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PubMed1993

p53 gene mutations in pontine gliomas of juvenile onset.

Using polymerase chain reaction-single strand polymorphism(PCR-SSCP) and nucleotide analyses, p53 gene mutation was examined in 13 pontine gliomas many of which were of juvenile onset. A total of 15 mutations were detected in 8 cases, of which 5 revealed multiple or tandem mutations. The mutations included 6 G:C-A:T and 4 A:T-G:C transitions and 4 G:C-T:A and 1 A:T-T:A transversions. There was only 1 transition at the CpG site. Normal tissues of the same patients revealed no mutation, suggesting that these mutations were somatic, but not of germ line, in nature. The pattern of mutation characterized by frequent multiple or tandem occurrence, predominancy of transition at non-CpG sites and relatively frequent transversions suggested that pontine glioma might be related with some mutagenic or carcinogenic agents.

Amino Acid Sequence↗
PubMed1992

Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions.

Thyroxine-binding globulin (TBG) is a liver glycoprotein that transports thyroid hormone in serum. In 1989, a variant TBG was reported with reduced binding affinity for thyroxine (T4) and triiodothyronine (T3) which results in low serum T4 and T3 levels. This variant, TBG-San Diego (TBG-SD), also displays reduced heat stability but has a normal isoelectric focusing pattern. We now report the sequence of the entire coding region of TBG-San Diego. It reveals two nucleotide substitutions: one located in exon 1 which results in the replacement of the normal Ser-23 (TCA) with threonine (ACA) and the other, located in exon 3, changes the normal codon 283 of TTG (leucine) with that of TTT, (phenylalanine). Allele specific amplification was used to search for both nucleotide substitutions in four affected members of the family. Results confirmed the co-segregation of these nucleotide substitutions with the TBG-SD phenotype. The substitution in codon 283 has been previously described and exists as a polymorphism in some ethnic groups or in combination with other TBG variants with different physical characteristics. Thus, it appears that the replacement of Ser-23 with threonine is responsible for the observed alterations in physical properties of TBG-San Diego.

Amino Acid Sequence↗
PubMed2006

Variable intensity of purifying selection on cytotoxic T-lymphocyte epitopes in hepatitis C virus.

In an analysis of the patterns of nucleotide diversity in 26 datasets providing population-level data on different genomic regions of different hepatitis C virus (HCV) subtypes, known cytotoxic T-lymphocyte (CTL) epitope regions in most cases showed evidence of the occurrence of purifying selection. Two main factors were found to be associated with the strength of purifying selection: (1) purifying selection was stronger in CTL epitopes in non-envelope proteins than in envelope proteins and (2) purifying selection was stronger when the epitope was "matched", i.e., when the described or "canonical" epitope sequence was present unaltered in at least one sequence in the dataset. Of all polymorphic sites, non-synonymous sites in matched CTL epitopes in non-envelope proteins had the lowest gene diversities, implying that these variants are subject to ongoing purifying selection. This in turn suggests that the population frequency of such variants may of be the result of a balance between opposing forces: on the one hand, positive selection favoring escape mutants in hosts that express the presenting MHC molecule and, on the other hand, purifying selection acting, in the absence of the presenting MHC molecule, to reduce the frequency of slightly deleterious variants.

Epitopes, T-Lymphocyte↗
PubMed2003

Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes.

Point mutation rates in exons (synonymous sites) and noncoding (introns and intergenic) regions are generally assumed to be the same. However, comparative sequence analyses of synonymous substitutions in exons (81 genes) and that of long intergenic fragments (141.3 kbp) of human and chimpanzee genomes reveal a 30%-60% higher mutation rate in exons than in noncoding DNA. We propose a differential CpG content hypothesis to explain this fundamental, and seemingly unintuitive, pattern. We find that the increased exonic rate is the result of the relative overabundance of synonymous sites involved in CpG dinucleotides, as the evolutionary divergence in non-CpG sites is similar in noncoding DNA and synonymous sites of exons. Expectations and predictions of our hypothesis are confirmed in comparisons involving more distantly related species, including human-orangutan, human-baboon, and human-macaque. Our results suggest an underlying mechanism for higher mutation rate in GC-rich genomic regions, predict nonlinear accumulation of mutations in pseudogenes over time, and provide a possible explanation for the observed higher diversity of single nucleotide polymorphisms (SNPs) in the synonymous sites of exons compared to the noncoding regions.

Animals↗
PubMed1995

Molecular variation of the human elastin (ELN) gene in a normal human population.

DNA sequence diversity in the human elastin genomic region has been estimated by RFLP analysis in a normal human population. The proportion of polymorphic nucleotides and the degree of nucleotide diversity were 0.0034 and 0.0018 respectively. It is argued that the estimate of nucleotide diversity does not indicate strong purifying selection in the region. A total of 144 restriction sites were sampled in each of 80 independent chromosomes representing the screening of 58080 bp overall. Six main haplotypes were constructed; they represent at least 84% of the 80 chromosomes sampled. Analysis for linkage disequilibrium revealed two statistically significant comparisons out of 54 tests, approximately the proportion that would be statistically significant at the 5% level by chance. A higher order quadrigenic disequilibrium was detected. The relationship between the physical distance separating polymorphic restriction sites and linkage disequilibrium is discussed. The development of elastin haplotypes and knowledge of the pattern of linkage disequilibrium should aid the study of elastin related disease and human evolution.

Blotting, Southern↗
PubMed2004

A comparison of different strategies for computing confidence intervals of the linkage disequilibrium measure D'.

Many linkage disequilibrium (LD) measures have been used to study LD patterns and for haplotype block partitioning. We examine the properties of one of these measures, Lewontin's D', in order to understand the dependency of its confidence interval (CI) to allele frequency and sample size as well as its applications in defining haplotype blocks. This measure and its CIs were used to partition haplotypes into blocks by Gabriel et al. as well as in many other applications. Gabriel et al. utilized a bootstrap approach to calculate the CI for D'. Under this method, over 1,000 bootstrap samples may be needed to obtain an accurate estimate of the CI for each pair of single nucleotide polymorphism (SNP) markers which can be very computationally intensive, particularly when many SNP markers are involved. We develop two alternative methods for calculating the CI for D' without bootstrap: one based on the approximate variance of D' given by Zapata et al. and the other based on a maximum likelihood estimate (MLE) of D' together with Fisher Information theory. Both methods depend on normal approximation for the estimates of D' for large sample sizes. We assess and compare the coverage of the CIs using the three methods through extensive simulations. We define the coverage as the fraction of times the estimated CI contains the true value of D'. In general, the average coverage of the bootstrap method is less than the pre-specified coverage. When the sample size is small (< or = 100), the remaining two methods slightly under estimate the coverage with MLE approach having smaller standard error compared to Zapata's method. When the sample size is large (> or = 200) , the estimated coverage from both Zapata's and MLE methods are very close to the pre-specified coverage with the MLE method having the smallest standard error among all three methods. In most typical scenarios, we recommend the use of MLE method for all sample sizes. Only under rare specific cases, would the bootstrap method be better suited for determining the CI, i.e. small sample size, at extreme allele frequencies and -3 < D' < 0.

Computational Biology↗
PubMed2005

The effect of polymorphisms in the enhancer of split gene complex on bristle number variation in a large wild-caught cohort of Drosophila melanogaster.

The Enhancer of split complex [E(spl)-C] in Drosophila encompasses a variety of functional elements controlling bristle patterning and on the basis of prior work is a strong candidate for harboring alleles having subtle effects on bristle number variation. Here we extend earlier studies identifying associations between complex phenotypes and polymorphisms segregating among inbred laboratory lines of Drosophila and test the influence of E(spl)-C on bristle number variation in a natural cohort. We describe results from an association mapping study using 203 polymorphisms spread throughout the E(spl)-C genotyped in 2000 wild-caught Drosophila melanogaster. Despite power to detect associations accounting for as little as 2% of segregating variation for bristle number, and saturating the region with single-nucleotide polymorphisms (SNPs), we identified no single SNP marker showing a significant (additive over loci) effect after correcting for multiple tests. Using a newly developed test we conservatively identify six regions of the E(spl)-C in which the insertion of transposable elements as a class contributes to variation in bristle number, apparently in a sex- or trait-limited fashion. Finally, we carry out all possible 20,503 two-way tests for epistasis and identify a slight excess of marginally significant interactions, although none survive multiple-testing correction. It may not be straightforward to extend the results of laboratory-based association studies to natural populations.

Animal Structures↗
PubMed2005

Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin.

The occurrence of obesity, eating disorders, and related diseases has increased in many parts of the world. Given that few strong genetic factors have been found, it is clear that these are complex multi-factorial diseases. The serotonin receptor 2C, a member of the 5-HTergic system, has been implicated in the control of phagia and obesity. We report a detailed investigation of linkage disequilibrium (LD) within and between the HTR2C promoter and the flanking sequences around a commonly utilized marker in the second coding exon of HTR2C. We suggest that inconsistent associations between HTR2C and several phenotypes, including obesity, may be due to the LD pattern across the gene in which recombination and gene conversion have been influential. The nucleotide and haplotype distribution is consistent with that of the neutral mutation model. The number of haplotypes suggests demographic influences or over dominant selection that may have a function in HTR2C expression. Using the fine LD pattern, we describe a possible association with promoter haplotypes and diplotypes, including a GT microsatellite, and body mass index (BMI) > or =30 kgm(-2) (P<0.0001). SNP -995G>A heterozygotes, as well as promoter diplotypes, were found to marginally influence higher serum leptin corrected for percentage body fat (P=0.01), which might suggest that these subjects are leptin resistant. Our results complement previous studies of HTR2C in both mice and humans, and suggest the importance of genetic variation and elucidating the fine LD structure in uncovering the genetic factors of obesity.

Adult↗
PubMed2000

Methylenetetrahydrofolate reductase 677 C --> T polymorphism, plasma folate, vitamin B(12) concentrations, and risk of preeclampsia among black African women from Zimbabwe.

We conducted a case control study at Harare Maternity Hospital, Zimbabwe. We genotyped a total of 171 cases with preeclampsia or eclampsia and 185 normotensive control subjects for the methylenetetrahydrofolate reductase (MTHFR) 677 C --> T genotype. The wild-type allele frequency among cases and controls was 91.2 and 91.3%, respectively. Only one subject (0.3%) was homozygous for the 677 C --> T MTHFR genotype and this subject had preeclampsia. After adjustment for confounding factors, there was statistically no significant association between maternal MTHFR genotype and risk of preeclampsia (adjusted odds ratio = 1.0; 95% CI, 0.5-1.9). In addition, plasma homocyst(e)ine, vitamin B(12), and folate concentrations were not statistically different between normotensive control subjects with wild-type genotype as compared with normotensive subjects who were heterozygous for the mutant allele. Conversely, there was a strong graded association between maternal plasma folate concentration and risk of preeclampsia. Women with plasma folate concentrations less than 5.7 nmol/L experienced a 10. 4-fold increase in risk of preeclampsia. There was no clear pattern of preeclampsia risk and vitamin B(12) concentrations.

Adolescent↗
PubMed1996

Analysis of the enterohemorrhagic Escherichia coli O157 DNA region containing lambdoid phage gene p and Shiga-like toxin structural genes.

In this study, we determined the nucleotide sequence of the p gene contained within a 5-kb EcoRI restriction fragment cloned from Shiga-like toxin II (SLT-II)-converting phage 933W of Escherichia coli O157:H7 strain EDL933. The p gene was 702 bp long and had 95.3% sequence similarity to the p gene of phage lambda. Multiple hybridization patterns were obtained when genomic DNA fragments were hybridized with both p and slt-I, slt-II, or slt-IIc sequences. All O157 isolates also possessed an analog of lambda gene p which was not linked with either slt-I or slt-II. Restriction fragment length polymorphism comparisons of clinical O157 isolates and derivates undergoing genotype turnover during infection were made, and loss of large DNA fragments that hybridized with slt-II and p sequences was observed. To further analyze the DNA region containing the p and slt genes, we amplified fragments by using a PCR with one primer complementary to p and the other complementary to either the slt-I or the slt-II gene. PCR analysis with enterohemorrhagic E. coli O157 and non-O157 strains yielded PCR products that varied in size between 5.1 and 7.8 kb. These results suggest that even within O157 isolates, the genomes of SLT-converting phages differ. The methods described here may assist in further investigation of SLT-encoding phages and their role in the epidemiology of infection with enterohemorrhagic E. coli.

Bacterial Toxins↗
PubMed2006

Association of toll-like receptor 4 polymorphisms with somatic cell score and lactation persistency in Holstein bulls.

Mastitis, an inflammatory disease of the mammary gland generally caused by intramammary infections, is the most frequently occurring disease in the North American dairy industry. Reduced milk yield, milk quality, and lactation persistency as well as early culling contribute to the economic losses associated with this disease. During intramammary infections, cells of the innate immune system become activated through pattern recognition receptors that recognize conserved molecular signatures associated with the invading pathogen. The quality, timing, and intensity of the host inflammatory and subsequent immune response determine the fate of this disease. Toll-like receptor 4 (TLR4) is an important pattern recognition receptor that recognizes endotoxins associated with gram-negative bacterial infections. Its role in pathogen recognition and subsequent initiation of the inflammatory and immune response makes it a suitable candidate gene for enhancing disease resistance in Canadian Holsteins. In this study, polymorphisms in the TLR4 gene were identified in the Canadian Holstein bull population. Genotypes and haplotypes were constructed, and their associations with somatic cell score and lactation persistency were determined. Sequencing of selective DNA pools was used to reveal polymorphisms in TLR4. Two DNA pools were constituted based on high and low estimated breeding values for somatic cell scores. A total of 3 single nucleotide polymorphisms (SNP), including 1 SNP in a putative promoter region (P-226) and 2 SNP in exon3 (E3+1656 and E3+2021) of TLR4 were detected. A total of 388 bulls were genotyped for the SNP, haplotypes were reconstructed, and their frequencies were obtained. Polymorphisms in these regions were found to be associated with estimated breeding values for lactation persistency, and somatic cell scores in the Canadian Holstein bull population. The unfavorable alleles at P-226 and E3+1656 were found at a frequency of 40 and 37%, respectively; hence, selection against these alleles is promising in Canadian Holsteins. Selection against the unfavorable allele, T at E3+2021, is limited because of its low frequency (7%). Two frequently occurring haplotypes (GCC and CTC) occurred in 86% of the Canadian Holstein bull population chosen for genotyping. The most frequent haplotype (GCC; 54%) was found to be associated with higher lactation persistency and lower somatic cell scores. The transversion SNP in the putative promoter region (P-226) was in a potential DNA binding site.

Animals↗
PubMed1998

[Origin and differentiation of domestic goose breeds in China, inferred from mitochondrial DNA polymorphism].

Mitochondrial DNAs (mtDNAs) of 138 samples from 11 domestic goose breeds in China were investigated by digesting, with 19 restriction endonucleases. Of 19 enzymes used, seven (Bcl I, Dra I, Eco RV, Hae II, Hinc II, Kpn I, Sac I) detected polymorphic patterns. By combining 27 restriction morphs, 138 individuals were classified into 6 mtDNA haplotypes. Phylogenetic tree was constructed by using UPGMA. There was no shared haplotype between Yili breed and the other 10 breeds. Genetic distance and UPGMA tree also suggested that Yili breed and other breeds came from different ancestors. Yili breed originated from Anser anser and other 10 breeds originated from Anser cygnoides. Restriction morphs digested with 4 enzymes (EcoRV, Hae II, Hinc II and Kpn I) could be used as maternal genetic markers to distinguish the two types of domestic geese. Mitochondrial DNA polymorphism was observed in the ten breeds of Anser cygnoides. Nucleotide diversity (pi), genetic distance between the two types and the average genetic distance among the ten breeds were estimated to be 0.025%, 0.266%, 0.029%, respectively. The breeds with white plume were affected by founder effect when they were formed. Swan domestic geese, Anser cygnoides domesticus, in China might come from two different populations of Anser cygnoides at two different places.

Animals↗
PubMed2005

Molecular epidemiology of SARS-associated coronavirus, Beijing.

Single nucleotide variations (SNVs) at 5 loci (17564, 21721, 22222, 23823, and 27827) were used to define the molecular epidemiologic characteristics of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) from Beijing patients. Five fragments targeted at the SNV loci were amplified directly from clinical samples by using reverse transcription-polymerase chain reaction (RT-PCR), before sequencing the amplified products. Analyses of 45 sequences obtained from 29 patients showed that the GGCTC motif dominated among samples collected from March to early April 2003; the TGTTT motif predominanted afterwards. The switch from GGCTC to TGTTT was observed among patients belonging to the same cluster, which ruled out the possibility of the coincidental superposition of 2 epidemics running in parallel in Beijing. The Beijing isolates underwent the same change pattern reported from Guangdong Province. The same series of mutations occurring in separate geographic locations and at different times suggests a dominant process of viral adaptation to the host.

Adult↗
PubMed1999

Evolution of the proximal promoter region of the mammalian growth hormone gene.

The evolutionary relationship between the proximal growth hormone (GH) gene promoter sequences of 12 mammalian species was explored by comparison of their trinucleotide composition and by multiple sequence alignment. Both approaches yielded results that were consistent with the known fossil record-based phylogeny of the analysed sequences, suggesting that the two methods of tree reconstruction might be equally efficient and reliable. The pattern of evolution inferred for the mammalian GH gene promoters was found to vary both temporally and spatially. Thus, two distinct regions devoid of any evolutionary changes exist in primates, but only one of these 'gaps' is also observed in rodents, and neither is seen in ruminants. Furthermore, different evolutionary rates must have prevailed during different periods of evolutionary time and in different lineages, with a dramatic increase in evolutionary rate apparent in primates. Since a similar pattern of discontinuity has been previously noted for the evolution of the GH-coding regions, it may reflect the action of positive selection operating upon the GH gene as a single cohesive unit. Strong evidence for the action of gene conversion between primate GH gene promoters is provided by the fact that the human GH1 and GH2 sequences, which are thought to have diverged before the divergence of Old World monkeys from great apes, are more similar to one another than either is to the rhesus monkey GH2 promoter. Finally, it was noted that a number of nucleotide positions in the GH1 gene promoter that are polymorphic in humans appear to be highly conserved in mammals. This apparent conundrum, which could represent a caveat for the interpretation of phylogenetic footprinting studies, is potentially explicable in terms either of reduced genetic diversity in highly inbred animal species or insufficient population data from non-human species.

Animals↗
PubMed2001

Structure of linkage disequilibrium and phenotypic associations in the maize genome.

Association studies based on linkage disequilibrium (LD) can provide high resolution for identifying genes that may contribute to phenotypic variation. We report patterns of local and genome-wide LD in 102 maize inbred lines representing much of the worldwide genetic diversity used in maize breeding, and address its implications for association studies in maize. In a survey of six genes, we found that intragenic LD generally declined rapidly with distance (r(2) < 0.1 within 1500 bp), but rates of decline were highly variable among genes. This rapid decline probably reflects large effective population sizes in maize during its evolution and high levels of recombination within genes. A set of 47 simple sequence repeat (SSR) loci showed stronger evidence of genome-wide LD than did single-nucleotide polymorphisms (SNPs) in candidate genes. LD was greatly reduced but not eliminated by grouping lines into three empirically determined subpopulations. SSR data also supplied evidence that divergent artificial selection on flowering time may have played a role in generating population structure. Provided the effects of population structure are effectively controlled, this research suggests that association studies show great promise for identifying the genetic basis of important traits in maize with very high resolution.

Chromosome Mapping↗
PubMed1998

Nonneutral evolution and differential mutation rate of gender-associated mitochondrial DNA lineages in the marine mussel Mytilus.

Mussels have two types of mitochondrial DNA (mtDNA). The M type is transmitted paternally, and the F type is transmitted maternally. To test hypotheses of the molecular evolution of both mtDNA genomes, 50 nucleotide sequences were obtained for 396 bp of the COIII gene of European populations of Mytilus edulis and the Atlantic and Mediterranean forms of M. galloprovincialis. Analysis based on the proportion of synonymous and nonsynonymous substitutions indicate that mtDNA is evolving in a non-neutral and complex fashion. Previous studies on American mussels demonstrated that the F genome experiences a higher purifying selection and that the M genome evolves faster. Here we show that these patterns also hold in European populations. However, in contrast to American populations, where an excess of replacement substitution between F and M lineages has been reported, a significant excess of replacement polymorphism within mtDNA lineages is observed in European populations of M. galloprovincialis. European populations also show an excess of replacement polymorphism within the F but not within the M genome with respect to American M. trossulus, as well as a consistent pattern of excess of rare variants in both F and M genomes. These results are consistent with a nearly neutral model of molecular evolution and a recent relaxation of selective constraints on European mtDNA. Levels of diversity are significantly higher for the M than F genome, and the M genome also accumulates synonymous and nonsynonymous substitutions at a higher rate, in contrast with earlier reports where no difference for the synonymous rate was observed. It is suggested that a subtle balance between relaxed selection and a higher mutation rate explains the faster evolutionary rate of the M lineage.

Animals↗
PubMed2001

Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with calcium overload and the delayed afterdepolarizations observed during digitalis toxicity. We speculated that a genetically determined abnormality of intracellular calcium handling might be the substrate of the disease; therefore, we considered the human cardiac ryanodine receptor gene (hRyR2) a likely candidate for this genetically transmitted arrhythmic disorder. METHODS AND RESULTS: Twelve patients presenting with typical catecholaminergic polymorphic ventricular tachycardia in the absence of structural heart abnormalities were identified. DNA was extracted from peripheral blood lymphocytes, and single-strand conformation polymorphism analysis was performed on polymerase chain reaction-amplified exons of the hRyR2 gene. Four single nucleotide substitutions leading to missense mutations were identified in 4 probands affected by the disease. Genetic analysis of the asymptomatic parents revealed that 3 probands carried de novo mutations. In 1 case, the identical twin of the proband died suddenly after having suffered syncopal episodes. The fourth mutation was identified in the proband, in 4 clinically affected family members, and in none of 3 nonaffected family members in a kindred with 2 sudden deaths that occurred at 16 and 14 years, respectively, in the sisters of the proband. CONCLUSIONS: We demonstrated that, in agreement with our hypothesis, hRyR2 is a gene responsible for catecholaminergic polymorphic ventricular tachycardia.

Adolescent↗
PubMed1997

Patterns of mitochondrial variation within and between African malaria vectors, Anopheles gambiae and An. arabiensis, suggest extensive gene flow.

Anopheles gambiae and An. arabiensis are mosquito species responsible for most malaria transmission in sub-Saharan Africa. They are also closely related sibling species that share chromosomal and molecular polymorphisms as a consequence of incomplete lineage sorting or introgressive hybridization. To help resolve these processes, this study examined the partitioning of mtDNA sequence variation within and between species across Africa, from both population genetic and phylogeographic perspectives. Based on partial gene sequences from the cytochrome b, ND1 and ND5 genes, haplotype diversity was high but sequences were very closely related. Within species, little or no population subdivision was detected, and there was no evidence for isolation by distance. Between species, there were no fixed nucleotide differences, a high proportion of shared polymorphisms, and eight haplotypes in common over distances as great as 6000 km. Only one of 16 shared polymorphisms led to an amino acid difference, and there was no compelling evidence for nonneutral variation. Parsimony networks constructed of haplotypes from both species revealed no correspondence of haplotype with either geography or taxonomy. This trend of low intraspecific genetic divergence is consistent with evidence from allozyme and microsatellite data and is interpreted in terms of both extensive gene flow and recent range expansion from relatively large, stable populations. We argue that retention of ancestral polymorphisms is a plausible but insufficient explanation for low interspecific genetic divergence, and that extensive hybridization is a contributing factor.

Animals↗