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PubMed2006

A bivariate functional mapping model for identifying haplotypes that control drug response for systolic and diastolic blood pressures.

A bivariate functional mapping model has been proposed to detect haplotype-based DNA sequence variants that regulate the response curves of systolic and diastolic blood pressures (SBP and DBP) to a particular drug. This model capitalizes on the haplotype structure constructed by single nucleotide polymorphisms (SNPs) and incorporates the mathematical aspects of pharmacodynamic reactions into the estimation process, aimed to identify DNA sequence variants responsible for drug response. In this way, by estimating and testing the curve parameters that define drug response, many genetically and clinically meaningful hypotheses regarding the degree and pattern of the genetic control of SBP and DBP can be formulated, tested and disseminated. In a pharmacogenetic study composed of 107 subjects, our bivariate model has probed two haplotypes within the beta 2AR candidate gene that exert a significant effect on both SBP and DBP respond to dobutamine. With this candidate gene, two SNPs are genotyped, with allele Gly16 (G) and Arg16 (A) at codon 16 and alleles Glu27 (G) and Gln27 (C) at codon 27, respectively. The significant haplotypes are [AC] for SBP and [GG] for DBP. This model provides a powerful tool for elucidating the genetic variants of drug response and ultimately designing personalized medications based on each patient's genetic makeup.

Algorithms↗
PubMed2004

Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia.

Familial hypercholesterolemia (FH) is a common, autosomal dominant disorder of lipid metabolism, caused by defects in the receptor-mediated uptake of LDL (low-density lipoproteins) due to mutations in the LDL receptor gene ( LDLR). Mutations underlying FH in Bulgaria are largely unknown. The aim of the present study was to provide information about the spectrum of point mutations in LDLR in a sample of 45 Bulgarian patients with severe hypercholesterolemia. Exons 3, 4, 6, 8, 9, and 14, previously shown to be mutational hot spots in LDLR, were screened using PCR-single-strand conformation polymorphism (SSCP). Samples with abnormal SSCP patterns were sequenced. Three different, hitherto undescribed point mutations (367T>A, 377T>A, 917C>A) and two previously described mutations (858C>A and 1301C>T) in eight unrelated patients were identified; four of the detected point mutations being missense mutations and one, a nonsense mutation. One of the newly described point mutations (917C>A) is a base substitution at a nucleotide position, at which two other different base substitutions have already been reported. Thus, all three possible base substitutions at this nucleotide position have been detected, making it a hot spot for point mutations causing FH. This is the first such mutational hot spot described in exon 6 of LDLR.

Bulgaria↗
PubMed2005

A common polymorphism in the SFTPD gene influences assembly, function, and concentration of surfactant protein D.

Surfactant protein D (SP-D) plays important roles in the host defense against infectious microorganisms and in regulating the innate immune response to a variety of pathogen-associated molecular pattern. SP-D is mainly expressed by type II cells of the lung, but SP-D is generally found on epithelial surfaces and in serum. Genotyping for three single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met(11)Thr), 160 (Ala(160)Thr), and 270 (Ser(270)Thr) of the SP-D gene was performed and related to the SP-D levels in serum. Individuals with the Thr/Thr(11)-encoding genotype had significantly lower SP-D serum levels than individuals with the Met/Met(11) genotype. Gel filtration chromatography revealed two distinct m.w. peaks with SP-D immunoreactivity in serum from Met/Met(11)-encoding genotypes. In contrast, Thr/Thr(11) genotypes lacked the highest m.w. form. A similar SP-D size distribution was found for recombinant Met(11) and Thr(11) expressed in human embryonic kidney cells. Atomic force microscopy of purified SP-D showed that components eluting in the position of the high m.w. peak consist of multimers, dodecamers, and monomers of subunits, whereas the second peak exclusively contains monomers. SP-D from both peaks bound to mannan-coated ELISA plates. SP-D from the high m.w. peak bound preferentially to intact influenza A virus and Gram-positive and Gram-negative bacteria, whereas the monomeric species preferentially bound to isolated LPS. Our data strongly suggest that polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and the concentration of the molecule in serum.

Alleles↗
PubMed2026

Shared candidate genes associated with variation in egg size in cold-adapted and artificially selected Drosophila melanogaster.

The development of most multicellular organisms begins with oogenesis, the production of the egg. In D. melanogaster, egg size is a highly polygenic trait closely related to fitness. Elements of shifts in egg size have been widely studied and modeled, but the genes underlying this variation are still poorly understood. This study aimed to identify candidate genes associated with processes underlying egg-size variation using D. melanogaster as a model. In selection experiments, we generated large-egg populations from a shared ancestral population using both cold-adaptation and artificial selection, and identified candidate genes for the large-egg phenotype. Using whole-genome DNA sequencing and strict computational filtering, we uncovered single-nucleotide polymorphisms in 10 genes. Characterization of these candidates revealed functions in cytoskeletal dynamics, DNA replication and repair, intracellular signaling, and stem cell maintenance and differentiation. RT-PCR and qPCR were used to validate gene expression differences between cold-adapted lines and the Oregon R control (OrR) in a subset of the candidates. In RT-PCR, stathmin demonstrated a modified expression pattern in all cold-adapted lines relative to OrR controls. In qPCR experiments, Pde1c had significantly higher expression (p&#x202f;<&#x202f;0.05) in the cold-adapted flies compared to OrR controls for all three fly cages tested. For Ino80, significantly higher expression was observed for one of three cages while one cage showed lower expression. We have assembled a candidate list we hope will be a useful resource for researchers across specialties, from germ cells to cytoskeletal dynamics, to further investigate the genetic and developmental aspects of variation in egg size in D. melanogaster.

Animals↗
PubMed2004

Haplotype block structures show significant variation among populations.

Recent studies suggest that haplotypes tend to have block-like structures throughout the human genome. Several methods were proposed for haplotype block partitioning and for tagging single-nucleotide polymorphism (SNP) identification. In population genetics studies, several research groups compared block structures across human populations. However, the measures used to quantify population similarity are either less than satisfactory or nonexistent. In this article, we propose several similarity measures to facilitate the comparisons of haplotype structures, namely block boundaries and tagging SNPs, across populations. With these measures, we can more objectively compare haplotype block structures and tagging SNP sets between different populations. In addition, these measures allow us to compare the results of different methods for block partition and tagging SNP identification. When we applied these measures to a real data set on chromosome 10 in 16 worldwide populations, we found that in this genome region: 1) haplotype block boundaries vary among populations, with European and some African populations showing similar boundaries but other populations showing other patterns; 2) tagging SNP sets are generally similar for populations with similar haplotype block structures but differ if the block structures differ; and 3) all but one of the block finding methods we tested yield consistent results, although variations exist regarding consistency. Our tentative results show that at least in the genome region studied, it is unlikely that a common haplotype pattern exists for all human populations: many populations, even in the same geographical region, may have different haplotype patterns.

Chromosome Mapping↗
PubMed2004

Effect of the methylenetetrahydrofolate reductase C677T polymorphism on patients with cisplatin/gemcitabine-treated stage IV non-small-cell lung cancer.

Single nucleotide polymorphisms (SNPs) in the metabolic pathways of S-adenosylmethionine have been related to global hypomethylation and a lower number of hypermethylated CpG islands of tumor suppressor genes. Hypermethylation of checkpoint and DNA repair genes has been shown to be indicative of chemosensitivity. In the present study, we have examined the SNP of methylenetetrahydrofolate reductase (MTHFR) C677T, which affects DNA methylation patterns and is linked to elevated plasma homocysteine levels in 208 patients with gemcitabine/cisplatin-treated stage IV non-small-cell lung cancer (NSCLC). No differences in response rate were observed according to the MTHFR genotype. However, time to progression was 7.4 months for 68 patients with CC genotype, 5.5 months for 108 patients with heterozygous CT genotype, and 5.2 months for 28 patients with TT genotype. These findings can lead us to distinguish different outcome patterns among patients with stage IV NSCLC whose similar clinical prognostic factors would otherwise indicate similar outcomes. Carriers of the MTHFR 677T allele could benefit from supplementation with folic acid and vitamin B12. The Spanish Lung Cancer Group has undertaken a phase III randomized trial to elucidate this concept.

Adult↗
PubMed1991

Genetic diversity of human parvovirus B19 determined using a set of restriction endonucleases recognizing four or five base pairs and partial nucleotide sequencing: use of sequence variability in virus classification.

Analysis of the restriction site polymorphism (RSP) of human parvovirus B19 using 12 restriction endonucleases (REs) recognizing four or five bp sequences (4- or 5-bp REs) revealed a significant difference between strains previously classified as being of the same genome type, and a relationship between two strains of different genome types, thereby indicating a global spread of B19 virus strains. These findings demonstrate the advantage of this set of 4- and 5-bp REs for the calculation of the degree of genetic diversity and clearly it is necessary to amend the taxonomy of B19 virus strains using these REs. We examined the nucleotide (nt) sequence between nt 3141 and 3411, at the N terminus of the VP2 protein coding region, in 12 B19 virus strains. The pattern of distribution of nucleotide differences between the strains confirmed the classification by RSP analysis. Between nt 3293 and nt 3364, a region in which an antigenic epitope may be encoded, there was no evidence of a nucleotide change causing an amino acid change. Thus, the amino acid sequence in this potential epitope is probably conserved.

Cloning, Molecular↗
PubMed2002

Segmental linkage disequilibrium within the dopamine transporter gene.

The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3' repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5' (distal promoter through intron 6) and 3' (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

Dopamine Plasma Membrane Transport Proteins↗
PubMed2004

Population genetic structure and phylogeographical pattern of a relict tree fern, Alsophila spinulosa (Cyatheaceae), inferred from cpDNA atpB- rbcL intergenic spacers.

Sequences of chloroplast DNA (cpDNA) atpB- rbcL intergenic spacers of individuals of a tree fern species, Alsophila spinulosa, collected from ten relict populations distributed in the Hainan and Guangdong provinces, and the Guangxi Zhuang region in southern China, were determined. Sequence length varied from 724 bp to 731 bp, showing length polymorphism, and base composition was with high A+T content between 63.17% and 63.95%. Sequences were neutral in terms of evolution (Tajima's criterion D=-1.01899, P>0.10 and Fu and Li's test D*=-1.39008, P>0.10; F*=-1.49775, P>0.10). A total of 19 haplotypes were identified based on nucleotide variation. High levels of haplotype diversity (h=0.744) and nucleotide diversity (Dij=0.01130) were detected in A. spinulosa, probably associated with its long evolutionary history, which has allowed the accumulation of genetic variation within lineages. Both the minimum spanning network and neighbor-joining trees generated for haplotypes demonstrated that current populations of A. spinulosa existing in Hainan, Guangdong, and Guangxi were subdivided into two geographical groups. An analysis of molecular variance indicated that most of the genetic variation (93.49%, P<0.001) was partitioned among regions. Wright's isolation by distance model was not supported across extant populations. Reduced gene flow by the Qiongzhou Strait and inbreeding may result in the geographical subdivision between the Hainan and Guangdong + Guangxi populations (FST=0.95, Nm=0.03). Within each region, the star-like pattern of phylogeography of haplotypes implied a population expansion process during evolutionary history. Gene genealogies together with coalescent theory provided significant information for uncovering phylogeography of A. spinulosa.

Biological Evolution↗
PubMed1993

DNA sequence polymorphism of the Chlamydia trachomatis omp1 gene.

The Chlamydia trachomatis major outer membrane protein gene (omp1) was amplified by polymerase chain reaction (PCR) from 89 clinical specimens, and restriction fragment length polymorphism (RFLP) patterns were analyzed after AluI or AluI and MspI digestion. Ten distinct RFLP omp1 genotypes were observed, although 4 types accounted for 70% of the isolates. The DNA sequence of variable domains (VDs) 1, 2, and 4 were determined for 49 samples. Thirty samples (61%) had prototype VD sequences, 15 (31%) had sequences that varied from prototype sequences, and 4 (8%) contained sequences from > 1 chlamydial isolates. Eleven of the 15 DNA sequence variations were one- or two-site nucleotide substitutions, 10 of which resulted in an amino acid change. Four DNA sequence variations were more extensive, with multiple nucleotide substitutions, insertions, or deletions. The data demonstrate that C. trachomatis isolates circulating in a relatively circumscribed geographic community exhibit remarkable omp1 DNA sequence polymorphism.

Amino Acid Sequence↗
PubMed2006

Identification of base pairs in single-nucleotide polymorphisms by MutS protein-mediated capillary electrophoresis.

Single-nucleotide polymorphisms (SNPs) are widespread genomic variations, which are associated with serious health disorders and drug resistance. Multiple clinical applications and studies of global population genetics require fast and informative analysis of SNPs. Most of conventional methods sense the presence of the SNP but cannot identify the base pair in it. Here we report simple identification of base pairs in SNPs without DNA sequencing. Our approach is based on the unique ability of MutS protein to bind different single-nucleotide mismatches in DNA with different affinities. Conceptually, the DNA in question is mixed with reference DNA, melted, and reannealed. If the DNA in question has an SNP, the products of reannealing will have two different single-nucleotide mismatches, which provide a base-pair-specific signature of the SNP. The products of reannealing are mixed with MutS, equilibrated, and separated by equilibrium capillary electrophoresis of equilibrium mixtures with MutS in the run buffer. The pattern of migration times of DNAs with mismatches is used for unequivocal identification of the base pair in the SNP. In addition to its ability to identify base pairs in SNPs, the new analytical approach is fast, simple, highly sensitive, and requires no quantitation. It will find applications in studies of heterogeneity of base pairs in known SNPs in large human populations.

Base Pairing↗
PubMedDate not supplied

Restriction enzyme analysis of mitochondrial DNA of Acanthamoeba strains in Japan.

Eight isolates, identified as either Acanthamoeba castellanii or A. polyphaga from human eye infections, contact lens containers, and soil in Japan, were characterized by restriction fragment length polymorphisms (RFLP) of mitochondrial DNA (mtDNA). Mitochondrial DNA was digested with either Bgl II, EcoR I, Hind III, Hpa I, Sca I or Xba I, electrophoresed in agarose gels, and stained with ethidium bromide. Four distinct RFLP phenotypes that refer to the collection of six fragment size patterns obtained for a single strain with six enzymes, were discovered among the eight strains used in this study. Three strains morphologically classified as A. polyphaga share a single RFLP phenotype with the Ma strain of A. castellanii. The interspecific sequence differences of 7.06-12.74% in DNA nucleotide were estimated from the proportion of DNA fragments shared by each pair of mtDNA.

Acanthamoeba↗
PubMed2005

Amount of introgression in flycatcher hybrid zones reflects regional differences in pre and post-zygotic barriers to gene exchange.

Introgression is the incorporation of alleles from one species or semispecies into the gene pool of another through hybridization and backcrossing. The rate at which this occurs depends on the frequency of hybridization and the fitness of hybrids and backcrosses compared to 'pure' individuals. The collared flycatcher (Ficedula albicollis) and the pied flycatcher (F. hypoleuca) co-exist and hybridize at low to moderate frequencies in a clinal hybrid zone in Central Europe and on the islands of Gotland and Oland off the Swedish east coast. Data on hatching success suggest that hybrids are less fertile in Central Europe compared to on the islands. Direct fitness estimates using molecular markers to infer paternity are consistent with the demographic data. Applying a tag-array-based minisequencing assay to genotype interspecific substitutions and single nucleotide polymorphisms we demonstrate that the amount of introgression from the pied to the collared flycatcher is higher in the two island populations (Gotland and Oland) than in two geographically distinct areas from the Central European hybrid zone (Czech Republic and Hungary). In all areas the amount of introgression from collared to pied flycatchers is very low or seemingly absent. The different patterns of introgression are consistent with regional differences in rates of hybridization and fitness of hybrids. We suggest that barriers to gene exchange may have been partly broken down on the islands due to asymmetric gene flow from allopatry. Alternatively, or in addition, more pronounced reinforcement of prezygotic isolation in Central Europe might have increased post-zygotic isolation through hitchhiking, since genes affecting pre and post-zygotic isolation are both sex-linked in these birds. One of our genetic markers appears to introgress from pied to collared flycatchers at a much higher rate than the other markers. We discuss the possibility that the introgressed marker may be linked to a gene which is under positive selection in the novel genetic background.

Animals↗
PubMed2006

Haplotype analysis in the presence of informatively missing genotype data.

It is common to have missing genotypes in practical genetic studies, but the exact underlying missing data mechanism is generally unknown to the investigators. Although some statistical methods can handle missing data, they usually assume that genotypes are missing at random, that is, at a given marker, different genotypes and different alleles are missing with the same probability. These include those methods on haplotype frequency estimation and haplotype association analysis. However, it is likely that this simple assumption does not hold in practice, yet few studies to date have examined the magnitude of the effects when this simplifying assumption is violated. In this study, we demonstrate that the violation of this assumption may lead to serious bias in haplotype frequency estimates, and haplotype association analysis based on this assumption can induce both false-positive and false-negative evidence of association. To address this limitation in the current methods, we propose a general missing data model to characterize missing data patterns across a set of two or more markers simultaneously. We prove that haplotype frequencies and missing data probabilities are identifiable if and only if there is linkage disequilibrium between these markers under our general missing data model. Simulation studies on the analysis of haplotypes consisting of two single nucleotide polymorphisms illustrate that our proposed model can reduce the bias both for haplotype frequency estimates and association analysis due to incorrect assumption on the missing data mechanism. Finally, we illustrate the utilities of our method through its application to a real data set.

Algorithms↗
PubMed2006

SSADH variation in primates: intra- and interspecific data on a gene with a potential role in human cognitive functions.

In the present study we focus on the nucleotide and the inferred amino acid variation occurring in humans and other primate species for mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase, a gene recently supposed to contribute to cognitive performance in humans. We determined 2527 bp of coding, intronic, and flanking sequences from chimpanzee, bonobo, gorilla, orangutan, gibbon, and macaque. We also resequenced the entire coding sequence on 39 independent chromosomes from Italian families. Four variable coding sites were genotyped in additional populations from Europe, Africa, and Asia. A test for constancy of the nonsynonymous vs. synonymous rates of nucleotide changes revealed that primates are characterized by largely variable d(N)/d(S) ratios. On a background of strong conservation, probably controlled by selective constraints, the lineage leading to humans showed a ratio increased to 0.42. Human polymorphic levels fall in the range reported for other genes, with a pattern of frequency and haplotype structure strongly suggestive of nonneutrality. The comparison with the primate sequences allowed inferring the ancestral state at all variable positions, suggesting that the c.538(C) allele and the associated functional variant is indeed a derived state that is proceeding to fixation. The unexpected pattern of human polymorphism compared to interspecific findings outlines the possibility of a recent positive selection on some variants relevant to new cognitive capabilities unique to humans.

Adaptation, Biological↗
PubMed1993

Differentiation of seven Eimeria species by random amplified polymorphic DNA.

Eimeria species were differentiated by the polymerase chain reaction using random amplified polymorphic DNA. Seven arbitrary primers ranging in length from ten to 20 nucleotides were used with DNA of seven species of eimerian oocysts to generate unique DNA fingerprints. DNA fragments ranging from 200 to 2200 base pairs (bp) were synthesized in the different reactions. Species-specific DNA fragment mobility patterns were observed in most cases. In several assays, multiple DNA fragments were synthesized and, in the majority of assays conducted, the Eimeria species could be easily differentiated. Only six of the 49 assays performed failed to generate DNA fragments.

Animals↗
PubMed2001

Two novel polymorphisms in the human transforming growth factor beta 2 gene.

We have identified two novel polymorphisms in the transforming growth factor beta 2 (TGFbeta2) gene; an insertion in the 5'-untranslated region (5'UTR) and a single nucleotide polymorphism (SNP) in exon 1. A 895-bp fragment was analysed covering part of the 5'UTR and exon 1. Single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR) products was performed to detect sequence variations. This was followed by the sequencing of samples demonstrating distinct banding patterns. A 4-bp insertion (ACAA) in the 5'UTR and a SNP (G > A) within exon 1 was identified. The 5'UTR polymorphism was found to be common in three Caucasian populations from Spain, Turkey and the UK. Exon 1 polymorphism is rare and results in an R to H amino acid substitution in codon 91. Both polymorphisms may prove useful for investigating possible associations of TGFbeta2 with disease.

5' Untranslated Regions↗