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PubMed1984

Mitochondrial DNA polymorphism in Japanese. I. Analysis with restriction enzymes of six base pair recognition.

The mitochondrial DNA (mtDNA) from 120 Japanese was analysed with 15 restriction enzymes that recognize six base pairs, of which 11 enzymes showed at least one atypical cleavage pattern. Digestion patterns with Hinc II and Hae II were highly polymorphic. The observed restriction enzyme morphs were classified into 22 types of distinct cleavage patterns. By pairwise comparison of each restriction type, the average number of nucleotide substitutions per nucleotide site (delta) was estimated at 0.00417, which agreed with the values obtained from other human populations in previous studies. There were 11 site gains, of which seven were transitions and four were transversions. Phylogenetic analysis of the present data suggested that the Japanese population conceals a considerably high degree of mtDNA diversity.

Base Composition↗

PubMed2003

An association study of angiotensinogen polymorphisms with serum level and hypertension in an African-American population.

OBJECTIVE: To evaluate the association of angiotensinogen (AGT) gene with AGT level and hypertension based on the overall genetic variation of the AGT gene in among African-Americans. METHODS: All non-rare single nucleotide polymorphisms (SNPs) in AGT were identified by resequencing 24 individuals. Five tagging SNPs were selected based on the pairwised linkage disequilibrium (LD) pattern and were genotyped in 284 individuals. Association studies of AGT level and hypertension were performed using these five tagging SNPs. RESULTS: No significant association with AGT level or hypertension was found in analyses of each of the five single SNPs. However, one of the haplotypes defined by these five SNPs was significantly associated with AGT level (P = 0.046), although this haplotype was not associated with hypertension. CONCLUSIONS: Identification of genetic polymorphisms associated with risk of hypertension has been frustratingly difficult. Two strategies adopted to improve precision are the use of intermediate phenotypes and summarization of genetic information using haplotypes. These strategies appeared to yield a modest increase in precision at the AGT locus with respect to the physiological intermediate, but did not lead to significant association of the molecular markers with hypertension. Additional research is required to increase confidence in haplotype mapping as an epidemiological analysis tool.

Adult↗

PubMedDate not supplied

Molecular evolution of the leptin exon 3 in some species of the family Canidae.

The structure of the leptin gene seems to be well conserved. The polymorphism of this gene in four species belonging to the Canidae family (the dog (Canis familiaris)--16 different breeds, the Chinese racoon dog (Nyctereutes procyonoides procyonoides), the red fox (Vulpes vulpes) and the arctic fox (Alopex lagopus)) were studied with the use of single strand conformation polymorphism (SSCP), restriction fragment length polymorphism (RFLP) and DNA sequencing techniques. For exon 2, all species presented the same SSCP pattern, while in exon 3 some differences were found. DNA sequencing of exon 3 revealed the presence of six nucleotide substitutions, differentiating the studied species. Three of them cause amino acid substitutions as well. For all dog breeds studied, SSCP patterns were identical.

Animals↗

PubMed2004

Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders.

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.

Adolescent↗

PubMed1993

Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes.

The tre oncogenic locus was identified in transformants receiving human DNA from Ewing's sarcoma cells EW1. Genetic elements of tre originate from chromosomes 5, 18, and 17. The TRE17 oncogene is consistently transcribed in various human cancer cells and proves oncogenic (onc) in expression vector-based assays. Here, the nucleotide sequence of TRE17 with defined noncoding and two coding exons (4,426 nucleotides) was compared with sequences cloned from placental DNA library or generated by polymerase chain reaction (PCR) from EW1 and independent healthy individuals. Cloned sequences displayed restriction site polymorphism, with different patterns for EW1 and normal tissues. Sequence analysis revealed that they originate from a family of homologous sequences alpha, beta, and gamma. TRE17 alpha and less frequent TRE17 beta (similarity score approximately equal to 88%) were found in both normal and EW1 cells. oncTRE17, classified as TRE17 beta, differed from the wild-type TRE17 beta, besides a few intronic changes, by a single-base frameshift insertion in one of the coding exons. TRE17 gamma, so far identified in EW1 but not in normal somatic cells, diverged from oncTRE17 by 6% nucleotide substitutions and by stop codons in each reading frame. The results are consistent with the possibility that TRE17 sequences other than oncTRE17 are translated if alternatively spliced. Expression of TRE17 in normal somatic cells was, however, not yet reported.

Amino Acid Sequence↗

PubMed2005

A case control study on the contribution of factor V-Leiden, prothrombin G20210A, and MTHFR C677T mutations to the genetic susceptibility of deep venous thrombosis.

BACKGROUND: Insofar as the inherited prothrombotic single nucleotide polymorphisms (SNPs) factor V G1691A (FV-Leiden), prothrombin (PRT) G20210A, and methylenetetrahydrofolate reductase (MTHFR), C677T are inherited risk factors of venous thromboembolism (VTE), the aim of this study was to determine the prevalence of single and combined SNPs in 198 patients with documented deep venous thrombosis (DVT), and 697 control subjects, and to estimate the associated risks. METHODS: Factor V-Leiden, PRT G20210A, and MTHFR C677T were analyzed by PCR and restriction fragment length polymorphism (RFLP). RESULTS: The prevalence of the heterozygote and homozygous variants for FV-Leiden (52.02 vs. 14.78%, RR 6.28), PRT G20210A (19.2 vs. 3.6%; RR 6.38), and to a lesser extent the T/T genotype of MTHFR C677T (20.71 vs. 11.0%; RR 1.49) were higher among DVT patients vs. controls, respectively. Two or more SNPs were detected in 90 of 198 patients (45.5%) and in 60 of 697 controls (8.6%), with odds ratios of 16.754 for joint occurrence of FV-Leiden and PRT G20210A, 10.471 for FV-Leiden and MTHFR C677T, and 6.283 for PRT G20210A SNPs and MTHFR 677T/T. Logistic regression analysis showed a further increased odds for FV-Leiden in combination with PRT G20210A (85.198) or homozygous MTHFR C677T (81.133), and to a lesser extent for PRT G20210A in combination with homozygous MTHFR C677T (20.812). CONCLUSIONS: This indicates that FV-Leiden and PRT G20210A, more than MTHFR C677T, are important risk factors for DVT, and that the presence of more than one prothrombotic SNPs was associated with a significant risk of DVT.

Case-Control Studies↗

PubMed2005

An artificial neural network for estimating haplotype frequencies.

The problem of estimating haplotype frequencies from population data has been considered by numerous investigators, resulting in a wide variety of possible algorithmic and statistical solutions. We propose a relatively unique approach that employs an artificial neural network (ANN) to predict the most likely haplotype frequencies from a sample of population genotype data. Through an innovative ANN design for mapping genotype patterns to diplotypes, we have produced a prototype that demonstrates the feasibility of this approach, with provisional results that correlate well with estimates produced by the expectation maximization algorithm for haplotype frequency estimation. Given the computational demands of estimating haplotype frequencies for 20 or more single-nucleotide polymorphisms, the ANN approach is promising because its design fits well with parallel computing architectures.

Algorithms↗

PubMed1994

Dissemination among staphylococci of DNA sequences associated with methicillin resistance.

DNA probes consisting of pUC19 containing cloned Staphylococcus aureus chromosomal fragments were constructed from two methicillin-resistant S. aureus strains with different DNA sequences 5' to mecA, the gene that mediates methicillin resistance. The probe from one strain, BMS1, contained a portion of the regulatory sequences (the terminal 641 bp of mecR1 and all of mecI) associated with the induction and repression of mecA transcription (pGO195). The second probe, from strain COL (pGO198), contained DNA not found in strain BMS1. This DNA was within the sequences added at the site of a mecR1 deletion. Genomic digests of 14 S. aureus isolates recovered between 1961 and 1969 all hybridized with pGO198. In contrast, 78% (36 of 46) of the S. aureus organisms isolated since 1988 hybridized with pGO195 but not with pGO198; the remainder hybridized with pGO198. No S. aureus isolates hybridized with both probes. Staphylococcus epidermidis digests hybridized with pGO198 (46%), pGO195 (14%), or both probes (35%); all 20 Staphylococcus haemolyticus isolates hybridized with pGO198. The restriction fragment length polymorphism patterns of all pGO198-hybridizing regions in S. aureus were identical to those in strain COL. In addition, the mecR1 deletion junction nucleotide sequences of eight S. aureus and six S. epidermidis isolates were identical. However, 21 of 23 S. epidermidis and all 20 S. haemolyticus isolates had from 5 to more than 20 additional chromosomal bands that hybridized with pGO198; none of 21 S. aureus isolates had additional hybridizing bands. These data suggest that the additional DNA responsible for the mecR1 deletion was part of a repetitive, and possibly mobile, element resident in coagulase-negative staphylococci but not in S. aureus. These data also support a hypothesis that the deletion event occurred in a coagulase-negative staphylococcus with subsequent acquisition of the interrupted sequences by S. aureus.

Base Sequence↗

PubMed2002

Polymorphism and selection at the SerH immobilization antigen locus in natural populations of Tetrahymena thermophila.

The SerH locus of Tetrahymena thermophila is one of several paralogous loci with genes encoding variants of the major cell surface protein known as the immobilization antigen (i-ag). The locus is highly polymorphic, raising questions concerning functional equivalency and selective forces acting on its multiple alleles. Here, we compare the sequences and expression of SerH1, SerH3, SerH4, SerH5, and SerH6. The precursor i-ags are highly similar. They are rich in alanine, serine, threonine, and cysteine and they share nearly identical ER translocation and GPI addition signals. The locations of the 39 cysteines are highly conserved, particularly in the 3.5 central, imperfect tandem repeats in which 8 periodic cysteines punctuate alternating short and long stretches of amino acids. Hydrophobicity patterns are also conserved. Nevertheless, amino acid sequence identity is low, ranging from 60.7 to 82.9%. At the nucleotide level, from 9.7 to 26.7% of nucleotide sites are polymorphic in pairwise comparisons. Expression of each allele is regulated by temperature-sensitive mRNA stability. H mRNAs are stable at <36 degrees but are unstable at >36 degrees. The H5 mRNA, which is less affected by temperature, has a different arrangement of the putative mRNA destabilization motif AUUUA. Statistical analysis of SerH genes indicates that the multiple alleles are neutral. Significantly low ratios of the rates of nonsynonymous to synonymous amino acid substitutions suggest that the multiple alleles are subject to purifying (negative) selection enforcing constraints on structure.

Amino Acid Sequence↗

PubMed2006

Family-based association analysis of hepatocyte growth factor (HGF) gene polymorphisms in high myopia.

PURPOSE: To investigate the association of high myopia with polymorphisms in the hepatocyte growth factor (HGF) gene, a potential candidate for myopia development. METHODS: Single nucleotide polymorphisms (SNPs) were screened and identified in the HGF gene region with denaturing high-performance liquid chromatography, and their linkage disequilibrium pattern was established in a Han Chinese population (n=150). Tag SNPs were selected and genotyped using restriction digestion and fluorescence polarization assays for 128 nuclear families with 133 severely myopic (mean spherical equivalent [MSE]<or=-10.0 D) offspring. A family-based association study was performed using FBAT and GenAssoc (Cambridge University, Cambridge, UK). RESULTS: Of three tag SNPs (HGF5-5b, HGFe9, and HGFe10b) selected for association study, HGF5-5b, located in the upstream region, was found to be associated with high myopia considered as a quantitative trait (MSE) in additive, dominant, and recessive models (P=0.0157, 0.0108, and 0.0108, respectively). The genotype relative risk was 2.19 for the genotype C/T, and 2.14 for T/T with reference to C/C of HGF5-5b. Significantly reduced transmission was demonstrated for the haplotypes C-A-C (HGF5-5b, HGFe9, and HGFe10b; P=0.0031) and C-A (HGF5-5b and HGFe9; P=0.0015) in the recessive model, whereas significantly increased transmission was found for haplotype T-C (HGF5-5b and HGFe10b; P=0.0040) under the dominant model. Preferential transmission of haplotypes remained significant even after correction for multiple comparisons. Analysis gave similar results, with myopia considered to be a qualitative trait. CONCLUSIONS: HGF is a potential locus associated with high myopia in the Han Chinese population. This is the first study reporting the association of an HGF gene polymorphism with high myopia.

Adult↗

PubMed2006

Sequencing analysis of ghrelin gene 5' flanking region: relations between the sequence variants, fasting plasma total ghrelin concentrations, and body mass index.

Ghrelin is a 28-amino-acid peptide with several functions linked to energy metabolism. Low ghrelin plasma concentrations are associated with obesity, hypertension, and type 2 diabetes mellitus, whereas high concentrations reflect states of negative energy balance. Several studies addressing the hormonal and neural regulation of ghrelin gene expression have been carried out, but the role of genetic factors in the regulation of ghrelin plasma levels remains unclear. To elucidate the role of genetic factors in the regulation of ghrelin expression, we screened 1657 nucleotides of the ghrelin gene 5' flanking region (promoter and possible regulatory sites) for new sequential variations from patient samples with low (n = 50) and high (n = 50) fasting plasma total ghrelin concentrations (low- and high-ghrelin groups). Eleven single nucleotide polymorphisms (SNPs), 3 of which were rare variants (allelic frequency less than 1%) were found in our population. The genotype distribution patterns of the SNPs did not differ between the study groups, except for SNP-501A>C (P = .039). In addition, the SNP-01A>C was associated with body mass index (BMI) (P = .018). This variant was studied further in our large and well-defined Oulu Project Elucidating Risk for Atherosclerosis (OPERA) cohort (n = 1045) by the restriction fragment length polymorphism (RFLP) technique. No significant association of SNP-501A>C genotypes with fasting ghrelin plasma concentrations was found in the whole OPERA population. However, the association of this SNP with BMI and with waist circumference reached statistical significance in OPERA (P = .047 and .049, respectively), remaining of borderline significance for BMI after adjustments (P = .055). The results indicate that factors other than the 11 SNPs found in this study in the 5' flanking region of ghrelin gene are the main determinants of ghrelin plasma levels. However, SNP-501 A>C genotype distribution seems to be different in subjects having the highest compared with those with the lowest ghrelin levels, and the SNP may be associated with BMI and waist circumference.

5' Flanking Region↗

PubMed2004

The beta-esterase gene cluster of drosophila melanogaster: is psiEst-6 a pseudogene, a functional gene, or both?

Pseudogenes have been defined as non-functional sequences of genomic DNA that are originally derived from functional genes, but exhibit degenerative features such as premature stop codons and frameshifts that prevent their expression. However, there is increasing evidence that pseudogenes are often evolutionarily conserved and may have retained some functional role or acquired new ones. Pseudogenes may exhibit non-functional features as well as functional ones. We investigate, as a model case, the beta-esterase gene cluster of Drosophila melanogaster that includes the Est-6 gene and the psiEst-6 putative pseudogene. We study four samples derived from natural populations of east Africa (Zimbabwe), Europe (Spain), North America (California), and South America (Venezuela). The level of nucleotide diversity is higher in Africa than in the non-African populations. There is twice more nucleotide diversity in psiEst-6 than in Est-6. Linkage disequilibrium within the beta-esterase gene cluster is strong in non-African samples, but much lower in Africa. The population recombination rate is the same for psiEst-6 and Est-6 in Africa, but significantly different in non-African samples. Intragenic gene conversion events are detected within Est-6 and, with much higher incidence, within psiEst-6; intergenic gene conversion events are rare. The extensive intragenic gene conversion within psiEst-6 can be explained by the invasion of retrotransposons that promote a form of homology-dependent gene conversion upon excision. Tests of neutrality with recombination are significant for the beta-esterase gene cluster in the non-African populations but not in Africa. The Est-6 gene sequences exhibit a well-known allozyme dimorphic structure. The sequences of psiEst-6 are also dimorphic in North and South America, but they do not correspond at all (South America) or only imperfectly (North America) to the Est-6 allozyme dimorphism. Sequence dimorphism is less pronounced in the European and African samples. We suggest that demographic history (bottleneck and admixture of genetically differentiated populations) is the major factor shaping the nucleotide pattern in the beta-esterase gene cluster. However, there are some clear indications of positive selection shaping the distribution of nucleotide polymorphism within the cluster. Intergenic epistatic selection may play an important role in the evolution of the beta-esterase gene cluster, preserving psiEst-6 from degenerative destruction and reflecting its functional interaction with Est-6. The Est-6 gene cluster of D. melanogaster represents an example of a functionally interacting complex ('intergene') in which two components (Est-6 and psiEst-6) or more are required to perform the final function.

Animals↗

PubMed2003

The coalescent and infinite-site model of a small multigene family.

The infinite-site model of a small multigene family with two duplicated genes is studied. The expectations of the amounts of nucleotide variation within and between two genes and linkage disequilibrium are obtained, and a coalescent-based method for simulating patterns of polymorphism in a small multigene family is developed. The pattern of DNA variation is much more complicated than that in a single-copy gene, which can be simulated by the standard coalescent. Using the coalescent simulation of duplicated genes, the applicability of statistical tests of neutrality to multigene families is considered.

Data Interpretation, Statistical↗

PubMed1993

Sequence variation in the noncoding region of human papillomavirus type 16 detected by single-strand conformation polymorphism analysis.

Human papillomavirus (HPV) type 16 variants were found by single-strand conformation polymorphism (SSCP) analysis of the noncoding region of the viral genome. Two sets of primers were used to analyze a 1018 bp region spanning nucleotides 7109-222. Twelve SSCP patterns were demonstrated among HPV 16 DNAs purified from 48 anal specimens from 24 homosexual men. Seven patterns were detected among 10 HPV 16 isolates from cervical carcinomas. In two pairs of sex partners, identical variants were recognized in each partner of the pair. Infection with two variants of HPV 16 from 2 specimens was observed in 1 of 21 subjects for whom there were multiple samples over time. DNA sequence analysis of 7 isolates confirmed that the SSCP technique showed polymorphisms only in fragments that had base substitutions and that all of these base substitutions resulted in detectable shifts in fragment mobility.

Anal Canal↗

PubMed2003

Inferences on the evolutionary history of the S-element family of Drosophila melanogaster.

The S-element family of transposable elements has been characterized in D. melanogaster. Attempts to find it in other Drosophila-related species have failed, suggesting that this element family may have recently invaded the D. melanogaster genome by horizontal transfer. In order to investigate its evolutionary history, we analyzed the patterns of DNA polymorphism among the S-element copies present in a sample genome (Drosophila Genome Project). The observed levels of nucleotide diversity are significantly lower than theoretical expectations based on the neutral model. This is consistent with evidence for ongoing gene conversion among copies and for purifying selection on the elements' sequences, particularly on the terminal inverted repeats. A phylogenetic analysis revealed that the members of the S-element family can be grouped into at least two genetically differentiated clusters. The level of divergence between these clusters suggests that the S elements invaded the genome of the ancestor of D. melanogaster before the speciation of the D. melanogaster complex. However, other relevant scenarios are also discussed.

Amino Acid Sequence↗

PubMed2005

Novel pheochromocytoma susceptibility loci identified by integrative genomics.

Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies. Multipoint parametric linkage analysis revealed identical LOD scores of 2.97 for chromosome 2cen and 16p13 loci. A two-locus parametric linkage analysis produced maximum LOD score of 5.16 under a double recessive multiplicative model, suggesting that both loci are required to develop the disease. Allele-specific loss of heterozygosity (LOH) was detected only at the chromosome 2 locus in all tumors from this family, consistent with a tumor suppressor gene. Four additional pheochromocytomas with a similar genetic pattern were identified through transcription profiling and helped refine the chromosome 2 locus. High-density LOH mapping with single nucleotide polymorphism-based array identified a total of 18 of 62 pheochromocytomas with LOH within the chromosome 2 region, which further narrowed down the locus to <2 cM. This finding provides evidence for two novel susceptibility loci for pheochromocytoma and adds a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly, complex traits may also be involved in other familial cancer syndromes.

Adrenal Gland Neoplasms↗

PubMed1989

Molecular forensics: applications, implications and limitations.

Genotyping with DNA probes can theoretically identify each person on earth. Naturally occurring variations in the nucleotide sequence of DNA (DNA sequence polymorphisms) result in genetic differences between people. The Southern blot technique can reveal characteristic DNA banding patterns at a specific genetic locus. The polymorphic DNA banding patterns at several genetic loci can be combined to help construct individual DNA "fingerprints". Such fingerprints can resolve identity in criminal and paternity cases. The appropriate technology is being used in North American law enforcement agency laboratories. Although some technical drawbacks still exist, DNA genotyping with the Southern blot technique and even newer methods will likely become the standard for individual identification. An understanding of the principles underlying DNA genotyping is required before informed decisions can be made regarding its potential widespread application.

DNA↗

PubMed2007

Common genetic variations in CCK, leptin, and leptin receptor genes are associated with specific human eating patterns.

Obesity has a heritable component; however, the heterogeneity of obesity complicates dissection of its genetic background. In this study, we therefore focused on eating patterns as specific traits within obesity. These traits have a heritable component; genes associated with a specific eating pattern have not yet been reported at the population level. In this study, we determined whether genetic variations in cholecystokinin (CCK) and leptin genes underlie specific eating patterns. We selected obese individuals showing extreme snacking behavior or use of excessive portion sizes from a large population-based sample (n = 17,357) from the Prospect-EPIC (European Prospective Study into Cancer and Nutrition) study. Using allele-specific PCRs, we tested several single nucleotide polymorphisms in the candidate genes and performed haplotype analysis. Obese carriers of common allelic variations in leptin or the leptin receptor gene had an increased risk to display extreme snacking behavior. In contrast, obese carriers of common allelic variations in CCK had an increased risk to eating increased meal sizes. In conclusion, we identified common allelic variants specifically associated with distinctly different eating patterns, namely extreme snacking behavior or excessive portion size.

Aged↗