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PubMed2006

Conservation of hotspots for recombination in low-copy repeats associated with the NF1 microdeletion.

Several large-scale studies of human genetic variation have provided insights into processes such as recombination that have shaped human diversity. However, regions such as low-copy repeats (LCRs) have proven difficult to characterize, hindering efforts to understand the processes operating in these regions. We present a detailed study of genetic variation and underlying recombination processes in two copies of an LCR (NF1REPa and NF1REPc) on chromosome 17 involved in the generation of NF1 microdeletions and in a third copy (REP19) on chromosome 19 from which the others originated over 6.7 million years ago. We find evidence for shared hotspots of recombination among the LCRs. REP19 seems to contain hotspots in the same place as the nonallelic recombination hotspots in NF1REPa and NF1REPc. This apparent conservation of patterns of recombination hotspots in moderately diverged paralogous regions contrasts with recent evidence that these patterns are not conserved in less-diverged orthologous regions of chimpanzees.

Animals↗

PubMed2001

[Strategies and methods to identify genes for complex diseases].

Genes underlie numerous human diseases and traits. Although we have witnessed a great deal of success in identifying disease-susceptible genes, the task remains challenging for most of the complex diseases. This paper reviews evidence for the role of genetic factors in complex diseases, and strategies that can potentially optimize our chance of success in identifying genes involved in complex diseases. Advances in molecular biology, particularly mapping of the human genome, statistical methods that provide more accurate models of complex patterns of inheritance, and advances in basic medical science, which have increased our understanding of disease pathophysiology, will ultimately strengthen the ability of the current generation of genetic epidemiological studies to identify the genetic basis of complex human disorders.

Chromosome Mapping↗

PubMed2001

Iodide organification defects resulting from cosegregation of mutated and null thyroid peroxidase alleles.

This report describes an intriguing combination of the thyroid peroxidase (TPO) alleles resulting in an iodide organification defect. Sequence analysis of the patient's TPO gene showed the presence of T-deletion in exon 14 of the TPO gene (T2512del). From the sequencing pattern, this new mutation of the TPO gene was thought to be homozygous. mRNA transfection studies in which mutated mRNA was transfected to CHO-K(1) cells by electroporation showed that the cells transfected with mutated mRNA expressed smaller TPO molecules than those of cells transfected with wild-type mRNA and that they had TPO activity. However, the smaller TPO molecules could not translocate onto the cell surface. To investigate T2512del in the parents, their genomic DNAs were sequenced. Results showed that the mother had T2512del but the father did not. However, when seven polymorphic positions reported earlier were analyzed, the mother showed two kinds of nucleotides at four positions but the patient and father showed only one nucleotide at all seven positions. We suspected a deletion of the TPO gene (2p25) in one of two second chromosomes, and analyzed the patient's chromosomes by FISH using TPO cDNA and N-myc genomic DNA as probes. N-myc genomic DNA exhibited two signals and TPO cDNA only one signal, although the G-band showed no morphological abnormalities. T2512-deleted and 2p25-deleted null alleles cosegregated from her parents, resulting in iodide organification defect in the patient.

Adult↗

PubMed2005

32-nucleotide deletion, associated with defence against hiv/aids, is a predominant mutation of CCR5 gene in the population of Georgia.

There is a special interest to investigate genetic peculiarities in the populations with a low HIV seroprevalence. Despite of presence of high-risk conditions for rapid spread of HIV/AIDS epidemics in Georgia, the prevalence of this infection in the country remains very low. We studied polymorphisms of CCR5 gene in Georgians. Blood samples from 190 women randomly selected from the cohort of pregnant women involved in the program of prevention of mother-to-child HIV transmission in Georgia have been investigated. Two-step PCR was used to amplify the whole CCR5 genetic sequence. Detection of mutations and polymorphisms was done by dHPLC. All samples showing specific patterns by dHPLC, were sequenced to identify the exact nature of the mutation. It was shown that CCR5-delta32 mutation is a predominant alteration of CCR5 gene among Georgians. All subjects bearing this mutation were heterozygotes. Frequency of delta32 CCR5 allele in the population of Georgia was equal to 5%. Only one case of R223Q mutation and two cases of mutations in the non-coding region of CCR5 gene were also found. Our findings differ from the existing data showing the absence of the CCR5-delta32 mutation among Georgians and provide further support to the hypothesis on a Northeastern European origin of this mutation and North to South gradient of its distribution.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Molecular epidemiology of severe acute respiratory syndrome-associated coronavirus infections in Taiwan.

BACKGROUND: In 2003, Taiwan experienced a series of outbreaks of severe acute respiratory syndrome (SARS) and 1 laboratory-contamination accident. Here we describe a new phylogenetic analytical method to study the sources and dissemination paths of SARS-associated coronavirus (SARS-CoV) infections in Taiwan. METHODS: A phylogenetic analytical tool for combining nucleotide sequences from 6 variable regions of a SARS-CoV genome was developed by use of 20 published SARS-CoV sequences; and this method was validated by use of 80 published SARS-CoV sequences. Subsequently, this new tool was applied to provide a better understanding of the entire complement of Taiwanese SARS-CoV isolates, including 20 previously published and 19 identified in this study. The epidemiological data were integrated with the results from the phylogenetic tree and from the nucleotide-signature pattern. RESULTS: The topologies of phylogenetic trees generated by the new and the conventional strategies were similar, with the former having better robustness than the latter, especially in comparison with the maximum-likelihood trees: the new strategy revealed that during 2003 there were 5 waves of epidemic SARS-CoV infection, which belonged to 3 phylogenetic clusters in Taiwan. CONCLUSIONS: The new strategy is more efficient than its conventional counterparts. The outbreaks of SARS in Taiwan originated from multiple sources.

Cross Infection↗

PubMed2006

Genetic variation in the hepatic lipase gene and the risk of coronary heart disease among US diabetic men: potential interaction with obesity.

AIMS/HYPOTHESIS: The -514 C to T polymorphism of the hepatic lipase gene (LIPC) has been associated with lowered LIPC activity and elevated HDL-cholesterol concentrations. Previous findings on the association of this polymorphism with the risk of CHD are inconsistent. Moreover, data on this association among diabetic patients are limited. We investigated the association of the LIPC polymorphism with CHD risk among US diabetic men and evaluated whether this association was modified by adiposity status. SUBJECTS AND METHODS: The case group consisted of 220 diabetic men who were recruited from the Health Professionals Follow-up Study (years 1986-2000) and were free of cardiovascular disease at baseline, but subsequently developed CHD. A total of 641 diabetic men from the same study but without cardiovascular disease constituted the control group. RESULTS: No overall association between the LIPC polymorphism and CHD risk was observed. However, we did observe a significant interaction between this polymorphism and BMI in association with CHD risk. Among obese men, after adjustment for age, duration of diabetes and major lifestyle factors, the CT or TT genotype was associated with an increased CHD risk compared with the CC genotype (odds ratio [OR] 2.52, 95% CI 1.08-5.90); the corresponding ORs (95% CI) were 0.99 (0.58, 1.69) for overweight men (25< or =BMI <30 kg/m(2)) and 0.37 (0.17, 0.79) for lean men (BMI <25 kg/m(2)) (p for interaction 0.001). Stratified analyses by waist circumference (tertiles) showed a similar pattern of interaction (adjusted p for interaction 0.023). CONCLUSION/INTERPRETATION: These data suggest that obesity may modify the association between the LIPC C(-514)T polymorphism and CHD risk among diabetic men.

Adult↗

PubMed2006

Genetic comparison of liver flukes, Clonorchis sinensis and Opisthorchis viverrini, based on rDNA and mtDNA gene sequences.

To clarify the genetic relationships between Clonorchis sinensis and Opisthorchis viverrini, patterns of inter-/intraspecific polymorphism were compared for four markers with nuclear ribosomal DNA (rDNA) and mitochondrial DNA (mtDNA) in liver flukes C. sinensis from Korea (Kimhae) and China (Shenyang and Nanning) and O. viverrini from Laos (Savannakhet). Intra- and interspecific variations in the 18S, ITS2, and 28S rDNA and mitochondrial cytochrome c oxidase subunit I (mtCOI) of mtDNA gene sequences were low and nearly identical. Three isolates of C. sinensis showed a high similarity (99-100%). No variation was detectable in the ITS2 sequence for the C. sinensis from Korea and China. ITS2 region sequences of O. viverrini vs C. sinensis showed 95% identity and differed at 28 nucleotide positions. Pairwise sequence divergence with three C. sinensis isolates and O. viverrini ranged from 0 to 3.94% in mtCOI gene. The mtCOI sequences were more highly conserved relative to the ITS2 sequences. These genetic data from different geographical areas showed that the liver flukes are not variable and are virtually identical almost despite belonging to entirely different genera.

Animals↗

PubMed2005

Identification and subgrouping of pigeon type Newcastle disease virus strains by restriction enzyme cleavage site analysis.

A host variant of Newcastle disease virus (NDV, genus Avulavirus, family Paramyxoviridae) is responsible for an autonomous disease in pigeons. It emerged in the late 1970s in the Mediterranean region. Despite great genetic diversity the vast majority of strains belong to a monophyletic group (sublineage VIb) within genotype VI of NDV strains that were indigenous in the region at that time. To date only a monoclonal antibody assay is available for the specific identification of pigeon type strains. A specific genetic assay is described suitable for the identification of pigeon isolates. Cleavage site analysis of a 1349 bp amplicon of the fusion protein gene was carried out using restriction enzymes (RE) HinfI, BstOI and RsaI. RE analysis of over 100 strains isolated between 1978 and 2002 deriving from 16 countries has revealed nine RE-patterns, which were progressive site variants of the parental (group VI) genotype. In spite of substantial site variation, extant pigeon viruses lacked a BstOI cleavage site at nucleotide 1601 shared by other NDV strains of chicken origin. RE analysis is a simple and reliable method both for the identification and subgrouping of pigeon type viruses.

Animals↗

PubMed1986

Molecular population genetics of the alcohol dehydrogenase gene region of Drosophila melanogaster.

Variation in the DNA restriction map of a 13-kb region of chromosome II including the alcohol dehydrogenase structural gene (Adh) was examined in Drosophila melanogaster from natural populations. Detailed analysis of 48 D. melanogaster lines representing four eastern United States populations revealed extensive DNA sequence variation due to base substitutions, insertions and deletions. Cloning of this region from several lines allowed characterization of length variation as due to unique sequence insertions or deletions [nine sizes; 21-200 base pairs (bp)] or transposable element insertions (several sizes, 340 bp to 10.2 kb, representing four different elements). Despite this extensive variation in sequences flanking the Adh gene, only one length polymorphism is clearly associated with altered Adh expression (a copia element approximately 250 bp 5' to the distal transcript start site). Nonetheless, the frequency spectra of transposable elements within and between Drosophila species suggests they are slightly deleterious. Strong nonrandom associations are observed among Adh region sequence variants, ADH allozyme (Fast vs. Slow), ADH enzyme activity and the chromosome inversion ln(2L)t. Phylogenetic analysis of restriction map haplotypes suggest that the major twofold component of ADH activity variation (high vs. low, typical of Fast and Slow allozymes, respectively) is due to sequence variation tightly linked to and possibly distinct from that underlying the allozyme difference. The patterns of nucleotide and haplotype variation for Fast and Slow allozyme lines are consistent with the recent increase in frequency and spread of the Fast haplotype associated with high ADH activity. These data emphasize the important role of evolutionary history and strong nonrandom associations among tightly linked sequence variation as determinants of the patterns of variation observed in natural populations.

Alcohol Dehydrogenase↗

PubMed1995

Differentiation of Bartonella-like isolates at the species level by PCR-restriction fragment length polymorphism in the citrate synthase gene.

The citrate synthase gene (gltA) of Bartonella henselae was cloned and sequenced to compare genetic divergence among alpha and gamma branches of the class Proteobacteria and to develop enhanced genotypic reagents for B. henselae identification. B. henselae gltA is 1,293 nucleotides in length and 63 to 66% homologous with corresponding gene sequences of Rickettsia prowazekii, Escherichia coli, and Coxiella burnetii. The observed genetic variability suggests that gltA sequences can provide a useful means for studying moderate divergence among related bacteria. Oligonucleotides specific for B. henselae gltA were evaluated for the ability to prime PCR amplification within the alpha and gamma branches of the proteobacteria. Under the conditions used, only B. henselae, Bartonella quintana, and R. prowazekii template DNAs yielded amplification products (approximately 380 bp). DNAs from 28 Bartonella-like isolates of feline origin were amplified by B. henselae primers and analyzed for restriction fragment length polymorphism. The resulting patterns for all 28 isolates were similar or identical to that of the recognized B. henselae strain. Current studies are aimed at optimization of PCR conditions for specificity and sensitivity of amplification of Bartonella sequences from clinical isolates.

Amino Acid Sequence↗

PubMed2006

Genetic association between schizophrenia and the DISC1 gene in the Scottish population.

Several lines of evidence support the involvement of the disrupted in schizophrenia 1 (DISC1) gene in schizophrenia susceptibility, including its original identification in a schizophrenia family with a chromosome translocation, several genetic association studies, and functional characterization of the gene product. In the present study, we have genotyped multiple SNP and microsatellite markers in a large Scottish case-control sample. We identified two SNPs and one microsatellite that show significant association with schizophrenia. The strongest association is with a haplotype of SNPs rs751229 and rs3738401, located at the 5' end of the gene; the C-A haplotype of these SNPs is associated with a relative risk of schizophrenia of 5 in our population. We also observe association with a microsatellite in intron 7, but no association with markers toward the 3' end of the gene. The results are in broad agreement with those of other genetic studies, but there are differences in terms of the precise patterns of association. This analysis further strengthens the candidacy of DISC1 as a risk factor for schizophrenia in the general population, and suggests that more intensive searching for causative variants is justified.

Adolescent↗

PubMed1981

The gene encoding the common alpha subunit of the four human glycoprotein hormones.

The gene encoding the common alpha subunit of the four human glycoprotein hormones, chorionic gonadotropin (CG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH), has been cloned in a bacteriophage lambda vector. Restriction endonuclease digestion of total human DNA suggests that the common alpha subunit is coded for by a single gene. Three distinct polymorphic hybridization patterns have been observed for this gene in the human population. The cloned gene encompasses a total of 9.4 kilobases (kb) and contains three intervening sequences whose locations have been established by restriction enzyme mapping and by DNA sequencing. One of the intervening sequences is located in the 5' untranslated region, generating a leader sequence that is separated from the rest of the gene by 6.4 kb. The other two intervening sequences are 1.7 and 0.4 kb long and are located within codon number 6, and between codons 67 and 68, respectively. The location of the 5' end of the mature transcript has been established by priming placental mRNA with a restriction fragment obtained from the cloned cDNA. A transcript of similar size for the alpha subunit gene has been detected in both the pituitary, where the gene is expressed for the synthesis of LH, FSH, and TSH, and the placenta, where the gene is expressed for the synthesis of CG. When parts of the 5' untranslated nucleotide sequences of the alpha subunit and the human growth hormone genes are compared a highly homologous region is observed. These otherwise unrelated genes share the common feature that they encode a secreted pituitary polypeptide hormone.

Base Sequence↗

PubMed2004

Microsatellite variation and evolutionary history of PCDHX/Y gene pair within the Xq21.3/Yp11.2 hominid-specific homology block.

To better understand the evolutionary dynamics of repetitive sequences in human sex chromosomes, we have analyzed seven new X/Y homologous microsatellites located within PCDHX/Y, one of the two recently described gene pairs in the Xq21.3/Yp11.2 hominid-specific homology block, in samples from Portugal and Mozambique. Sharp differences were observed on X/Y allele distributions, concerning both the presence of private alleles and a different modal repeat length for X-linked and Y-linked markers, and this difference was statistically significant. Higher diversity was found in X-linked microsatellites than in their Y chromosome counterparts; when comparing populations, Mozambicans showed more allele diversity for the X chromosome, but the contrary was true for the Y chromosome microsatellites. Evolutionary patterns, relying on intragenic PCDHX/Y SNPs, also revealed distinct scenarios for X and Y chromosomes. Greater microsatellite diversity was displayed by African X chromosomes within the most common haplotypes shared by both populations, whereas higher microsatellite diversity was found in Portugal for the ancestral Y chromosome haplotype. The most frequent PCDHY haplotype in Portuguese was the derived one, and it was not found in Mozambicans. TMRCA estimated by the rho parameter resulted in 13,700 years (7,500-20,000 years), which is consistent with a recent, post-Out-of-Africa origin for this haplotype. In conclusion, the newly described microsatellite loci generally displayed greater X-linked to Y-linked diversity and this pattern was also detected with slower evolving markers, with a remarkable differentiation between populations observed for Y chromosome haplotypes and, thus, greater divergence among Y chromosomes in human populations.

Africa↗

PubMed2026

Cross-kingdom genomic variation in chicken gut microbiomes: insights from China's diverse local breeds.

BACKGROUND: The gut microbiome possesses substantial genetic diversity that supports microbial adaptation, but the genomic variation patterns across its prokaryotic and viral populations remain incompletely characterized. RESULTS: Through integrated metagenomic and metatranscriptomic analysis of ten indigenous chicken breeds from China, we recovered 1527 representative prokaryotic MAGs, 37,555 representative DNA viral contigs, and 1867 representative RNA viral contigs (primarily comprising Bacillota/Bacteroidota, Uroviricota, and Lenarviricota/Pisuviricota, respectively). By integrating complementary short-read and long-read metagenomics with metatranscriptomics, we identified structural variants (SVs) and single-nucleotide variants (SNVs) in these cross-kingdom genomes. Positive SV-SNV density correlations occurred consistently across all microbial groups, indicating coordinated mutational processes. DNA viruses exhibited the highest variant prevalence (86.9% SNVs, 47.7% SVs), with temperate phages accumulating significantly more variants than virulent phages. Functionally, prokaryotic variants accumulated in carbohydrate metabolism and amino acid metabolism, while viral variants demonstrated broad metabolic hijacking. Horizontal gene transfer (HGT) was characterized by a strong virus-associated signature (69.40% of 536 events) and marked by an asymmetric pattern, with phage-to-bacteria (P-to-B) flow alone constituting 37.50% of all events. Random forest analysis revealed a strong bidirectional predictive relationship between SV and SNV densities across prokaryotic, DNA viral, and RNA viral populations, suggesting coupled genomic instability. Niche breadth emerged as a major driver of SNVs across kingdoms and was positively correlated with variant density. In prokaryotes, HGT events significantly shaped variant patterns. For viruses, genomic GC content was an important factor and consistently showed a negative correlation with SNV density in both DNA and RNA viruses. CONCLUSIONS: These findings demonstrate that coordinated mutational processes and kingdom-specific intrinsic factors drive genomic variation, with viruses serving as key genetic exchange vectors in chicken gut ecosystems. Video Abstract.

Animals↗

PubMed1993

The origin and genetic differentiation of native breeds of pigs in southwest China: an approach from mitochondrial DNA polymorphism.

Mitochondrial DNA (mtDNA) of six breeds of native domestic pigs from Yunnan province, southwest China, and two wild boars obtained from Sichuan, China, and Vietnam was analyzed using 20 restriction endonucleases that recognize six nucleotides. Restriction maps were made by double-digestion methods and polymorphic sites were located on the map. According to their mtDNA restriction types, all the breeds were classified into six groups. Genetic distances among groups were calculated to define their phylogenetic relationships. The relationship between the Sichuan wild boar and domestic pigs is close, while the Vietnamese wild boar is relatively far from them, so the domestic pigs in southwest China are likely to have originated from a wild pig which distributed in west China. We compare our results with previous reports in literature and discuss the relationship among Chinese pigs, Japanese pigs, and European pigs. The mtDNA cleavage pattern of the Mingguang pig digested by EcoRV was identical to that of Duroc; mutations at the EcoRI site, detected in the mtDNA of two Dahe pigs, are the same as in the Vietnamese wild boar, suggesting that mutational hot spots exist in the mtDNA of pigs.

Animals↗

PubMed1998

Genetic analysis of the CYP2D6 gene in patients with Parkinson's disease.

To further investigate the association between Parkinson's disease (PD) and genetic polymorphism of the CYP2D6 gene, a mutant allele (CVP2D6J) frequently observed in the Japanese population and related to EM/PM polymorphism (phenotypically, individuals are either extensive metabolizers [EM] or poor metabolizers [PM] of debrisoquine) was investigated. The CYP2D6J gene with a nucleotide substitution from C to T at position 188 (the HphI site in exon 1), which reduces CYP2D6 enzyme activity, was analyzed by polymerase chain reaction (PCR) and by digestion with HphI. No significant relationship was observed between PD patients and controls for this mutation. This suggests that the EM/PM polymorphism of CYP2D6 contributes little to the pathogenesis of PD. To further study the molecular basis for the relationship between PD and CYP2D6, the heterogeneity of CYP2D6 was investigated by combined genotype analysis of the two mutant CYP2D6 genes (ie, CYP2D6J, the HphI site mutation in exon 1, and CYP2D6L, the HhaI site mutation in exon 6). Although some characteristic patterns of the combined genotypes were observed in both PD patients and controls, a strong association between the heterogeneity of the CYP2D6 gene and PD was not shown by combined genotype analysis.

Alleles↗

PubMed2002

Molecular characterization of chicken syndecan-2 proteoglycan.

A partial syndecan-2 sequence (147 bp) was obtained from chicken embryonic fibroblast poly(A)+ RNA by reverse transcription-PCR. This partial sequence was used to produce a 5'-end-labelled probe. A chicken liver cDNA library was screened with this probe, and overlapping clones were obtained encompassing the entire cDNA of 3 kb. The open reading frame encodes a protein of 201 amino acids. The cytoplasmic domain is identical with that of mammalian syndecan-2, and highly similar to those of Xenopus laevis and zebrafish syndecan-2. The transmembrane domain is identical with that of mammalian and zebrafish syndecan-2, and highly similar to that of Xenopus laevis syndecan-2. The ectodomain is 45-62% identical with that of zebrafish, Xenopus laevis and mammalian syndecan-2. Two coding single nucleotide polymorphisms were observed. In vitro transcription and translation yielded a product of 30 kDa. Western blotting of chicken embryonic fibroblast cell lysates with species-specific monoclonal antibody mAb 8.1 showed that chicken syndecan-2 is substituted with heparan sulphate, and that the major form of chicken syndecan-2 isolated from chicken fibroblasts is consistent with the formation of SDS-resistant dimers, which is common for syndecans. A 5'-end-labelled probe hybridized to two mRNA species in chicken embryonic fibroblasts, while Northern analysis with poly(A)+ RNAs from different tissues of chicken embryos showed wide and distinct distributions of chicken syndecan-2 during embryonic development. This pattern was different from that reported for syndecan-4, but consistent with the roles of syndecan-2 in neural maturation and in mesenchymal-matrix interactions.

Amino Acid Sequence↗

PubMed1998

Application of a time-dependent coalescence process for inferring the history of population size changes from DNA sequence data.

Distribution of pairwise differences of nucleotides from data on a sample of DNA sequences from a given segment of the genome has been used in the past to draw inferences about the past history of population size changes. However, all earlier methods assume a given model of population size changes (such as sudden expansion), parameters of which (e.g., time and amplitude of expansion) are fitted to the observed distributions of nucleotide differences among pairwise comparisons of all DNA sequences in the sample. Our theory indicates that for any time-dependent population size, N(tau) (in which time tau is counted backward from present), a time-dependent coalescence process yields the distribution, p(tau), of the time of coalescence between two DNA sequences randomly drawn from the population. Prediction of p(tau) and N(tau) requires the use of a reverse Laplace transform known to be unstable. Nevertheless, simulated data obtained from three models of monotone population change (stepwise, exponential, and logistic) indicate that the pattern of a past population size change leaves its signature on the pattern of DNA polymorphism. Application of the theory to the published mtDNA sequences indicates that the current mtDNA sequence variation is not inconsistent with a logistic growth of the human population.

Algorithms↗