secreted by many cells. Expression of the matrix metalloproteinase 9 (MMP9) gene is increased in a variety of renal diseases. Several genetic studies have associated MMP9 with end-stage renal disease (ESRD). METHODS: In this study, 2.2 kb of the promoter region and all 13 exons (3.3 kb) of MMP9 genomic DNA were scanned for polymorphisms. Genetic associations between MMP9 polymorphisms and renal disease were evaluated. RESULTS: Eleven single-nucleotide polymorphisms (SNPs; 4 promoter, 6 coding region, and 1 3' untranslated region [UTR]) were identified in Caucasians and 19 SNPs (11 promoter, 8 coding region, 1 3' UTR) were identified in African Americans. A previously identified highly polymorphic (CA)n repeat in the promoter region of MMP9 also was evaluated. We found 15 alleles in Caucasians and 14 alleles in African Americans. Allele frequencies, genotypes, and 3-marker haplotypes were compared between patient and control populations. Differences were not observed using single-locus analyses. Two haplotypes that included the (CA)n repeat allele in African-American patients with type 2 diabetic nephropathy (T2DM/ESRD) showed borderline significant differences. Dichotomizing the (CA)n repeat distribution showed that shorter alleles in Caucasian cases were associated with ESRD using an additive disease-predisposing model (P = 0.05). Analysis of the (CA)n repeat in expanded sets of subjects showed strong evidence for an association of shorter alleles with ESRD in Caucasians (P = 0.00012) and suggested a similar trend in African Americans with T2DM/ESRD (P = 0.086) and subjects without T2DM/ESRD (P = 0.047). CONCLUSION: This comprehensive analysis of MMP9 and renal disease suggests a possible role for the (CA)n repeat in renal disease, consistent with previous reports.

3' Untranslated Regions↗
PubMed1994

[Directed character of genetic variation during long-term selection of Drosophila melanogaster strains for adaptively important characters].

Related fly strains that were selected for differences in reproductive function for about 700 generations were studied. The low-active (LA) strain differs from other related and highly active strains of interest at a set of characters. Qualitative differences in the spectrum of viability mutations are retained in strains selected in opposite directions. Low-active strains carry a great number of deleterious mutations. Such mutations are rare in the related highly active strains. Moreover, about 50% of chromosomes in the highly active strains carry supervital mutations, which increase viability. Recombination analysis showed the presence of at least several viability mutations in each chromosome of the strains studied. Unlike highly active strains, the low-active ones are characterized by an extremely high spontaneous mutation rate. The conservation of genetic heterogeneity observed in long-term selected strains, as well as the high mutation rate, must be connected with regular changes in the spectrum of retrotransposons (MDG1, MDG3) and hobo elements characteristic of the strains studied. A special crossing system that induces a sharp increase in LA induction potential in the H-E system of hybrid dysgenesis was developed.

Adaptation, Physiological↗
PubMed2000

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

Adult↗
PubMed1999

AFLP fingerprinting: an efficient technique for detecting genetic variation of Xanthomonas axonopodis pv. manihotis.

Xanthomonas axonopodis pv. manihotis (Xam) is the causative agent of cassava bacterial blight (CBB), a worldwide disease that is particularly destructive in South America and Africa. CBB is controlled essentially through the use of resistant varieties. To develop an appropriate disease management strategy, the genetic diversity of the pathogen's populations must be assessed. Until now, the genetic diversity of Xam was characterized by RFLP analyses using ribotyping, and plasmid and genomic Xam probes. We used AFLP (amplified fragment length polymorphism), a novel PCR-based technique, to characterize the genetic diversity of Colombian Xam isolates. Six Xam strains were tested with 65 AFLP primer combinations to identify the best selective primers. Eight primer combinations were selected according to their reproducibility, number of polymorphic bands and polymorphism detected between Xam strains. Forty-seven Xam strains, originating from different Colombian ecozones, were analysed with the selected combinations. Results obtained with AFLP are consistent with those obtained with RFLP, using plasmid DNA as a probe. Some primer combinations differentiated Xam strains that were not distinguished by RFLP analyses, thus AFLP fingerprinting allowed a better definition of the genetic relationships between Xam strains.

Bacterial Typing Techniques↗
PubMed2004

Interaction between genetic variations in DNA repair genes and plasma folate on breast cancer risk.

Folate status has been inversely associated with breast cancer risk. Because folate deficiency can cause DNA damage, such as uracil misincorporation, single strand breaks, and double strand breaks, genetic polymorphisms in base excision repair and double strand break repair genes may lead to variation in DNA repair proficiency and modify the effect of folate on breast cancer risk. We prospectively investigated the a priori hypothesized interaction between plasma folate levels and five nonsynonymous polymorphisms in the XRCC1, XRCC2, and XRCC3 genes on breast cancer risk in a nested case-control study within the Nurses' Health Study (712 case-control pairs). Suggestive evidence of interaction was seen for two of these polymorphisms. Compared with the reference group of non-carriers in the lowest quartile of plasma folate, the reduction in risk (66%) was statistically significant among XRCC1 194Trp carriers in the highest quartile (multivariate odds ratio, 0.34; 95% confidence interval, 0.16-0.72). The inverse association between XRCC1 194Trp and breast cancer risk was attenuated by lower plasma folate status. The inverse association between plasma folate level and breast cancer risk was stronger among 194Trp carriers (P, trend = 0.01) than non-carriers (P, trend = 0.09). We also observed that the positive association between the XRCC2 188His allele and breast cancer risk was only significant in women in the lowest plasma folate quartile (carriers versus non-carriers; multivariate odds ratio, 2.04; 95% confidence interval, 1.05-3.97), and this excess risk was abolished among those with higher plasma folate levels. Moreover, the inverse association between plasma folate level and breast cancer risk was stronger among XRCC2 188His carriers (P, trend = 0.004) than non-carriers (P, trend = 0.09). Although none of the statistical tests for interaction was significant, these data give some support for the hypothesis that genetic variations in DNA repair genes may modify the relation between plasma folate level and breast cancer risk.

Adult↗
PubMed2006

Genetic variation in the nucleotide excision repair pathway and colorectal cancer risk.

Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons, which are found in two putative risk factors for colorectal cancer, tobacco smoke and meat cooked at high temperature. To examine the association between common genetic variants in NER genes and the risk of colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in 11 NER genes were genotyped in 250 colorectal cancer cases and a subcohort of 2,224 participants. Incidence rate ratios (RR) and 95% confidence intervals (95% CI) were estimated using a modified Cox regression model and robust variance estimate. The ERCC6 1213G variant, which is thought to reduce NER capacity, was associated with an increased risk of colorectal cancer compared with the homozygous wild type (RR, 1.36; 95% CI, 1.00-1.86 and RR, 2.64; 95% CI, 1.53-4.58 for the RG and GG genotypes respectively with P(trend) = 0.0006). Having at least one XPC 492H allele was also associated with an increased risk of colorectal cancer (RR, 1.75; 95% CI, 1.20-2.57). When the combined effects of ERCC6 R1213G and XPC R492H were examined, the risk of colorectal cancer significantly increased with increasing number of variant alleles (P(trend) = 0.00003). Our study suggests that genetic polymorphisms in the NER genes, ERCC6 and XPC, may be associated with an increased risk of colorectal cancer.

Adult↗
PubMed1996

Genetic variation in Australian spotted fever group rickettsiae.

Rickettsiae were isolated by cell culture of buffy coat blood from six patients with spotted fever from southeastern Australia and Flinders Island in Bass Strait. The isolates were genetically compared with two previous Rickettsia australis patient isolates. The genus-specific 17-kDA genes from the isolates were compared after DNA amplification and restriction fragment analysis of the amplified DNA. This comparison revealed that mainland rickettsial isolates from southeastern Australia were identical to two previous isolates of R. australis from northeastern Australia. Rickettsial isolates from Flinders Island were distinct from the mainland isolates. The 16S rRNA gene sequences from the isolates were determined and compared. The Flinders Island rickettsial agent was most closely related (0.3% structural divergence) to Rickettsia rickettsii, Rickettsia conorii, and Rickettsia slovaca. The Flinders Island rickettsial agent was 1.3 and 2.1% structurally divergent from R. australis and Rickettsia akari, respectively. The 16S rRNA gene sequence from the Flinders Island agent shows that this rickettsia is more closely related to the rickettsial spotted fever group than is R. australis. We conclude that there are two populations of spotted fever group rickettsiae in Australia and propose that the genetically distinct causative organism of Flinders Island spotted fever be designated Rickettsia honei. The extent of distribution and animal host reservoirs remain to be elucidated.

Adult↗
PubMed1985

Genetic variation of haemoglobin alpha- and beta-chains in rabbits detected by isoelectric focusing and reversed-phase chromatography.

Previous studies on the amino acid sequences and on the amino acid composition of peptides revealed genetic polymorphism both of the haemoglobin alpha-chain (Hb alpha) and beta-chain (Hb beta) in rabbits. In this study, rabbit haemolysates were analysed by isoelectric focusing in a narrow pH range (6.7-7.7) and by reversed-phase chromatography. Two variants were found for both Hb alpha and Hb beta. The two methods detected the same variants in this material. Inheritance data were consistent with the hypothesis that the observed Hb alpha and Hb beta variants were each controlled by two codominant, autosomal alleles. Haemoglobin polymorphism appears to be frequent in domestic rabbits since both variants of each chain were observed in all the three breeds studied.

Animals↗