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1.
Clin Genet ; 88(1): e1-4, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25930971

ABSTRACT

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.


Subject(s)
Amino Acid Transport System ASC/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Mutation, Missense , Amino Acid Sequence , Child , Child, Preschool , DNA Mutational Analysis , Exons , Female , Gene Frequency , Humans , Infant , Infant, Newborn , Jews/genetics , Male , Molecular Sequence Data , Pedigree , Siblings
2.
Genetics ; 178(4): 2069-79, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18430934

ABSTRACT

In this article we present a new heuristic approach (informative recombinations, InfRec) to analyze recombination density at the sequence level. InfRec is intuitive and easy and combines previously developed methods that (i) resolve genotypes into haplotypes, (ii) estimate the minimum number of recombinations, and (iii) evaluate the fraction of informative recombinations. We tested this approach in its sliding-window version on 117 genes from the SeattleSNPs program, resequenced in 24 African-Americans (AAs) and 23 European-Americans (EAs). We obtained population recombination rate estimates (rho(obs)) of 0.85 and 0.37 kb(-1) in AAs and EAs, respectively. Coalescence simulations indicated that these values account for both the recombinations and the gene conversions in the history of the sample. The intensity of rho(obs) varied considerably along the sequence, revealing the presence of recombination hotspots. Overall, we observed approximately 80% of recombinations in one-third and approximately 50% in only 10% of the sequence. InfRec performance, tested on published simulated and additional experimental data sets, was similar to that of other hotspot detection methods. Fast, intuitive, and visual, InfRec is not constrained by sample size limitations. It facilitates understanding data and provides a simple and flexible tool to analyze recombination intensity along the sequence.


Subject(s)
Models, Genetic , Recombination, Genetic/genetics , Base Pairing , Chromosomes, Human , Computer Simulation , Histocompatibility Antigens Class II/genetics , Humans , Interleukins/genetics , Likelihood Functions , Sequence Analysis, DNA , Software
3.
J Med Genet ; 45(4): 200-9, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17965227

ABSTRACT

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) (MIM 270 400) is an autosomal recessive multiple congenital anomalies/mental retardation syndrome caused by mutations in the Delta7-sterol reductase (DHCR7, E.C.1.3.1.21) gene. The prevalence of SLOS has been estimated to range between 1:15000 and 1:60000 in populations of European origin. METHODS AND RESULTS: We have analysed the frequency, origin, and age of DHCR7 mutations in European populations. In 263 SLOS patients 10 common alleles (c.964-1G>C, p.Trp151X, p.Thr93Met, p.Val326Leu, p.Arg352Trp, p.Arg404Cys, p.Phe302Leu, p.Leu157Pro, p.Gly410Ser, p.Arg445Gln) were found to constitute approximately 80% of disease-causing mutations. As reported before, the mutational spectra differed significantly between populations, and frequency peaks of common mutations were observed in North-West (c.964-1G>C), North-East (p.Trp151X, p.Val326Leu) and Southern Europe (p.Thr93Met). SLOS was virtually absent from Finland. The analysis of nearly 8000 alleles from 10 different European populations confirmed a geographical distribution of DHCR7 mutations as reported in previous studies. The common Null mutations in Northern Europe (combined ca. 1:70) occurred at a much higher frequency than expected from the reported prevalence of SLOS. In contrast the most common mutation in Mediterranean SLOS patients (p.Thr93Met) had a low population frequency. Haplotypes were constructed for SLOS chromosomes, and for wild-type chromosomes of African and European origins using eight cSNPs in the DHCR7 gene. The DHCR7 orthologue was sequenced in eight chimpanzees (Pan troglodytes) and three microsatellites were analysed in 50 of the SLOS families in order to estimate the age of the three major SLOS-causing mutations. CONCLUSIONS: The results indicate a time of first appearance of c.964-1G>C and p.Trp151X some 3000 years ago in North-West and North-East Europe, respectively. The p.Thr93Met mutations on the J haplotype has probably first arisen approximately 6000 years ago in the Eastern Mediterranean. Together, it appears that a combination of founder effects, recurrent mutations, and drift have shaped the present frequency distribution of DHCR7 mutations in Europe.


Subject(s)
Evolution, Molecular , Mutation , Oxidoreductases Acting on CH-CH Group Donors/genetics , Smith-Lemli-Opitz Syndrome/genetics , Alleles , Animals , Base Sequence , DNA Primers/genetics , Europe , Founder Effect , Genetics, Population , Haplotypes , Humans , Pan troglodytes/genetics , Polymorphism, Single Nucleotide , Smith-Lemli-Opitz Syndrome/enzymology
4.
Pharmacogenomics J ; 7(2): 144-52, 2007 Apr.
Article in English | MEDLINE | ID: mdl-16847467

ABSTRACT

N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent.


Subject(s)
Arylamine N-Acetyltransferase/genetics , Genetic Variation , Indians, North American/genetics , Open Reading Frames , Acetylation , Americas/epidemiology , Arylamine N-Acetyltransferase/metabolism , DNA Mutational Analysis , Evolution, Molecular , Gene Frequency , Genetics, Population , Genotype , Haplotypes , Humans , Mutation , Phenotype , Polymorphism, Single Nucleotide , Siberia/epidemiology
5.
Ann Hum Genet ; 69(Pt 3): 275-87, 2005 May.
Article in English | MEDLINE | ID: mdl-15845032

ABSTRACT

Ethiopia is central to population genetic studies investigating the out of Africa expansion of modern humans, as shown by Y chromosome and mtDNA studies. To address the level of genetic differentiation within Ethiopia, and its relationship to Sub-Saharan Africa and Eurasia, we studied an 8 kb segment of the X-chromosome from 72 chromosomes from the Amhara, Oromo and Ethiopian Jews, and compared these results with 804 chromosomes from Middle Eastern, African, Asian and European populations, and 22 newly typed Saharawi. Within Ethiopia the two largest ethnic groups, the Amhara and Oromo, were not found to be statistically distinct, based on an exact test of haplotype frequencies. The Ethiopian Jews appear as an admixed population, possibly of Jewish origin, though the data remain equivocal. There is evidence of a close relationship between Ethiopian and Yemenite Jews, likely a result of indirect gene flow. Within an African and Eurasian context, the distribution of alleles of a variable T(n) repeat, and the spread of haplotypes containing Africa-specific alleles, provide evidence of a genetic continuity from Sub-Saharan Africa to the Near East, and furthermore suggest that a bottleneck occurred in Ethiopia associated with an out of Africa expansion. Ethiopian genetic heterogeneity, as evidenced by principal component analysis of haplotype frequencies, most likely resulted from periods of subsequent admixture. While these results are from the analysis of one locus, we feel that in association with data from other marker systems they add a complementary perspective on the history of Ethiopia.


Subject(s)
Chromosomes, Human, X/genetics , Genetics, Population , Jews/genetics , Population Dynamics , Africa , Asia , Base Sequence , Biological Evolution , DNA, Mitochondrial/genetics , Ethiopia , Europe , Female , Haplotypes , Humans , Male , Molecular Sequence Data , Movement
6.
Endocr Relat Cancer ; 10(2): 225-59, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12790786

ABSTRACT

In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.


Subject(s)
Genetic Predisposition to Disease/genetics , Loss of Heterozygosity , Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Chromosome Mapping , Humans , Male
7.
Am J Hum Genet ; 69(5): 1113-26, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11582570

ABSTRACT

We studied mutations in the mtDNA control region (CR) using deep-rooting French-Canadian pedigrees. In 508 maternal transmissions, we observed four substitutions (0.0079 per generation per 673 bp, 95% CI 0.0023-0.186). Combined with other familial studies, our results add up to 18 substitutions in 1,729 transmissions (0.0104), confirming earlier findings of much greater mutation rates in families than those based on phylogenetic comparisons. Only 12 of these mutations occurred at independent sites, whereas three positions mutated twice each, suggesting that pedigree studies preferentially reveal a fraction of highly mutable sites. Fitting the data through use of a nonuniform rate model predicts the presence of 40 (95% CI 27-54) such fast sites in the whole CR, characterized by the mutation rate of 274 per site per million generations (95% CI 138-410). The corresponding values for hypervariable regions I (HVI; 1,729 transmissions) and II (HVII; 1,956 transmissions), are 19 and 22 fast sites, with rates of 224 and 274, respectively. Because of the high probability of recurrent mutations, such sites are expected to be of no or little informativity for the evaluation of mutational distances at the phylogenetic time scale. The analysis of substitution density in the alignment of 973 HVI and 650 HVII unrelated European sequences reveals that the bulk of the sites mutate at relatively moderate and slow rates. Assuming a star-like phylogeny and an average time depth of 250 generations, we estimate the rates for HVI and HVII at 23 and 24 for the moderate sites and 1.3 and 1.0 for the slow sites. The fast, moderate, and slow sites, at the ratio of 1:2:13, respectively, describe the mutation-rate heterogeneity in the CR. Our results reconcile the controversial rate estimates in the phylogenetic and familial studies; the fast sites prevail in the latter, whereas the slow and moderate sites dominate the phylogenetic-rate estimations.


Subject(s)
DNA, Mitochondrial/genetics , Mutation/genetics , Phylogeny , Regulatory Sequences, Nucleic Acid/genetics , Canada , Europe , Female , France/ethnology , Humans , Kinetics , Male , Models, Genetic , Mutagenesis/genetics , Pedigree , Sequence Alignment
8.
Int J Cancer ; 92(2): 220-5, 2001 Apr 15.
Article in English | MEDLINE | ID: mdl-11291049

ABSTRACT

Breast cancer is the most frequent malignancy among women. Since genetic factors such as BRCA1 and BRCA2 as well as reproductive history constitute only 30% of the cause, environmental exposure may play a significant role in the development of breast cancer. Likewise, the relevant enzymes involved in the biotransformation of xenobiotics (from tobacco smoke, diet or other environmental sources) might play a role in breast carcinogenesis. Since individuals with modified ability to metabolize these carcinogens could have a different risk for breast cancer, we investigated the role of cytochromes P-450 (CYP1A1, CYP2D6), glutathione-S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) gene variants in breast carcinogenesis. A case-control study was conducted on 149 women with breast carcinoma and 207 healthy controls, both of French-Canadian origin. The CYP1A1*4 allele was found to be a significant risk determinant of breast carcinoma (OR = 3.3, 95% CI 1.1-9.7), particularly among post-menopausal women (OR = 4.0, 95% CI 1.2-13.8). The frequency of NAT2 rapid acetylators was increased among smokers (OR = 2.6, 95% CI 0.8-8.2), while the NAT1*10 allele conferred a 4-fold increase in risk among women who consumed well-done meat (OR = 4.4, 95% CI 1.0-18.9). These data suggest that CYP1A1*4, NAT1 and NAT2 variants are involved in the susceptibility to breast carcinoma by modifying the impact of exogenous and/or endogenous exposures.


Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Carcinogens/metabolism , Carcinoma/enzymology , Carcinoma/genetics , Genetic Predisposition to Disease , Arylamine N-Acetyltransferase/genetics , Breast Neoplasms/epidemiology , Canada/epidemiology , Carcinoma/epidemiology , Case-Control Studies , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP2D6/genetics , Environmental Exposure , Female , France/ethnology , Gene Frequency , Genotype , Glutathione Transferase/genetics , Humans , Isoenzymes/genetics , Menopause , Middle Aged , Polymorphism, Genetic , Risk Factors
9.
Rev Environ Health ; 16(4): 263-79, 2001.
Article in English | MEDLINE | ID: mdl-12041882

ABSTRACT

The origin of acute lymphoblastic leukemia (ALL), the most common pediatric cancer, can be explained by a combination of genetic factors and environmental exposure. The environmental toxicants to which an individual is exposed are biotransformed and eliminated from the body after metabolic conversion mediated by Phase I and Phase II xenobiotic-metabolizing enzymes. Phase I enzymes catalyze hydroxylation, reduction and oxidation reactions of xenobiotics (carcinogens/drugs), often converting them into more active or toxic compounds. Phase II enzymes catalyze conjugation reactions (glucuronidation, acetylation, methylation), thereby converting the metabolites into non-reactive, water-soluble products that are eliminated from the organism. The genetic polymorphism underlying the variation in enzyme activity can modify susceptibility to diverse adult cancers, probably by influencing the activation and removal of toxicants or drugs. Here we present an overview of the role of genetic variants of certain Phase I and Phase II enzymes in the development of childhood ALL, a good model for such studies because of its short latency period. The genetic contribution to the development of ALL is examined by association studies that analyze the loci of Phase I enzymes (cytochrome P-450, myeloperoxidase) and Phase II enzymes (quinone-oxidoreductase, glutathione-S-transferase, N-acetyltransferase). The loci of the enzyme variants CYPlA1, CYP2E1, NQO1, GSTM1, GSTP1, NAT2 are associated with disease development, and evidence of gene-gene interactions has emerged as well. Despite the improvements in treatment, resistant cases of ALL remain a leading cause of cancer-related death in children. Although the underlying mechanism of drug resistance is not well understood, differences in the capacity of ALL patients to process drugs and environmental carcinogens could play a role by modifying the risk of recurrent malignancy, as well as the response to therapy. Therefore, polymorphic genes encoding carcinogen- and drug-metabolizing enzymes may not only increase the risk of ALL but also influence the risk of relapse in patients. We found that the prognosis of patients with CYPlA1 and NQO1 variants was worse than that of patients who lack these variants. We conclude that genotyping ALL patients for functional polymorphisms of candidate genes can become an important tool in predicting disease outcome.


Subject(s)
Genetic Predisposition to Disease , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Treatment Outcome , Carcinogens/adverse effects , Carcinogens/metabolism , Child , Drug Resistance , Humans , Pharmacogenetics , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
10.
Genetics ; 156(2): 799-808, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11014825

ABSTRACT

An important question in the ongoing debate on the origin of Homo sapiens is whether modern human populations issued from a single lineage or whether several, independently evolving lineages contributed to their genetic makeup. We analyzed haplotypes composed of 35 polymorphisms from a segment of the dystrophin gene. We find that the bulk of a worldwide sample of 868 chromosomes represents haplotypes shared by different continental groups. The remaining chromosomes carry haplotypes specific for the continents or for local populations. The haplotypes specific for non-Africans can be derived from the most frequent ones through simple recombination or a mutation. In contrast, chromosomes specific for sub-Saharan Africans represent a distinct group, as shown by principal component analysis, maximum likelihood tree, structural comparison, and summary statistics. We propose that African chromosomes descend from at least two lineages that have been evolving separately for a period of time. One of them underwent range expansion colonizing different continents, including Africa, where it mixed with another, local lineage represented today by a large fraction of African-specific haplotypes. Genetic admixture involving archaic lineages appears therefore to have occurred within Africa rather than outside this continent, explaining greater diversity of sub-Saharan populations observed in a variety of genetic systems.


Subject(s)
Black People/genetics , Chromosome Mapping , Hominidae/genetics , Phylogeny , White People/genetics , Africa , Africa South of the Sahara , Algorithms , Animals , Databases as Topic , Female , Haplotypes , Humans , Likelihood Functions , Male , X Chromosome , Y Chromosome
11.
Leuk Lymphoma ; 38(5-6): 447-62, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10953966

ABSTRACT

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The origin of this disease can be explained by a combination of genetic susceptibility factors and environmental exposures. For the purpose of our study it can be considered as a complex disease, caused by the "carcinogenic" effect of the environment modified by a series of genes. In population, these genes tend to occur in allelic forms representing functional polymorphisms thus explaining inter-individual variability in cancer susceptibility. The latter can be evaluated more realistically in childhood ALL than in sporadic cancers of the adult because of its relatively short latency period. We asked therefore, the question about the role of genes controlling the efficiency of xenobiotics metabolism in childhood leukemogenesis. Xenobiotics (drugs and carcinogens) are excreted from the body after metabolic conversion by enzymes mediating oxidation activation (Phase I) and conjugation detoxificaton (Phase II). Functional variants of these enzymes, resulting from known DNA polymorphisms in the corresponding genes, were shown to influence the risk to a variety of solid tumours in adults. A case-control study on ALL patients and healthy controls in a French-Canadian population was carried out by examining the loci of Phase I, CYP1A1 and CYP2D6, as well as Phase II enzymes, GSTM1, GSTT1, NAT1 and NAT2. The NAT2 slow-acetylator, CYP1A1*2A and GSTM1 null genotypes were shown to be significant risk determinants of ALL (OR=1.6, 1.8 and 1.8, respectively), whereas, polymorphisms in CYP2D6 and GSTT1 genes did not seem to play an important role in the aetiology of ALL. Interestingly, the risk associated with NAT2 slow-acetylators was most apparent among males homozygous for NAT1*4 (OR=3.3) whereas girls carrying the CYP1A1*4 allele were significantly underrepresented in the patient group (OR=0.2). These findings point to a gender-specific effect of DNA variants which, at least in part, may explain why ALL is more prevalent among boys. To assess gene-gene interactions, NAT2 slow-acetylators were considered together with GSTM1 null genotypes and CYP1A1*2A alleles. The combined presence of two risk-elevating genotypes appeared to confer an increased risk of ALL among the carriers (OR=2.6). This risk was increased further (OR=3.3) when all three genotypes occurred in the same individuals indicating that the combination of susceptibility variants is more predictive of risk then either of them independently. The association of leukemogenesis in children with metabolising gene variants suggests causal relation to environmental exposures.


Subject(s)
Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adult , Child , Child, Preschool , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Xenobiotics/metabolism
12.
Neurology ; 54(12): 2322-4, 2000 Jun 27.
Article in English | MEDLINE | ID: mdl-10881262

ABSTRACT

The GAA triplet repeat expansion that causes Friedreich ataxia is found only in individuals of European, North African, Middle Eastern, or Indian origin (Indo-European and Afro-Asiatic speakers). Analysis of normal alleles of the GAA repeat and of closely linked markers suggests that expansions arose through a unique two-step process. A major implication of these findings is that Friedreich ataxia may not exist among sub-Saharan Africans, Amerindians, and people from China, Japan, and Southeast Asia.


Subject(s)
Friedreich Ataxia/ethnology , Friedreich Ataxia/genetics , Iron-Binding Proteins , Trinucleotide Repeat Expansion/genetics , Africa, Northern , Alleles , Asia , Asian People/genetics , Black People/genetics , Europe , Founder Effect , Genetic Linkage , Genetic Markers , Haplotypes , Humans , Middle East , Phosphotransferases (Alcohol Group Acceptor)/genetics , White People/genetics , Frataxin
13.
Cancer Causes Control ; 11(6): 547-53, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10880037

ABSTRACT

OBJECTIVE: To evaluate the effect of parental smoking on childhood acute lymphoblastic leukemia and to determine if it is modified by child genetic polymorphisms. METHODS: We carried out a case-control study in Quebec, Canada, including 491 incident cases aged 0-9 years and as many healthy controls matched on age and sex. Each parent was interviewed separately with respect to smoking habits during and after pregnancy. In addition, we carried out a case-only substudy with 158 cases classified according to presence or absence of the alleles *2A, *2B, and *4 in the CYP1A1 gene. RESULTS: There were small risk increases with maternal smoking during the later trimesters. Interaction odds ratios were increased (although often not significantly) for the CYP1A1*4 allele at high levels of maternal smoking in the last trimesters and at low level of paternal postnatal smoking, and decreased for the CYP1A1*2B allele. The latter appeared to confer a protective advantage at low levels for maternal prenatal smoking and at high levels for paternal postnatal smoking. CONCLUSIONS: Reported smoking habits showed no association with leukemia; risks for genetic polymorphisms lacked precision but indicated that the effect of parental smoking could be modified by variant alleles in the CYP1A1 gene.


Subject(s)
Cytochrome P-450 CYP1A1/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Smoking , Alleles , Case-Control Studies , Child , Child, Preschool , Fathers , Female , Genetic Predisposition to Disease , Humans , Infant , Logistic Models , Male , Odds Ratio , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Pregnancy , Prenatal Exposure Delayed Effects , Quebec/epidemiology , Smoking/epidemiology , Surveys and Questionnaires , Tobacco Smoke Pollution/adverse effects
14.
Cancer Epidemiol Biomarkers Prev ; 9(6): 557-62, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10868688

ABSTRACT

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. In utero and postnatal exposures to various carcinogens may play a role in the etiology of this disease. N-acetyltransferases, encoded by the NAT1 and NAT2 genes are involved in the biotransformation of aromatic amines present in tobacco smoke, environment, and diet. Their rapid and slow acetylation activity alleles have been shown to modify the risk to a variety of solid tumors in adults. To investigate the role of NAT1 and NAT2 variants as risk-modifying factors in leukemogenesis, we conducted a case-control study on 176 ALL patients and 306 healthy controls of French-Canadian origin. Slow NAT2 acetylation genotype was found to be a significant risk determinant of ALL (odds ratio, 1.5; 95% confidence interval, 1.0-2.2) because of overrepresentation of the alleles NAT2*5C and *7B and underrepresentation of NAT2*4. Besides a slight increase in NAT1*4 allele frequency among cases, no independent association of NAT1 acetylation genotypes and ALL risk was observed. However, the risk associated with NAT2 slow acetylators was more apparent among homozygous individuals for NAT1*4 (odds ratio, 1.9; 95% confidence interval, 1.1-3.4). When NAT2 slow acetylators were considered together with the other risk-elevating genotypes, GSTM1 null and CYP1A1*2A, the risk of ALL increased further, which showed that the combination of these genotypes is more predictive of risk then either of them independently. These findings suggest that leukemogenesis in children is associated with carcinogen metabolism and consequently related to environmental exposures.


Subject(s)
Acetyltransferases/genetics , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies , Child , Environmental Exposure , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Odds Ratio , Risk Factors
15.
J Mol Biol ; 298(3): 365-77, 2000 May 05.
Article in English | MEDLINE | ID: mdl-10772856

ABSTRACT

We characterized short interspersed elements (SINEs), of the CORE-suprafamily in egg-laying (monotremes), pouched (marsupials) and placental mammals. Five families of these repeats distinguished by the presence of distinct LINE-related 3'-segments shared tRNA-like promoter and the central core region. The putative active elements were reconstructed from the alignment of genomic repeats representing molecular fossils of sequences that amplified in the past and since then underwent multiple mutations. Their mode of proliferation by retroposition was indicated by the presence of: (1) internal RNA PolIII promoter; (2) simple sequence repeated tail; (3) direct repeats; and (4) subfamilies recording the evolution of elements. The copy number of CORE-SINEs in placental genomes was estimated at about 300,000; they were highly divergent and apparently ceased to amplify before radiation of these lineages. On the other hand, among almost half a million fossil elements present in marsupials and monotremes, the youngest subfamilies could still be retropositionally active. CORE-SINEs terminate in sequence repeats of a few nucleotides similar to their 3'-segment LINE-homologues, CR1, L2 and Bov-B. These three LINE elements fall into clades distinct from that of L1 elements which, similar to their co-amplifying SINEs, end in a poly(A) tail. We propose a model in which new CORE-families, with distinct 3'-segments, are created at the RNA level due to template switching between LINE and CORE-RNA during reverse transcription. The proposed mechanism suggests that such an adaptation to the changing amplification machinery facilitated the survival and prosperity of CORE-elements over long evolutionary periods in different lineages.


Subject(s)
Evolution, Molecular , Mammals/genetics , Short Interspersed Nucleotide Elements/genetics , Animals , Base Sequence , Blotting, Southern , Consensus Sequence/genetics , DNA, Satellite/genetics , Databases, Factual , Gene Amplification/genetics , Gene Dosage , Genome , Humans , Long Interspersed Nucleotide Elements/genetics , Marsupialia/genetics , Models, Genetic , Molecular Sequence Data , Monotremata/genetics , Mutation/genetics , Phylogeny , Recombination, Genetic/genetics , Sequence Alignment , Transcription, Genetic/genetics
16.
Mol Biol Evol ; 16(11): 1633-40, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10555294

ABSTRACT

DNA variability was investigated in the last intron of the Y-chromosome-specific zinc finger gene, ZFY, and its X homolog on Xp21.3, ZFX. No polymorphisms were found in the 676-bp ZFY segment in a sample of 205 world-wide-distributed Y chromosomes, other than a solitary nucleotide variant in one individual (nucleotide diversity pi = 0.0014%). In contrast, 10 segregating sites (pi = 0.082%) were identified within 1,089 bp of the ZFX sequence in a sample of 336 X chromosomes. Four of these polymorphisms, which contributed most of the diversity, were located within an Alu insert disrupting the ZFY-ZFX homology (pi Alu = 0.24%). The diversity in the homologous portion of the ZFX intron, although higher than that in ZFY, was lower than that found in genomic segments believed to evolve neutrally; interspecies divergence in both segments was also reduced. Although this suggests that the evolution of both ZFY and ZFX homologs may not be entirely neutral, both Tajima and HKA tests did not reject neutrality. The lack of statistical significance may be attributed to a lack of power in these tests (the low divergence and variability values reduce the power of the HKA and Tajima tests, respectively); furthermore, Homo sapiens has recently undergone a rapid population growth, and selection is more difficult to detect in an expanding population. Therefore, the failure to reject neutrality does not necessarily indicate the absence of selection. In this context, the phylogenetic argument was given more weight in out interpretations. The high level of sequence identity in ZFY and ZFX segments, in spite of their separation 80-130 MYA, reflects a lower mutation rate as compared with other segments believed to undergo unconstrained evolution. Thus, the possibility of weak selection contributing to the low level of nucleotide diversity in the last ZFY intron cannot be excluded and should be kept in mind in the population genetics studies based on Y chromosome variability.


Subject(s)
DNA-Binding Proteins/genetics , Genetic Variation , Introns , Selection, Genetic , Base Sequence , DNA Primers , Evolution, Molecular , Humans , Kruppel-Like Transcription Factors , Polymorphism, Single Nucleotide , Transcription Factors , Zinc Fingers
17.
Anal Biochem ; 275(1): 84-92, 1999 Nov 01.
Article in English | MEDLINE | ID: mdl-10542112

ABSTRACT

Drugs and carcinogens are excreted from the body after metabolic conversion involving enzymes mediating oxidative metabolism and conjugation. Many of the corresponding genes exhibit functional polymorphisms that contribute to individual cancer susceptibility. To increase the efficiency and to facilitate genotyping, we developed a combined approach (PCR-ASO) which includes multiplex PCR and allele-specific oligonucleotide (ASO) hybridization. PCR primer pairs were used to amplify the following alleles/variants: CYP1A1*1, *2A, *2B; CYP2D6*3, *4; NAT1*4, *3, *10, *11, *14, *15; and NAT2*4, *5A, *5B, *5C, *6A, *7B. The products were dot-blotted and polymorphisms were detected by hybridization with ASO probes for both wild-type and variant sites in parallel. This approach was validated by genotyping DNA samples from a French-Canadian population that was previously analyzed by PCR-RFLP. The variants frequencies were compared with the data on other populations available in the literature. The PCR-ASO assay appears to be simple, efficient, and cost-effective, particularly if a large number of samples are to be screened for several DNA variants. This approach has potential for automation with microplates and robotic workstations for high throughput.


Subject(s)
Arylamine N-Acetyltransferase/analysis , Cytochrome P-450 CYP1A1/analysis , Cytochrome P-450 CYP2D6/analysis , Isoenzymes/analysis , Polymerase Chain Reaction/methods , Arylamine N-Acetyltransferase/genetics , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP2D6/genetics , Humans , Immunoblotting/methods , Isoenzymes/genetics , Oligonucleotides/metabolism , Polymorphism, Genetic
18.
Epidemiology ; 10(5): 481-7, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10468419

ABSTRACT

We conducted a population-based case-control study of childhood acute lymphoblastic leukemia (ALL) to evaluate the risk posed by reported exposure to pesticides used in and around the home. We compared 491 cases 0-9 years of age to as many controls. We also conducted a case-only study on a subsample of 123 cases to evaluate gene-environment interaction between child genotype and maternal exposure during pregnancy as well as child exposure after birth. We used the polymerase chain reaction (PCR) approach to analyze polymorphisms in CYP1A1, CYP2D6, GSTT1, and GSTM1 genes, which encode enzymes involved in carcinogen metabolism. Indoor use of some insecticides by the owners and pesticide use in the garden and on interior plants, in particular frequent prenatal use, was associated with increased risks up to severalfold in magnitude. Interaction odds ratios were increased among carriers of the CYP1A1m1 and CYP1a1m2 mutations when mother during pregnancy or the child had been exposed to certain indoor insecticides. No such effects were observed in the presence of other tested polymorphisms.


Subject(s)
Pesticides/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Prenatal Exposure Delayed Effects , Case-Control Studies , Child , Child, Preschool , Confidence Intervals , Cytochrome P-450 CYP1A1/genetics , Female , Genetic Predisposition to Disease/epidemiology , Humans , Infant , Infant, Newborn , Logistic Models , Male , Maternal Exposure/adverse effects , Maternal Exposure/statistics & numerical data , Odds Ratio , Pesticides/classification , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Pregnancy , Quebec/epidemiology
19.
Genetics ; 152(3): 1091-101, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10388827

ABSTRACT

With 10 segregating sites (simple nucleotide polymorphisms) in the last intron (1089 bp) of the ZFX gene we have observed 11 haplotypes in 336 chromosomes representing a worldwide array of 15 human populations. Two haplotypes representing 77% of all chromosomes were distributed almost evenly among four continents. Five of the remaining haplotypes were detected in Africa and 4 others were restricted to Eurasia and the Americas. Using the information about the ancestral state of the segregating positions (inferred from human-great ape comparisons), we applied coalescent analysis to estimate the age of the polymorphisms and the resulting haplotypes. The oldest haplotype, with the ancestral alleles at all the sites, was observed at low frequency only in two groups of African origin. Its estimated age of 740 to 1100 kyr corresponded to the time to the most recent common ancestor. The two most frequent worldwide distributed haplotypes were estimated at 550 to 840 and 260 to 400 kyr, respectively, while the age of the continentally restricted polymorphisms was 120 to 180 kyr and smaller. Comparison of spatial and temporal distribution of the ZFX haplotypes suggests that modern humans diverged from the common ancestral stock in the Middle Paleolithic era. Subsequent range expansion prevented substantial gene flow among continents, separating African groups from populations that colonized Eurasia and the New World.


Subject(s)
DNA-Binding Proteins/genetics , Genealogy and Heraldry , Haplotypes , Introns , Polymorphism, Genetic , Humans , Kruppel-Like Transcription Factors , Male , Models, Genetic , Time Factors , Transcription Factors , X Chromosome
20.
Br J Cancer ; 79(7-8): 1012-7, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10098729

ABSTRACT

To study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11-q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11-q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction.


Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 5/genetics , DNA-Binding Proteins/genetics , Loss of Heterozygosity , Multidrug Resistance-Associated Proteins , Neoplasm Proteins/genetics , Adaptor Proteins, Signal Transducing , Carrier Proteins , DNA Repair/genetics , Female , Humans , Microsatellite Repeats/genetics , MutL Protein Homolog 1 , MutS Homolog 3 Protein , Nuclear Proteins
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