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PubMed2006

Combining multiple microarrays in the presence of controlling variables.

MOTIVATION: Microarray technology enables the monitoring of expression levels for thousands of genes simultaneously. When the magnitude of the experiment increases, it becomes common to use the same type of microarrays from different laboratories or hospitals. Thus, it is important to analyze microarray data together to derive a combined conclusion after accounting for the differences. One of the main objectives of the microarray experiment is to identify differentially expressed genes among the different experimental groups. The analysis of variance (ANOVA) model has been commonly used to detect differentially expressed genes after accounting for the sources of variation commonly observed in the microarray experiment. RESULTS: We extended the usual ANOVA model to account for an additional variability resulting from many confounding variables such as the effect of different hospitals. The proposed model is a two-stage ANOVA model. The first stage is the adjustment for the effects of no interests. The second stage is the detection of differentially expressed genes among the experimental groups using the residuals obtained from the first stage. Based on these residuals, we propose a permutation test to detect the differentially expressed genes. The proposed model is illustrated using the data from 133 microarrays collected at three different hospitals. The proposed approach is more flexible to use, and it is easier to accommodate the individual covariates in this model than using the meta-analysis approach. AVAILABILITY: A set of programs written in R will be electronically sent upon request.

Algorithms↗
PubMed2025

Influence of Ancestral and Geographic Factors on Intracerebral Hemorrhage Risks Among Africans and Americans.

BACKGROUND: We investigated whether risk factors for intracerebral hemorrhage (ICH) among indigenous Africans (IA) would vary in prevalence and effect compared with self-reported African, Hispanic, and White Americans by comparing data from 2 independent population-based case-control studies conducted in West Africa and the United States. METHODS: We compared ICH risk factors common to the SIREN (Stroke Investigative Research and Educational Network: 1100 case-control pairs) and the ERICH (Ethnic/Racial Variation of Intracerebral Hemorrhage: 999 case-control pairs African American participants, 998 case-control pairs, Hispanic Americans, 1000 case-control pairs, White Americans) studies. Ethnicity/Race was self-reported. The effect measure of interest is the odds ratio (OR). To test for differences in the effects of the risk factors between the SIREN IA study population and each of the ERICH study populations, a test for heterogeneity was computed using the R program, metagen (version 4.9-6). RESULTS: ICH occurred at a younger age among IA (54.3±13.4 years), African Americans (58.0±12.7), and Hispanic Americans (58.9±14.3), compared with White Americans (69.1±13.9). The largest distinction was for hypertension, where IA exhibited a much larger risk of ICH than the American study population (OR, 67.02 [95% CI, 33.30-134.85]), African American (OR, 3.71 [95% CI, 2.53-5.44]); Hispanic (OR, 3.55 [95% CI, 2.54-4.92]), and White population (OR, 2.69 [95% CI, 1.95-3.69]). Current alcohol use exhibited increased risk in IA (OR, 2.24 [95% CI, 1.36-3.67]), but not in African Americans (OR, 0.63 [95% CI, 0.46-0.86]), Hispanic (OR, 0.87 [95% CI, 0.65-1.17]), and White Americans (OR, 0.51 [95% CI, 0.38-0.69]). CONCLUSIONS: Identical or comparable risk factors do not consistently result in the same disease risk across different cultures and regions. Therefore, to improve our understanding of the genetic determinants and biological pathways driving ICH risk, it is crucial to study multiple populations, including IA, while accounting for the influence of environmental and social factors.

Adult↗
PubMed1979

The electroencephalogram (EEG) as a research tool in human behavior genetics: psychological examinations in healthy males with various inherited EEG variants. I. Rationale of the study. Material. Methods. Heritability of test parameters.

In the first section of this paper, various research designs in human behavior genetics are compared. In this context, the commonly used concept of biometric genetics is critically evaluated from the point of view of science theory. It is contrasted with the Mendelian gene concept, which, in principle, leads to a much deeper theoretical understanding by offering clues for basic mechanisms. To explore this advantage fully, a research strategy is needed that first looks for genetic variability in a physiological parameter of possible importance for human behavior and then tries to explore the influence of this parameter on the function of the human brain and on behavior. If possible, this genetic parameter should be selected in a way that inferences as to the mechanism of its influence on behavior become feasible. Such genetic variability is provided by the hereditary variants of the normal EEG discovered by earlier work (cf. Vogel, 1970). In the following section, a research program on 298 adult healthy males, most of them soldiers, with various inherited EEG variants is described. Apart from controls with inconspicuous EEGs, this material comprises probands with the following EEG variants: low-voltage (N); low-voltage borderline (NG); monotonous alpha-waves (R); occipital fast alpha-variants (BO); fronto-precentral beta-groups (BG), and diffuse beta-waves (BD). In addition to an EEG examination, the probands were examined with various test methods measuring intelligence (IST; LPS; Raven); working speed and concentration (d-2; KLT); personal attitudes (MMPI; 16PF; RKS); and sensory and motor abilities (flicker fusion; tachistoscopy; reaction time to optic, acoustic and combined stimuli; two-hand dexterity; pursuit rotor; tapping). In a supplementary twin study on 52 male adult twin pairs (26 MZ, 26 DZ), heritabilities were determined for the test scores included in the main study. For most test scores, heritabilities are relatively low; the data are compared with those from the literature. We conclude that the test methods utilized in the main study (on EEG variants) are expected to demonstrate at the most a small to moderate correlation of the EEGs with psychological phenotypes as defined by test examinations, even if a major part of the genetic variability underlying these phenotypes would be due to differences in brain physiology that could be revealed by EEG variation.

Adult↗
PubMed2003

Statistical approaches for estimating actinobacterial diversity in marine sediments.

Bacterial diversity in a deep-sea sediment was investigated by constructing actinobacterium-specific 16S ribosomal DNA (rDNA) clone libraries from sediment sections taken 5 to 12, 15 to 18, and 43 to 46 cm below the sea floor at a depth of 3,814 m. Clones were placed into operational taxonomic unit (OTU) groups with >/= 99% 16S rDNA sequence similarity; the cutoff value for an OTU was derived by comparing 16S rRNA homology with DNA-DNA reassociation values for members of the class Actinobacteria. Diversity statistics were used to determine how the level of dominance, species richness, and genetic diversity varied with sediment depth. The reciprocal of Simpson's index (1/D) indicated that the pattern of diversity shifted toward dominance from uniformity with increasing sediment depth. Nonparametric estimation of the species richness in the 5- to 12-, 15- to 18-, and 43- to 46-cm sediment sections revealed a trend of decreasing species number with depth, 1,406, 308, and 212 OTUs, respectively. Application of the LIBSHUFF program indicated that the 5- to 12-cm clone library was composed of OTUs significantly (P = 0.001) different from those of the 15- to 18- and 43- to 46-cm libraries. F(ST) and phylogenetic grouping of taxa (P tests) were both significant (P < 0.00001 and P < 0.001, respectively), indicating that genetic diversity decreased with sediment depth and that each sediment community harbored unique phylogenetic lineages. It was also shown that even nonconservative OTU definitions result in severe underestimation of species richness; unique phylogenetic clades detected in one OTU group suggest that OTUs do not correspond to real ecological groups sensu Palys (T. Palys, L. K. Nakamura, and F. M. Cohan, Int. J. Syst. Bacteriol. 47:1145-1156, 1997). Mechanisms responsible for diversity and their implications are discussed.

Actinobacteria↗
PubMedDate not supplied

The HUMFIBRA (FGA) polymorphism in an italian population and a world-wide frequency distribution analysis.

OBJECTIVE: The study investigated the highly polymorphic HumFGA short tandem repeat in a sample of 219 unrelated and native individuals from Bologna, and analysed a complete database of FGA allele frequency distributions in 57 world-wide populations collected from the literature. METHOD: The HumFGA polymorphism was screened by automated fluorescence analysis of PCR-amplified labelled sample fragments performed with an ABI PRISM 310 Genetic Analyser. Genetic distances (Dsw, delta mu2 and Fst) between populations were computed with the MSAT.2 program. Non-metric multidimensional scaling (nmMDS) and neighbour-joining trees (NJTs) were used to investigate patterns of population affinities. Correspondence analysis of the genetic relationships among populations was also performed. MAIN RESULTS AND CONCLUSIONS: The FGA microsatellite locus is a population marker with a high degree of polymorphism throughout the world. Fourteen HumFGA alleles, ranging in size from 18 to 29 repeats, were identified and sequenced in the Bologna population. The sample was in Hardy-Weinberg equilibrium and had a heterozygosity value of 0.86. Results obtained from the multivariate analyses were consistent in showing great similarity among Europeans. The few African populations investigated were characterized by an even higher level of polymorphism, probably related to the ancient peopling of that continent.

Databases, Genetic↗
PubMed2026

Mining of important genetic loci and evaluation of genetic effects for growth traits in Baicheng You Chicken.

The Baicheng You Chicken is a precious indigenous breed in Xinjiang, China, prized for its strong disease and stress resistance and superior meat quality. However, the lack of scientific breeding and conservation has led to poor production performance, particularly in growth traits. In this study, we collected phenotypic and whole-genome resequencing data from 1,535 18-week-old Baicheng You Chickens (180 males and 1,355 females). After stringent quality control (SNP call rate > 95%, minor allele frequency > 1%), we constructed the breed's first comprehensive SNP-based genome-wide variation map, which comprised 2,020,743 high-quality SNPs across the genome. The filtered SNPs had high mapping quality (99.73% mapped to the bGalGal1.mat.broiler.GRCg7b reference genome, Q30 = 93.26%) and a reasonable Ti/Tv ratio (2.596), guaranteeing the reliability of subsequent analyses. We estimated genetic effects (SNP-based heritability and phenotypic variance explained (PVE) by individual loci) via the restricted maximum likelihood (REML) method, and performed a genome-wide association study (GWAS) using a mixed linear model (MLM) - with sex as a fixed effect and principal components to correct for population stratification - to identify significant loci and their effect sizes (Beta). All eight growth traits showed moderate to high heritability: body weight (BW) had the highest heritability (0.86&#xb1;0.11), while chest width (CW, 0.41&#xb1;0.08) and body slanting length (BSL, 0.43&#xb1;0.09) were the lowest; keel length (KL), chest girth (CG), pelvic width (PW), chest depth (CD) and shank length (SL) had heritabilities of 0.50&#xb1;0.09, 0.46&#xb1;0.09, 0.54&#xb1;0.09, 0.67&#xb1;0.10 and 0.74&#xb1;0.10, respectively. GWAS identified 145 significant SNPs, with a maximum Beta value of 0.39 and PVE ranging from 1.25% to 6.25%. We annotated 22 candidate genes, with TAPT1, IGF2BP1, ADGRB3, LDB2, NCAPG and LCORL as key candidates. These quantifiable genetic markers and effect estimates provide direct targets for marker-assisted selection (MAS) and valuable resources for future genomic selection (GS) programs, offering a practical approach to improve the breed's slow growth while preserving its unique meat quality.

Baicheng You Chicken↗
PubMed2002

Enhancement of vitamin E levels in corn.

Vitamin E is the common name that describes eight naturally occurring compounds possessing alpha-tocopherol activity. These eight vitamin E compounds are collectively termed tocols, and all have antioxidant activity. There is natural variation among different corn breeding lines for levels of tocols. The two predominant isomers present in corn grain are gamma-tocopherol and alpha-tocopherol. Alpha-tocopherol is considered more desirable for human and animal consumption because it has higher biological activity than gamma-tocopherol. Most corn breeding lines naturally have much more gamma-tocopherol than alpha-tocopherol. Therefore a breeding goal is to increase levels of alpha-tocopherol relative to gamma-tocopherol. However, recent research suggests that gamma-tocopherol and compounds metabolized from it have properties important to human health that are unique from properties of alpha-tocopherol. Therefore it may be desirable to not only increase levels of alpha-tocopherol in corn grain, but also levels of gamma-tocopherol. Determination of levels of tocopherols in corn grain is very laborious, requires HPLC analysis and is too time consuming for use in routine commercial corn breeding programs. Therefore we are performing biotechnology enabled molecular marker mapping of chromosomal regions with genes that control levels and ratios of alpha- and gamma-tocopherol. Breeders can use molecular markers we have identified to expediently select for desirable alleles of genes that will improve levels of alpha- and gamma-tocopherol in corn grain, without having to perform laborious HPLC assays. Another biotechnology strategy we have initiated is genetic transformation of corn with the gamma-tocopherol methyl transferase gene to enhance conversion of gamma-tocopherol to alpha-tocopherol and thus increase levels of alpha-tocopherol. This transgenic strategy has been demonstrated in the model plant Arabidopsis, and we are now applying this approach to corn.

Biotechnology↗
PubMed2004

An empirical test of the treatment of indels during optimization alignment based on the phylogeny of the genus Secale (Poaceae).

The ability of the program POY, implementing optimization alignment, to deal with major indels is explored and discussed in connection with a phylogenetic analysis of the genus Secale based on partial Adh1 sequences. The Adh1 sequences used span exon 2-4. Nearly all variation is found in intron 2 and intron 3, which form the basis for the phylogenetic analyses. Both in some ingroup and outgroup taxa intron 3 has a major duplication. Previous phylogenetic analyses have repeatedly confirmed monophyly of both Secale and Hordeum, the latter being part of the outgroup. However, optimization alignment only recovers both genera as monophyletic when knowledge of the duplication is incorporated in the analysis. The phylogenetic relationships within Secale are not clearly resolved. Subspecific taxa of Secale strictum have identical sequences and they are confined to a monophyletic group. However, the two subspecific taxa of Secale cereale do not form a monophyletic group, and the position of Secale sylvestre is uncertain.

Algorithms↗
PubMed2000

Chromosome instability contributes to loss of heterozygosity in mice lacking p53.

The p53 tumor suppressor protein participates in multiple cellular processes including cell cycle checkpoints and programmed cell death. In cell lines, loss of p53 function is associated with increased genetic instability including aneuploidy, gene amplification, and point mutation. Although similar genetic instability often accompanies the progression of malignancy in tumors, its role in tumor initiation in normal cells is not clear. To study whether or not loss of p53 leads to genetic instability in normal cells in vivo, we have examined mechanisms of loss of heterozygosity (LOH) at the Aprt (adenine phosphoribsyltransferase) and flanking loci in normal fibroblasts and T lymphocytes of p53-deficient mice. Somatic cell variants that arose in vivo as a consequence of genetic or epigenetic alterations abolishing Aprt function were selected and expanded in vitro by virtue of their resistance to 2,6-diaminopurine (DAP). We observed that p53 null mice produced about three times as many DAP-resistant fibroblast colonies than wild-type mice, but the frequency of DAP-resistant T lymphocyte colonies was not significantly changed. Mitotic recombination, but not point mutation, partly accounted for the increase in the frequency of DAP-resistant fibroblasts. Most significantly, chromosome loss/duplication and interstitial deletion, which were extremely rare events in the wild-type mice, represented a significant proportion of LOH events in both fibroblasts and T lymphocytes of p53 null mice. Also, increased interstitial deletion was observed in fibroblasts of p53 heterozygous mice. These data suggest that increased genetic variation, including chromosome instability, starts at the initiation stage of tumorigenesis when functional p53 is absent or reduced.

Aneuploidy↗
PubMed2006

Persistence of genetic variants of the arctic fox strain of Rabies virus in southern Ontario.

Genetic-variant analysis of rabies viruses provides the most sensitive epidemiologic tool for following the spread and persistence of these viruses in their wildlife hosts. Since its introduction by a southern epizootic movement that began in the far north, the arctic fox (AFX) strain of Rabies virus has been enzootic in Ontario for almost 50 y. Prior genetic studies identified 4 principal genetic variants (ONT.T1 to ONT.T4) that were localized to different regions of the province; furthermore, these viruses could be distinguished from the variant circulating in northern regions of Quebec, Newfoundland, and arctic zones, ARC.T5. Despite an intensive provincial control program undertaken over the last decade that involved aerial distribution of baits laden with rabies vaccine to combat fox rabies throughout the enzootic zone of Ontario, pockets of rabies activity persist. Re-evaluation of the genetic characteristics of the viral variants circulating in these areas of persistence has been undertaken. These data demonstrate that the recent outbreaks are, with 1 exception, due to persistence of the regional variant first identified in the area in the early 1990s. In contrast, the disease in the Georgian Bay area is a consequence of the incursion of a variant previously found further south. An outbreak that occurred in northern Ontario north and west of North Bay and in the neighboring border areas of Quebec in 2000-2001 was due to renewed incursion of the ARC.T5 variant from more northerly areas.

Animals↗
PubMed2004

Gene conversion and functional divergence in the beta-globin gene family.

Different models of gene family evolution have been proposed to explain the mechanism whereby gene copies created by gene duplications are maintained and diverge in function. Ohta proposed a model which predicts a burst of nonsynonymous substitutions following gene duplication and the preservation of duplicates through positive selection. An alternative model, the duplication-degeneration-complementation (DDC) model, does not explicitly require the action of positive Darwinian selection for the maintenance of duplicated gene copies, although purifying selection is assumed to continue to act on both copies. A potential outcome of the DDC model is heterogeneity in purifying selection among the gene copies, due to partitioning of subfunctions which complement each other. By using the d(N)/ d(S) (omega) rate ratio to measure selection pressure, we can distinguish between these two very different evolutionary scenarios. In this study we investigated these scenarios in the beta-globin family of genes, a textbook example of evolution by gene duplication. We assembled a comprehensive dataset of 72 vertebrate beta-globin sequences. The estimated phylogeny suggested multiple gene duplication and gene conversion events. By using different programs to detect recombination, we confirmed several cases of gene conversion and detected two new cases. We tested evolutionary scenarios derived from Ohta's model and the DDC model by examining selective pressures along lineages in a phylogeny of beta-globin genes in eutherian mammals. We did not find significant evidence for an increase in the omega ratio following major duplication events in this family. However, one exception to this pattern was the duplication of gamma-globin in simian primates, after which a few sites were identified to be under positive selection. Overall, our results suggest that following gene duplications, paralogous copies of beta-globin genes evolved under a nonepisodic process of functional divergence.

Animals↗
PubMed1998

Major gene control of human body height, weight and BMI in five ethnically different populations.

Pedigree samples were collected from five ethnically and geographically different populations: Kirghizians, Turkmenians, Chuvashians, Israelis and Mexicans. All studied individuals were assessed for body height, weight and BMI. The sample size in the studied pedigrees ranged from 381 to 1811 individuals. Segregation analysis of these traits preliminarily adjusted for sex and age was performed by means of program package MAN that provides parameter estimates for the major gene effects, for the residual within the genotype correlations between relatives and for the assortative mating. By the usual transmission probability tests, the 'environmental' model was strongly rejected for all measured traits in all 5 populations. The major gene mode of inheritance, however, was accepted for all traits. The results of analysis in 5 populations were remarkably similar, and showed that except for Mexican sample, the proportion of variance attributable to major gene effect ranged between 37 and 53% for body weight and height. In the Mexican sample it explained only about 14% of the body weight variation. The proportion of inter-individual variation in BMI attributable to major gene effect was consistently lower in all populations in comparison with height and weight and ranged between 17 and 40%. Strong assortative mating in body height, as estimated by correlation between putative major gene genotypes in spouses, was found in four populations, not including Mexican pedigrees.

Adolescent↗
PubMed1995

Effective size of populations under selection.

Equations to approximate the effective size (Ne) of populations under continued selection are obtained that include the possibility of partial full-sib mating and other systems such as assortative mating. The general equation for the case of equal number of sexes and constant number of breeding individuals (N) is Ne = 4N/[2(1 - alpha I) + (Sk2 + 4Q2C2) (1 + alpha I + 2 alpha O)], where Sk2 is the variance of family size due to sampling without selection, C2 is the variance of selective advantages among families (the squared coefficient of variation of the expected number of offspring per family), alpha I is the deviation from Hardy-Weinberg proportions, alpha O is the correlation between genes of male and female parents, and Q2 is the term accounting for the cumulative effect of selection on an inherited trait. This is obtained as Q = 2/[2 - G(1 + r)], where G is the remaining proportion of genetic variance in selected individuals and r is the correlation of the expected selective values of male and female parents. The method is also extended to the general case of different numbers of male and female parents. The predictive value of the formulae is tested under a model of truncation selection with the infinitesimal model of gene effects, where C2 and G are a function of the selection intensity, the heritability and the intraclass correlation of sibs. Under random mating r = alpha I = -1/(N - 1) and alpha O = 0. Under partial full-sib mating with an average proportion beta of full-sib matings per generation, r approximately beta and alpha O approximately alpha I approximately beta/(4 - 3 beta). The prediction equation is compared to other approximations based on the long-term contributions of ancestors to descendants. Finally, based on the approach followed, a system of mating (compensatory mating) is proposed to reduce rates of inbreeding without loss of response in selection programs in which selected individuals from the largest families are mated to those from the smallest families.

Animals↗
PubMed2000

Common and rare ABCA1 variants affecting plasma HDL cholesterol.

Mutations in ABCA1, a member of the ATP-binding cassette family, have been shown to underlie Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA), which are genetic disorders that are characterized by depressed concentrations of plasma high density lipoprotein (HDL) cholesterol. An important question is whether common variants within the coding sequence of ABCA1 can affect plasma HDL cholesterol in the general population. To address this issue, we developed a screening strategy to find common ABCA1 variants. This strategy involved long-range amplification of genomic DNA by using coding sequences only, followed by deep sequencing into the introns. This method helped us to characterize a new set of amplification primers, which permitted amplification of virtually all of the coding sequence of ABCA1 and its intron-exon boundaries with a single DNA amplification program. With these new sequencing primers, we found 3 novel ABCA1 mutations: a frameshift mutation (4570insA, A1484S-->X1492), a missense mutation (A986D) in a TD family, and a missense mutation (R170C) in aboriginal subjects with FHA. We also used these sequencing primers to characterize 4 novel common amino acid variants in ABCA1, in addition to 5 novel common silent variants. We tested for association of the ABCA1 I/M823 variant with plasma HDL cholesterol in Canadian Inuit and found that M823/M823 homozygotes had significantly higher plasma HDL cholesterol compared with subjects with the other genotypes. The results provide proof of principle of the effectiveness of this approach to identify both rare and common ABCA1 genomic variants and also suggest that common amino acid variation in ABCA1 is a determinant of plasma HDL cholesterol in the general population.

ATP Binding Cassette Transporter 1↗
PubMed1998

A simple method for the production of highly competent cells of Agrobacterium for transformation via electroporation.

The introduction of binary plasmids into Agrobacterium hosts for Agrobacterium-mediated transformation of plants is most readily achieved by electroporation. However, occasionally, no transformed colonies are recovered and the transformation program is delayed. Poor transformation rates are commonly associated with particular combinations of Agrobacterium strains and plasmid-selection markers. In order to avoid this problem, it is important for the bacteria to have a highly competent status for reception of plasmid DNA. It is also important to optimize the level of antibiotic for the selection of transformed colonies. In this article, we demonstrate that transformation competence is strongly related to the phase of growth at which a bacterial culture is prepared for electroporation, and we describe a simple procedure that allows the level of transformation-competent cells to be maximized. We have observed that there is significant variation between transformed Agrobacterium strains in the levels of antibiotic tolerance; we define the antibiotic levels that are appropriate for selection of three Argobacterium tumefaciens (EHA101, LBA4404, C58) and two Agrobacterium rhizogenes (LBA9402, Ar2626) strains, transformed with three alternative resistance markers (spectinomycin(res), kanamycin(res), and gentamycin(res)).

Agrobacterium tumefaciens↗
PubMed1987

Ethics of reproductive technology: AFS recommendations, dissent.

The Ethics Committee of the American Fertility Society recently released its report, "Ethical Considerations of the New Reproductive Technologies." The report examines general ethical, legal, and biological aspects of and makes ethical recommendations on procreative technologies, from standard in vitro fertilization, through all its possible variations and accompaniments, including donor gametes and preembryos, surrogate mothers, and cryopreservation. The judgment of ethical acceptability of third-party involvement in reproductive technology is the report's weakest aspect. The potential impact of such participation was not sufficiently weighed because of primacy given to a single value: the provision of a baby to an individual couple, or even an individual, who could not otherwise have one. A dissent to the report is based on two analyses: Third-party involvement itself violates the marriage covenant, independent of any potential damaging effects or benefits, and relaxation of marital exclusivity could harm the marriage (and marriage in general) and the prospective child. The committee also failed to resolve the problem of preembryo status. Instead, it recommended that local programs offering reproductive assistance draw up their own policies.

Advisory Committees↗
PubMed2005

Nonstructural 5A gene variability of hepatitis C virus (HCV) during a 10-year follow up.

BACKGROUND: Seven patients with chronic hepatitis C virus (HCV) infection were followed up for 10 years in order to analyze the molecular evolution of the HCV nonstructural 5A (NS5A) gene. METHODS: Serum samples were obtained from seven patients with anti-HCV who were HCV-RNA positive. The HCV NS5A region, including the interferon sensitivity-determining region (ISDR), protein kinase R binding domain (PKR-BD), and V3 was amplified and cloned, and then sequenced. The nucleotide sequences of the region at the beginning and at the end of the 10 years were aligned with the CLUSTAL W program, version 1.8, and the corresponding amino-acid sequences were deduced. RESULTS: The three serine residues at positions 2197, 2201, and 2204, suggested to be important for hyperphosphorylation of NS5A, were highly conserved in different patients and were within the quasispecies of each patient. The wild-type ISDR or minimally mutated strain was dominant in all the patients and the number of quasispecies decreased over time. CONCLUSIONS: Our findings showed that the functional domains of NS5A were generally conserved over an interval of 10 years. Quasispecies distribution was variable and distinctly clustered over time during the natural course of HCV infection. These results may contribute to better understanding of HCV natural infection.

Adult↗
PubMed2001

A tournament of linkage tests in complex inheritance.

The performance of some weakly parametric linkage tests in common use was compared on 200 replicates of oligogenic inheritance from Genetic Analysis Workshop 10. Each random sample for the quantitative trait was dichotomized at different thresholds and also selected through 2 affected sibs, generating 8 combinations of sample and variable. The variance component program SOLAR performed best with a continuous trait, even in selected samples, when the population mean was used. The sib-pair program SIBPAL2 was best in most other cases when the phenotype product, population mean, and empirical estimates of pair correlations were used. The BETA program that introduced phenotype products was slightly more powerful than maximum likelihood scores under the null hypothesis and approached but did not exceed SIBPAL2 under its optimal conditions. Type I errors generally exceeded expectations from a chi(2) test, but were conservative with respect to bounds on lods. All methods can be improved by use of the population mean, empirical correlations, logistic representation for affection status, and correct lods for samples that favour the null hypothesis. It remains uncertain whether all information can be extracted by weakly parametric methods and whether correction for ascertainment bias demands a strongly parametric model. Performance on a standard set of simulated data is indispensable for recognising optimal methods.

Algorithms↗