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PubMed2005

Power function of the reference change value in relation to cut-off points, reference intervals and index of individuality.

The reference change value, defined as RCV = 1.96 x 2(1/2) x(s(I)(2) +s A(2))(1/2), where s(I) is within-subject biological variation and s A is analytical variation, has been used for many years to take clinical decisions in patient monitoring. Furthermore, the index of individuality was defined as II = (s(I)(2) +s(A)(2))(1/2)/s(G) , where s(G) is the between-subject biological variation. This index has been simplified by later authors to s(I)/s(G) and has been used in monitoring situations to determine the utility of population-based reference intervals. Harris stated that when the index of individuality is lower than 0.6, the specific reference interval of the individual - when available - is better than the population-based reference interval. However, if a change within a patient is equivalent to the RCV applied for the significant difference between two measurements, the probability of detecting this change is only 50% (the same probability of missing it). Therefore, to obtain a higher probability of detecting a change by the RCV (e.g., 90%) the interpretation of the index of individuality has to be reconsidered. This contribution compares the power of the RCV to the use of cut-off points and population-based reference intervals. The benefits of the RCV compared to the distance to cut-off point or reference limit are also described in relation to the index of individuality.

Analysis of Variance↗
PubMed2004

Sex-specific meiotic drive and selection at an imprinted locus.

We present a one-locus model that breaks two symmetries of Mendelian genetics. Whereas symmetry of transmission is breached by allowing sex-specific segregation distortion, symmetry of expression is breached by allowing genomic imprinting. Simple conditions for the existence of at least one polymorphic stable equilibrium are provided. In general, population mean fitness is not maximized at polymorphic equilibria. However, mean fitness at a polymorphic equilibrium with segregation distortion may be higher than mean fitness at the corresponding equilibrium with Mendelian segregation if one (or both) of the heterozygote classes has higher fitness than both homozygote classes. In this case, mean fitness is maximized by complete, but opposite, drive in the two sexes. We undertook an extensive numerical analysis of the parameter space, finding, for the first time in this class of models, parameter sets yielding two stable polymorphic equilibria. Multiple equilibria exist both with and without genomic imprinting, although they occurred in a greater proportion of parameter sets with genomic imprinting.

Chromosome Mapping↗
PubMed2004

Application of coalescent methods to reveal fine-scale rate variation and recombination hotspots.

There has been considerable recent interest in understanding the way in which recombination rates vary over small physical distances, and the extent of recombination hotspots, in various genomes. Here we adapt, apply, and assess the power of recently developed coalescent-based approaches to estimating recombination rates from sequence polymorphism data. We apply full-likelihood estimation to study rate variation in and around a well-characterized recombination hotspot in humans, in the beta-globin gene cluster, and show that it provides similar estimates, consistent with those from sperm studies, from two populations deliberately chosen to have different demographic and selectional histories. We also demonstrate how approximate-likelihood methods can be used to detect local recombination hotspots from genomic-scale SNP data. In a simulation study based on 80 100-kb regions, these methods detect 43 out of 60 hotspots (ranging from 1 to 2 kb in size), with only two false positives out of 2000 subregions that were tested for the presence of a hotspot. Our study suggests that new computational tools for sophisticated analysis of population diversity data are valuable for hotspot detection and fine-scale mapping of local recombination rates.

DNA↗
PubMed2004

A separation-of-timescales approach to the coalescent in a continuous population.

This article presents an analysis of a model of isolation by distance in a continuous, two-dimensional habitat. An approximate expression is derived for the distribution of coalescence times for a pair of sequences sampled from specific locations in a rectangular habitat. Results are qualitatively similar to previous analyses of isolation by distance, but account explicitly for the location of samples relative to the habitat boundaries. A separation-of-timescales approach takes advantage of the fact that the sampling locations affect only the recent coalescent behavior. When the population size is larger than the number of generations required for a lineage to cross the habitat range, the long-term genealogical process is reasonably well described by Kingman's coalescent with time rescaled by the effective population size. This long-term effective population size is affected by the local dispersal behavior as well as the geometry of the habitat. When the population size is smaller than the time required to cross the habitat, deep branches in the genealogy are longer than would be expected under the standard neutral coalescent, similar to the pattern expected for a panmictic population whose population size was larger in the past.

Data Interpretation, Statistical↗
PubMed2004

Robust transmission/disequilibrium test for incomplete family genotypes.

Several solutions have been proposed to extend the transmission disequilibrium test (TDT) to include cases with missing parental genotype. However, completion of the missing parental genotype may bias the test if the underlying missing data mechanism is informative. Furthermore, all these solutions resolve the problem of missing parental genotype, while offspring with missing genotypes are typically ignored. We propose here an extension to the TDT, called robust TDT (rTDT), able to handle incomplete genotypes on both parents and children and that does not rest on any assumption about the missing data mechanism. rTDT returns minimum and maximum values of TDT that are consistent with all the possible completions of the missing data. We also show that, in some situations, rTDT can achieve both greater power and greater significance than the popular TDT analysis of incomplete data. rTDT is applied to a database of markers of susceptibility to Crohn's disease and it shows that only 2 of the 11 markers originally associated with the phenotype do not depend on assumptions about the missing data mechanism.

Crohn Disease↗
PubMed2005

Quantitative trait Loci analysis using the false discovery rate.

False discovery rate control has become an essential tool in any study that has a very large multiplicity problem. False discovery rate-controlling procedures have also been found to be very effective in QTL analysis, ensuring reproducible results with few falsely discovered linkages and offering increased power to discover QTL, although their acceptance has been slower than in microarray analysis, for example. The reason is partly because the methodological aspects of applying the false discovery rate to QTL mapping are not well developed. Our aim in this work is to lay a solid foundation for the use of the false discovery rate in QTL mapping. We review the false discovery rate criterion, the appropriate interpretation of the FDR, and alternative formulations of the FDR that appeared in the statistical and genetics literature. We discuss important features of the FDR approach, some stemming from new developments in FDR theory and methodology, which deem it especially useful in linkage analysis. We review false discovery rate-controlling procedures--the BH, the resampling procedure, and the adaptive two-stage procedure-and discuss the validity of these procedures in single- and multiple-trait QTL mapping. Finally we argue that the control of the false discovery rate has an important role in suggesting, indicating the significance of, and confirming QTL and present guidelines for its use.

Chromosome Mapping↗
PubMed2006

Reinforcement and the genetics of hybrid incompatibilities.

Recent empirical studies suggest that genes involved in speciation are often sex-linked. We derive a general analytic model of reinforcement to study the effects of sex linkage on reinforcement under three forms of selection against hybrids: one-locus, two-locus, and ecological incompatibilities. We show that the pattern of sex linkage can have a large effect on the amount of reinforcement due to hybrid incompatibility. Sex linkage of genes involved in postzygotic isolation generally increases the strength of reinforcement, but only if genes involved in prezygotic isolation are also sex linked. We use exact simulations to test the accuracy of the approximation and find that qualitative predictions made assuming weak selection can hold when selection is strong. Our simulations also show that incompatibilities that evolve in allopatry by drift or weak selection are likely to be lost by swamping during secondary contact, even when selection against hybrids is strong.

Alleles↗
PubMed2006

Association mapping with single-feature polymorphisms.

We develop methods for exploiting "single-feature polymorphism" data, generated by hybridizing genomic DNA to oligonucleotide expression arrays. Our methods enable the use of such data, which can be regarded as very high density, but imperfect, polymorphism data, for genomewide association or linkage disequilibrium mapping. We use a simulation-based power study to conclude that our methods should have good power for organisms like Arabidopsis thaliana, in which linkage disequilibrium is extensive, the reason being that the noisiness of single-feature polymorphism data is more than compensated for by their great number. Finally, we show how power depends on the accuracy with which single-feature polymorphisms are called.

Algorithms↗
PubMed2006

The Hill-Robertson effect and the evolution of recombination.

In finite populations, genetic drift generates interference between selected loci, causing advantageous alleles to be found more often on different chromosomes than on the same chromosome, which reduces the rate of adaptation. This "Hill-Robertson effect" generates indirect selection to increase recombination rates. We present a new method to quantify the strength of this selection. Our model represents a new beneficial allele (A) entering a population as a single copy, while another beneficial allele (B) is sweeping at another locus. A third locus affects the recombination rate between selected loci. Using a branching process model, we calculate the probability distribution of the number of copies of A on the different genetic backgrounds, after it is established but while it is still rare. Then, we use a deterministic model to express the change in frequency of the recombination modifier, due to hitchhiking, as A goes to fixation. We show that this method can give good estimates of selection for recombination. Moreover, it shows that recombination is selected through two different effects: it increases the fixation probability of new alleles, and it accelerates selective sweeps. The relative importance of these two effects depends on the relative times of occurrence of the beneficial alleles.

Alleles↗
PubMed2006

Mammalian mRNA splice-isoform selection is tightly controlled.

Post-transcriptional RNA processing is an important regulatory control mechanism for determining the phenotype of eukaryotic cells. The processing of a transcribed RNA species into alternative splice isoforms yields products that can perform different functions. Each type of cell in a multi-cellular organism is presumed to actively control the relative quantities of alternative splice isoforms. In this study, the alternatively spliced isoforms of five mRNA transcription units were examined by quantitative reverse transcription-PCR amplification. We show that interindividual variation in splice-isoform selection is very highly constrained when measured in a large population of genetically diverse mice (i.e., full siblings; N = 150). Remarkably, splice-isoform ratios are among the most invariant phenotypes measured in this population and are confirmed in a second, genetically distinct population. In addition, the patterns of splice-isoform selection show tissue-specific and age-related changes. We propose that splice-isoform selection is exceptionally robust to genetic and environmental variability and may provide a control point for cellular homeostasis. As a consequence, splice-isoform ratios may be useful as a practical quantitative measure of the physiological status of cells and tissues.

Age Factors↗
PubMed2004

Intron size correlates positively with recombination rate in Caenorhabditis elegans.

A negative correlation between intron size and recombination rate has been reported for the Drosophila melanogaster and human genomes. Population-genetic models suggest that this pattern could be caused by an interaction between recombination rate and the efficacy of natural selection. To test this idea, we examined variation in intron size and recombination rate across the genome of the nematode Caenorhabditis elegans. Interestingly, we found that intron size correlated positively with recombination rate in this species.

Animals↗
PubMed2004

Whole-genome scan in thelytokous-laying workers of the Cape honeybee (Apis mellifera capensis): central fusion, reduced recombination rates and centromere mapping using half-tetrad analysis.

While workers of almost all subspecies of honeybee are able to lay only haploid male eggs, Apis mellifera capensis workers are able to produce diploid female eggs by thelytokous parthenogenesis. Cytological analyses have shown that during parthenogenesis, egg diploidy is restored by fusion of the two central meiotic products. This peculiarity of the Cape bee preserves two products of a single meiosis in the daughters and can be used to map centromere positions using half-tetrad analysis. In this study, we use the thelytokous progenies of A. m. capensis workers and a sample of individuals from a naturally occurring A. m. capensis thelytokous clone to map centromere position for most of the linkage groups of the honeybee. We also show that the recombination rate is reduced by >10-fold during the meiosis of A. m. capensis workers. This reduction is restricted to thelytokous parthenogenesis of capensis workers and is not observed in the meiosis of queen within the same subspecies or in arrhenotokous workers of another subspecies. The reduced rate of recombination seems to be associated with negative crossover interference. These results are discussed in relation to evolution of thelytokous parthenogenesis and maintenance of heterozygosity and female sex after thelytoky.

Animals↗
PubMed2006

Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population.

Regulatory T lymphocytes play a crucial role in modulating potentially self-reactive clones, and dysfunction of this cell type contributes to autoimmune disease. FOXP3 is a critical determinant of CD(4+)CD(25+)T regulatory (T(reg)) cell development and function. The aim of this study was to investigate whether genetic polymorphisms at the FOXP3 locus predispose to autoimmune endocrinopathies. Five single nucleotide polymorphisms (SNPs) and two microsatellite polymorphisms were genotyped in our Caucasian cohorts of 633 unrelated Graves' disease (GD) subjects, 104 autoimmune Addison's disease (AAD) subjects and 528 healthy controls. SNP genotyping was performed by either restriction enzyme digestion or by primer-extension-MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) assay. Microsatellites were analysed using fluorescent PCR. Case-control analysis was performed using chi(2) testing on contingency tables for allele frequency. Haplotype analysis was performed using the UNPHASED package. No evidence for disease association was found with any of the seven polymorphisms in either of the GD or AAD subjects as compared with controls (P = 0.26-0.94). Haplotype analysis found a weak evidence for the association of a minor haplotype with GD; this was not significant when corrected for multiple testing. This study has found no robust evidence that FOXP3 gene polymorphism contributes to the susceptibility to GD or AAD in the UK population.

Addison Disease↗
PubMed2006

The relationship of transforming growth factor-beta1 gene polymorphism, its plasma level, and gingival overgrowth in renal transplant recipients receiving different immunosuppressive regimens.

BACKGROUND: Cyclosporin A (CsA) induces gingival overgrowth (GO) in patients who seem to be prone to this disorder. It is still impossible to determine which patients will develop GO. Patients treated with the new immunosuppressive drug tacrolimus seem not to have GO. The aims of this study were to investigate transforming growth factor-beta1 (TGF-beta1) gene polymorphisms in renal transplant recipients treated with CsA or tacrolimus and to establish an association between these polymorphisms and TGF-beta1 plasma concentration and the incidence of GO. METHODS: The examined group consisted of 134 renal transplant recipients. Ninety-two underwent CsA treatment (50 with and 42 without GO), and 42 underwent tacrolimus treatment. Age, gender, time after transplantation, calcineurin inhibitor total dosage, number of teeth, and sulcus bleeding index were analyzed. TGF-beta1 plasma levels were estimated in 60 CsA- and 30 tacrolimus-treated patients. Two biallelic polymorphisms of the TGF-beta1 gene were studied at codon 10 (at position +869) and at codon 25 (at position +915) in patients from the examined group and in 108 healthy volunteers (the control group). RESULTS: The distribution of the high, intermediate, and low TGF-beta1 producer phenotypes was comparable in all the studied groups and in the healthy controls. The high producer phenotype was more frequent in patients with GO. TGF-beta1 levels in the CsA group showed correlation with the phenotypes. The lowest incidence of GO was observed in the 10C/C genotype, whereas the highest was observed in the 10T/C genotype. CONCLUSION: High and intermediate TGF-beta1 producer phenotypes and heterozygous genotype 10T/C might be considered risk factors for GO in patients treated with CsA.

Adult↗
PubMed2002

Influence of GSTT1 and GSTM1 genotypes on sunburn sensitivity.

BACKGROUND: Exposure to sunlight may cause sunburn, skin cancer or phototoxic reactions to certain drugs such as Hypericum extract. All these are ultraviolet B (UVB)-mediated reactions which may be modulated by individual genetic susceptibility. UVB exposure results in oxidative stress. Many products of oxidative stress are detoxified by glutathione-S-transferases mu 1 (GSTM1) and theta 1 (GSTT1). Deletion polymorphisms (genotype *0/*0) of GSTM1 and GSTT1 occur in 50% and 20% of Caucasians, respectively. By affecting the individual ability to detoxify oxidative stress-related products, they may influence the severity of the cutaneous photoreaction. METHODS: Minimal erythema doses (MED) of UVB irradiation on the skin were determined in 110 subjects who were selected according to their GSTT1 genotype (28 GSTT1*0/*0, 54 GSTT1*A/*0, and 28 GSTT1*A/*A). Genotypes were detected with novel polymerase chain reaction (PCR) assays that allow the differentiation between homozygous and heterozygous GSTT1 and GSTM1 deletions. RESULTS: In the absence of GSTT1 enzyme, the susceptibility of individuals to UVB-induced inflammatory skin reactions increased significantly (p = 0.02, ANCOVA). 'Gene-equivalents' were calculated from the number of functional GSTM1 and GSTT1 alleles as a measure of the gene-dose. UVB sensitivity correlated with gene dose up to a threshold above which additional GSTT1 or GSTM1 alleles did not provide additional protection. Volunteers who were homozygously deficient in GSTT1 and GSTM1 were most sensitive to UVB. Interestingly, individuals with high GSTM1 gene-doses showed increased photosensitization after administration of Hypericum extract (St. John's wort). CONCLUSION: Individuals harboring the *0/*0 genotype of GSTT1 and/or GSTM1 showed enhanced UVB-induced cutaneous damage. Moreover, GST genotypes modulated Hypericum-induced photosensitization.

Adolescent↗
PubMed2005

SeqState: primer design and sequence statistics for phylogenetic DNA datasets.

Choosing and designing primers based on available DNA sequence data and statistical contrasting of domains or structural features is a common routine among molecular biologists. Currently available, free software tools were found to lack desirable features related to these tasks. This was the motivation for developing a new program, SeqState. SeqState locates regions that remain to be sequenced in phylogenetic DNA datasets, evaluates user-provided primers and selects primers best suited to fill gaps in the sequences. If the primers provided by the user are unsuitable, new primers are designed. Primers can be loaded from a primer database, be supplied as part of the alignment or be entered manually. The position of internal primers is automatically localised in the loaded data file. Primers can be edited, and changes and new primers can be saved to the database. Primer sheets allow the user to view internal dimers, complements to a second primer, mismatches to all loaded sequences, and other primer characteristics. Calculation of various sequence statistics can be requested for the whole dataset or parts thereof (character sets), with standard errors estimated by bootstrapping. Insertion-deletion events can be evaluated statistically and encoded for subsequent phylogenetic analysis according to several published coding principles.

Algorithms↗
PubMed2005

Divergent selection for uterine capacity in rabbits. I. Genetic parameters and response to selection.

A 10-generation divergent selection experiment for uterine capacity (UC) measured as litter size in unilaterally ovariectomized females was carried out in rabbits. A total of 2,996 observations on uterine capacity of does (up to four parities) was recorded. Laparoscopy was performed at d 12 of their second gestation, and ovulation rate (OR) and number of implanted embryos (IE) were recorded in 735 does. Prenatal survival (PS) was assessed as UC/OR, embryo survival (ES) as IE/OR, and fetal survival (FS) as UC/IE. Genetic parameters and genetic trends were inferred using Bayesian methods. Marginal posterior distributions of all unknowns were estimated by Gibbs sampling. Heritabilities of UC, OR, IE, ES, FS, and PS were 0.11, 0.32, 0.22, 0.04, 0.14, and 0.09, respectively. Genetic and phenotypic correlations between FS and ES were low, suggesting different biological mechanisms for the two periods of survival. After 10 generations of selection, the divergence was approximately 1.5 rabbits, or approximately 1% per generation. Approximately one-half of this response was obtained in the first two generations of selection, which may suggest the presence of a major gene segregating in the base population.

Animals↗
PubMed2005

Estimation of correlation between maternal permanent environmental effects of related dams in beef cattle.

Weaning weights from Gelbvieh (GV; n = 82,138) and Limousin (LM; n = 88,639) calves were used to estimate genetic and environmental variance components with models that included different values for the correlation (lambda) between permanent environmental effects of dams and their daughters. Each analysis included fixed discrete effects of contemporary group, sex of calf, age of dam at calving, and month of calving, a fixed continuous effect of age of calf, random direct and maternal additive genetic effects, permanent environmental effects due to dams, and residual effects. The REML procedure was employed with a "grid search," in which the likelihood was computed for a series of values for lambda. For both breeds, models that included a nonzero value for lambda fitted the data significantly better than the model that did not include lambda. The maximum restricted likelihood was obtained for lambda of approximately -0.2 for both breeds. Estimates of residual and direct genetic variances were similar for all values of lambda, including zero; however, estimates of maternal genetic variance and maternal heritability increased slightly, and maternal permanent environmental variance and the proportion of the maternal variance to the total (phenotypic) variance decreased slightly, when the correlated structure for permanent environmental effects was assumed. As the value of lambda became more negative, absolute values of the direct-maternal genetic covariance and direct-maternal correlation estimates were decreased. Pearson and rank correlations for direct genetic, maternal genetic, and maternal environmental effects estimated with and without lambda were very high (>0.99). These results indicated that the linear relationship between maternal permanent environmental effects of dams and their daughters for weaning weight is negative but low in both breeds. Considering this relationship in the operational model did not significantly affect estimated breeding values, and thus, it may not be important in genetic evaluations.

Animals↗