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At least 523 records · Page 29Linked to original sources
PubMed2000

Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype.

The acetylator phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NAT1 alleles. The distribution (%) of slow:rapid acetylator phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rephenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NAT1 alleles was similar in all three groups. It is evident from the amount of discordance between caffeine phenotype and dapsone phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.

Acetylation↗
PubMed2004

Genetic variants of the human H+/dipeptide transporter PEPT2: analysis of haplotype functions.

PEPT2 is a high-affinity H+/dipeptide transporter expressed in kidney, brain, lung, and mammary gland. The physiological role of PEPT2 in kidney is to reabsorb small peptides generated by luminal peptidases. PEPT2 is also a transporter for peptide-like drugs such as penicillins and cephalosporins. We have conducted a haplotype analysis of 27 single nucleotide polymorphisms located in or near exons of the human gene encoding hPEPT2 (SLC15A2), using genotyping data from 247 genomic DNA samples from the Coriell collection. Our analysis reveals that hPEPT2 has a >6-kilobase sequence block with at least 10 abundant polymorphisms in almost complete linkage disequilibrium. As a result, only two main hPEPT2 variants exist (hPEPT2*1 and *2) with several phased amino acid substitutions, present in substantial frequencies in all ethnic groups tested. When expressed in Chinese hamster ovary cells, hPEPT2*1 and *2 displayed similar Vmax values for glycyl-sarcosine (Gly-Sar), but they differed significantly in their Km values (83 +/- 16 and 233 +/- 38 microM, respectively). Moreover, hPEPT2*1 and *2 differed in their pH sensitivity for H+/Gly-Sar transport. In addition, hPEPT2*1 and *2 generated varying levels of mRNA in nine heterozygous kidney tissue samples, including one allele expressing no detectable mRNA, suggesting the presence of cis-acting polymorphisms affecting transcription or mRNA processing. The results indicate that polymorphisms in the gene encoding hPEPT2 can alter substrate transport and therefore could affect drug disposition in vivo.

Alleles↗
PubMed1998

A collaborative genetic study on the STR system FGA in two Austrian population samples.

Population genetic data of the short tandem repeat system FGA were determined by PCR analysis in two Austrian population samples, one population north of the Alps and one population south of the Alps. A total of 15 different alleles could be observed in 500 unrelated individuals. No significant differences were found between the phenotype frequencies in the two populations, as determined by R x C contingency test, so the populations could be pooled for further analysis. Both the single populations and the pooled population are in accordance with Hardy-Weinberg equilibrium. FGA proves to be very efficient for both stain analysis and paternity testing. The presented allele and genotype data allow the statistical interpretation of this system for Austrians.

Alleles↗
PubMed2001

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Adult↗
PubMed2006

Residual linkage: why do linkage peaks not disappear after an association study?

Family-based candidate gene and genome-wide association studies are a logical progression from linkage studies for the identification of gene and polymorphisms underlying complex traits. An efficient way to analyse phenotypic and genotypic data is to model linkage and association simultaneously. An important result from such an analysis is whether any evidence for linkage remains after fitting polymorphisms at candidate genes (residual linkage), because this may indicate locus and allelic heterogeneity in the population and will influence subsequent molecular strategies. Here we report that substantial residual linkage is to be expected, even under genetic homogeneity and when the underlying causal polymorphisms are genotyped and fitted in the model. We simulated a powerful design to detect linkage to quantitative trait loci, with 5, 10 or 20 causal SNPs spread throughout the genome. These SNPs were responsible for all genetic variation, and hence for both linkage and association. Residual linkage at the largest linkage peak from a genome-wide scan was substantial, with mean LOD scores of 0.4, 0.7, and 1.4 for the case of 5, 10 and 20 underlying causal SNPs, respectively. For less powerful designs, the proportion of the original LOD scores that remains after association will be even larger. All cases of 'significant' residual linkage are false positives. The reason for the apparent paradox of detecting residual linkage after fitting causal polymorphisms is that the linkage signals at the largest peaks in a genome-scan are severely inflated, even if all peaks correspond to true linkage. Our findings are general and apply to linkage mapping of any phenotype and to any pedigree structure.

Computer Simulation↗
PubMed2026

Selphi, a tool for improving genotype imputation accuracy.

Genotype imputation is a powerful tool for inferring missing genotype data in large-scale genetic studies. Over the last two decades, multiple imputation algorithms have been developed, steadily improving in speed and overall accuracy. However, accurate imputation of rare and infrequent variants remains a challenge, largely because existing methods rely on local haplotype matching within genomic windows and do not fully exploit the extended patterns of haplotype sharing that span entire chromosomes. Here we present Selphi, a new genotype imputation algorithm that combines the Positional Burrows-Wheeler Transform (PBWT) with a multi-stage haplotype selection heuristic operating across entire chromosomes. When compared to state-of-the-art methods Beagle 5.4, IMPUTE5, and Minimac4, Selphi showed higher accuracy on the 1000 Genomes Project and TOPMed datasets, across all super-populations and allele frequencies. Similarly, Selphi achieved higher accuracy than Beagle 5.4 on the UK Biobank dataset, which translated into improved concordance with hc-WGS GWAS summary statistics at known trait-associated loci and more accurate polygenic risk scores (PRS). Selphi outputs standard VCF files with genotype dosages (DS), haplotype-specific allele probabilities (AP1, AP2), and a per-variant dosage R-squared quality score (DR2), enabling direct integration with downstream analytical pipelines including standard post-imputation quality filtering.

Genome-Wide Association Study↗
PubMed1999

The utility of short tandem repeat loci beyond human identification: implications for development of new DNA typing systems.

Since the first characterization of the population genetic properties of repeat polymorphisms, the number of short tandem repeat (STR) loci validated for forensic use has now grown to at least 13. Worldwide variations of allele frequencies at these loci have been studied, showing that variations of interpopulation diversity at these loci do not compromise the power of identification of individuals. However, data collected for validation of these loci for forensic use has utility beyond human identification; the origin and past migration history of modern humans can be reconstructed from worldwide variations at these loci. Furthermore, complex forensic cases previously unresolvable can now be investigated with the help of the validated STR loci. Here, we provide the absolute power of the validated set of 13 STR loci for addressing these issues using multilocus genotype data on 1,401 individuals belonging to seven populations (US European-American, US African-American, Jamaican, Italian, Swiss, Chinese and Apache Native-American). Genomic research is discovering new classes of polymorphic loci (such as the single nucleotide polymorphisms, SNPs) and lineage markers (such as the mitochondrial DNA and Y-chromosome markers); our aim, therefore, was to determine how many SNP loci are needed to match the power of this set of 13 STR loci. We conclude that the current set of STR loci is adequate for addressing most problems of human identification (including interpretations of DNA mixtures). However, if suitable number of SNPs are used that would match the power of the STR loci, they alone cannot resolve more complex cases unless they are supplemented by the validated STR loci.

Chromosome Mapping↗
PubMed2003

Bayesian analysis of multilocus association in quantitative and qualitative traits.

A Bayesian model-based method for multilocus association analysis of quantitative and qualitative (binary) traits is presented. The method selects a trait-associated subset of markers among candidates, and is equally applicable for analyzing wide chromosomal segments (genome scans) and small candidate regions. The method can be applied in situations involving missing genotype data. The number of trait loci, their marker positions, and the magnitudes of their gene effects (strengths of association) are all estimated simultaneously. The inference of parameters is based on their posterior distributions, which are obtained through Markov chain Monte Carlo simulations. The strengths of the approach are: 1) flexible use of oligogenic models with unknown number of loci, 2) performing the estimation of association jointly with model selection, and 3) avoidance of the multiple testing problem, which typically complicates the approaches based on association testing. The performance of the method was tested and compared to the multilocus conditional search procedure by analyzing two simulated data sets. We also applied the method to cystic fibrosis haplotype data (two-locus haplotypes), where gene position has already been identified. The method is implemented as a software package, which is freely available for research purposes under the name BAMA.

Algorithms↗
PubMed2005

CYP19 (aromatase) haplotypes and endometrial cancer risk.

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)(n) repeat polymorphism in intron IV as well as a 3'UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case-control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989-1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning > 123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency > or = 5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13-2.48) to 2.07 (95% CI 1.33-3.23), comparing variant allele carriers to wild-type homozygotes. We observed significant interactions between menopausal status and 2 of the high-risk loci (p = 0.03 and p < 0.01), with > 2-fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high-frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women.

Adult↗
PubMed2005

A male-specific quantitative trait locus on 1p21 controlling human stature.

BACKGROUND: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. OBJECTIVE: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. METHODS: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. RESULTS: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. CONCLUSIONS: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.

Adult↗
PubMed2004

Genetic association mapping under founder heterogeneity via weighted haplotype similarity analysis in candidate genes.

Taking advantage of increasingly available high-density single nucleotide polymorphism (SNP) markers within genes and across genomes, more and more genetic association studies began to use multiple closely linked markers in candidate genes. A practical analytical challenge arising in such studies is the possibility that not all case chromosomes have inherited disease-causing mutations from a common ancestral chromosome (founder heterogeneity). To alleviate the problem, we propose a method that applies a clustering algorithm to haplotype similarity analysis. The method identifies a sequence of nested subsets of case chromosomes by a peeling procedure, where each subset is relatively homogeneous. The average similarity score estimated from each subset in the sequence is compared to that estimated in controls, and a raw (unadjusted for multiple comparisons) P value is obtained. The test for the association between the trait and the candidate gene is based on the minimum raw P value observed in the comparison sequence, with its significance level estimated by a permutation procedure. The method can be applied to both haplotype and genotype data. Simulation studies suggest that our method has the correct type I error rate, and is generally more powerful than existing methods of haplotype similarity analysis.

Alleles↗
PubMedDate not supplied

A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution.

Hydatidiform mole is a benign trophoblastic neoplasia characterized by an abnormal development of the embryo and proliferation of placental villi. Using microsatellite markers amplified by the polymerase chain reaction, we have performed a genetic study on eight independent molar tissues occurring in two sisters. Karyotype and genotype data demonstrate a diploid and biparental constitution in seven of the analyzed moles suggesting a common mechanism underlying the etiology of the various molar pregnancies in this family. The data reported here suggest that complete and partial hydatidiform moles are not always separate entities and that women with familial recurrent hydatidiform moles are homozygous for an autosomal recessive mutation.

Diploidy↗
PubMed2006

First evidence of pfcrt mutant Plasmodium falciparum in Madagascar.

The island of Madagascar, lying in the Indian Ocean approximately 250 miles from the African coast, has so far remained one of the few areas in the world without noticeable Plasmodium falciparum high-grade chloroquine (CQ) resistance. Here we report genotyping data on pfcrt in Madagascar. The pfcrt K76T mutation, which is critical for resistance to CQ, was detected in six (3.3%) of 183 P. falciparum isolates screened, within the mutant haplotypes CVIET and CVIDT. This is the first observation of pfcrt mutant parasites on the island. The current massive distribution of CQ for in-home management of fever in children will promote the dissemination of these mutant CQ-resistant parasites. In this context, genotyping of pfcrt remains a useful tool for CQ resistance surveillance as the prevalence of pfcrt mutations is far from saturation in Madagascar.

Animals↗
PubMed2025

Molecular signatures of adaptive introgression and selection in contact zones of closely related pine species (Pinus genus).

BACKGROUND: Natural hybridization plays a key role in shaping genetic diversity, local adaptation, and the dynamics of speciation through interspecific gene flow. Hybrid zones serve as valuable natural systems for studying these processes. In this research, we used genotypic data at thousands of nuclear SNPs to investigate genomic outcomes of hybridization and selection across three contact zones of closely related pine species including Scots pine (Pinus sylvestris L.) and dwarf mountain pine (P. mugo T.). Reference allopatric stands of parental species were used to assess introgression dynamics. RESULTS: Individuals from the hybrid zones showed distinct genetic ancestry patterns and were assigned to groups including putative pure species, first-generation hybrids, and advanced backcrosses. Genotypes of the majority of hybrids were shifted towards P. mugo ancestry. Most outlier loci were shared across all sympatric populations, although some were specific to individual contact zones. The identified outliers were mainly associated with regulatory biological processes related to phosphorylation, proteolysis, and transmembrane transport. Signatures of local adaptation varied in different genetic classes in contact zones and they were strongest in pure P. sylvestris and hybrids with a majority of P. sylvestris ancestry. The pattern suggests that it may be driven by adaptation to peat bog habitats situated outside the species&#x2019; core ecological niche. CONCLUSIONS: Our findings indicate strong selective pressure acting on multiple genes in groups of hybrids and pure Pinus sylvestris individuals across all studied hybrid zones. In contrast, the weaker signal of selection observed in individuals with P. mugo ancestry suggests that relict populations of this species, which historically spread across postglacial peat bogs, were pre-adapted to such environments. While several outlier loci were shared across different contact zones, others were unique for one of them, indicating that local environmental pressures and adaptive introgression shape the genomic composition of the populations. These results highlight the role of hybridization in generating adaptive diversity and emphasize the evolutionary significance of hybrid zones in pines.

Hybridization, Genetic↗
PubMed2005

A method for identifying genes related to a quantitative trait, incorporating multiple siblings and missing parents.

When studying either qualitative or quantitative traits, tests of association in the presence of linkage are necessary for fine-mapping. In a previous report, we suggested a polytomous logistic approach to testing linkage and association between a di-allelic marker and a quantitative trait locus, using genotyped triads, consisting of an individual whose quantitative trait has been measured and his or her two parents. Here we extend that approach to incorporate marker information from entire nuclear families. By computing a weighted score function instead of a maximum likelihood test, we allow for both an unspecified correlation structure between siblings and "informative" family size. Both this approach and our original approach allow for population admixture by conditioning on parental genotypes. The proposed method allows for missing parental genotype data through a multiple imputation procedure. We use simulations based on a population with admixture to compare our method to a popular non-parametric family-based association test (FBAT), testing the null of no association in the presence of linkage.

Alleles↗
PubMed2002

Accessing single nucleotide polymorphisms in genomic DNA by direct multiplex polymerase chain reaction amplification on oligonucleotide microarrays.

This study introduces a DNA microarray-based genotyping system for accessing single nucleotide polymorphisms (SNPs) directly from a genomic DNA sample. The described one-step approach combines multiplex amplification and allele-specific solid-phase PCR into an on-chip reaction platform. The multiplex amplification of genomic DNA and the genotyping reaction are both performed directly on the microarray in a single reaction. Oligonucleotides that interrogate single nucleotide positions within multiple genomic regions of interest are covalently tethered to a glass chip, allowing quick analysis of reaction products by fluorescence scanning. Due to a fourfold SNP detection approach employing simultaneous probing of sense and antisense strand information, genotypes can be automatically assigned and validated using a simple computer algorithm. We used the described procedure for parallel genotyping of 10 different polymorphisms in a single reaction and successfully analyzed more than 100 human DNA samples. More than 99% of genotype data were in agreement with data obtained in control experiments with allele-specific oligonucleotide hybridization and capillary sequencing. Our results suggest that this approach might constitute a powerful tool for the analysis of genetic variation.

Algorithms↗
PubMed2005

Exploring Lactobacillus plantarum genome diversity by using microarrays.

Lactobacillus plantarum is a versatile and flexible species that is encountered in a variety of niches and can utilize a broad range of fermentable carbon sources. To assess if this versatility is linked to a variable gene pool, microarrays containing a subset of small genomic fragments of L. plantarum strain WCFS1 were used to perform stringent genotyping of 20 strains of L. plantarum from various sources. The gene categories with the most genes conserved in all strains were those involved in biosynthesis or degradation of structural compounds like proteins, lipids, and DNA. Conversely, genes involved in sugar transport and catabolism were highly variable between strains. Moreover, besides the obvious regions of variance, like prophages, other regions varied between the strains, including regions encoding plantaricin biosynthesis, nonribosomal peptide biosynthesis, and exopolysaccharide biosynthesis. In many cases, these variable regions colocalized with regions of unusual base composition. Two large regions of flexibility were identified between 2.70 and 2.85 and 3.10 and 3.29 Mb of the WCFS1 chromosome, the latter being close to the origin of replication. The majority of genes encoded in these variable regions are involved in sugar metabolism. This functional overrepresentation and the unusual base composition of these regions led to the hypothesis that they represented lifestyle adaptation regions in L. plantarum. The present study consolidates this hypothesis by showing that there is a high degree of gene content variation among L. plantarum strains in genes located in these regions of the WCFS1 genome. Interestingly, based on our genotyping data L. plantarum strains clustered into two clearly distinguishable groups, which coincided with an earlier proposed subdivision of this species based on conventional methods.

Bacterial Proteins↗
PubMed2002

No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network.

A recent study by Ingram et al. [2000b: Teratology 62:393-405] suggests a (His)73(Arg) polymorphism (A:G) in HOXA1 contributes substantially to a liability for autism. Using 68 individuals diagnosed with Autism Spectrum Disorders, they found a significant dearth of G homozygotes and biased transmission of G alleles from parents to affected offspring, especially from mothers. Because the connection between HOXA1 and liability to autism is compelling, we attempted to replicate their finding using a larger, independent sample from the Collaborative Programs of Excellence in Autism (CPEA) network. In our data, genotype frequencies conform to Hardy-Weinberg equilibrium; allele transmissions meet Mendelian expectations; and there is no obvious sex-biased allele transmission. Based on our sample size, calculations suggest that we would have at least 95% power to detect linkage and association even if the A:G polymorphism were to account for only 1% of the heritability of autism. Therefore, although we cannot exclude the possibility that the samples in the two studies are intrinsically different, our data from our sample argue against a major role for HOXA1 (His)73(Arg) in liability to autism.

Asperger Syndrome↗