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C S Haley

Publications and source records attributed to C S Haley.

At least 37 records · Page 2Linked to original sources
PubMed2002

Simple deterministic identity-by-descent coefficients and estimation of QTL allelic effects in full and half sibs.

Accurate and rapid methods for the detection of quantitative trait loci (QTLs) and evaluation of consequent allelic effects are required to implement marker-assisted selection in outbred populations. In this study, we present a simple deterministic method for estimating identity-by-descent (IBD) coefficients in full- and half-sib families that can be used for the detection of QTLs via a variance-component approach. In a simulated dataset, IBD coefficients among sibs estimated by the simple deterministic and Markov chain Monte Carlo (MCMC) methods with three or four alleles at each marker locus exhibited a correlation of greater than 0.99. This high correlation was also found in QTL analyses of data from an outbred pig population. Variance component analysis used both the simple deterministic and MCMC methods to estimate IBD coefficients. Both procedures detected a QTL at the same position and gave similar test statistics and heritabilities. The MCMC method, however, required much longer computation than the simple method. The conversion of estimated QTL genotypic effects into allelic effects for use in marker-assisted selection is also demonstrated.

Animals↗
PubMed2002

Approaches to interval mapping of QTL in a multigeneration pedigree: the example of porcine chromosome 4.

Quantitative trait loci (QTLs) have been mapped in many studies of F2 populations derived from crosses between diverse lines. One approach to confirming these effects and improving the mapping resolution is genetic chromosome dissection through a backcrossing programme. Analysis by interval mapping of the data generated is likely to provide additional power and resolution compared with treating data marker by marker. However, interval mapping approaches for such a programme are not well developed, especially where the founder lines were outbred. We explore alternative approaches to analysis using, as an example, data from chromosome 4 in an intercross between wild boar and Large White pigs where QTLs have been previously identified. A least squares interval mapping procedure was used to study growth rate and carcass traits in a subsequent second backcross generation (BC2). This procedure requires the probability of inheriting a wild boar allele for each BC2 animal for locations throughout the chromosome. Two methods for obtaining these probabilities were compared: stochastic or deterministic. The two methods gave similar probabilities for inheriting wild boar alleles and, hence, gave very similar results from the QTL analysis. The deterministic approach has the advantage of being much faster to run but requires specialized software. A QTL for fatness and for growth were confirmed and, in addition, a QTL for piglet growth from weaning at 5 weeks up to 7 weeks of age and another for carcass length were detected.

Alleles↗
PubMed2002

No detectable association of the ESR PvuII mutation with sow productivity in a Meishan x Large White F2 population.

The polymorphism at the PvuII recognition site in the ESR gene showed no statistically significant association with sow productivity traits in a Meishan x Large White F2 population. Estimates of the effect on litter size were, however, in the opposite direction and statistically different from previously published estimates. Taken together with results from other publications, results here indicate that this PvuII polymorphism displays different degrees of linkage disequilibrium with a gene or genes controlling litter size in different populations.

Animals↗
PubMed2002

Mapping of quantitative trait loci for body weight at three, six, and nine weeks of age in a broiler layer cross.

An F2 chicken population was established from a cross of a broiler sire-line and an egg laying (White Leghorn) line. There were two males and two females from both lines in the base population. The F1 progeny consisted of 8 males and 32 females. Over 500 F2 offspring from five hatches were reared to slaughter at a live weight of 2 kg at 9 wk of age. Body weights at 3, 6, and 9 wk were recorded. The DNA was extracted from blood samples, and genotypes for 101 microsatellite markers were determined. Data of 466 individuals from 30 families were available for analysis. Interval mapping QTL analyses were carried out. The QTL significant at the genome wide level that affected body weight at two ages were identified on chromosomes 1, 2, 4, 7, and 8 and a QTL on Chromosome 13 influenced body weight at all three ages. Genetic effects were generally additive, and the broiler allele increased body weight in all cases. The effects for significant individual QTL accounted for between 0.2 and 1.0 phenotypic standard deviations and the sum of the additive effects accounted for approximately 0.75 of the line difference in body weight at 6 wk of age. The largest single additive effect was on chromosome 4, and the effect of substituting one copy of the gene was an increase in weight of 249 g. Interactions of the QTL with sex or family were unimportant. There was no evidence for imprinting or of two or more QTL at the same location for any of the traits.

Aging↗
PubMed2001

Right ventricular hypertrophy secondary to pulmonary hypertension is linked to rat chromosome 17: evaluation of cardiac ryanodine Ryr2 receptor as a candidate.

BACKGROUND: Fischer 344 (F344) rats are relatively resistant to hypoxia-induced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the differential response. METHODS AND RESULTS: Male F(2) offspring from an F344xWKY intercross were exposed to hypoxia (10% O(2)) for 3 weeks, and pulmonary artery pressure and cardiac chamber weights were measured. Genomic DNA was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identified on rat chromosome 17 (lod score 6.5) that accounted for 22% of the total variance of RV weight in the F(2) population and was independent of pulmonary artery pressure. The peak was centered over marker D17Rat41, close to Chrm3, with a 1-lod support interval of 5 cM. Comparison of homologous regions in mice and humans suggested that Ryr2, the cardiac isoform of the ryanodine receptor, colocalizes with our QTL. A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene Chrm3 within our QTL. [(3)H]Ryanodine binding to cardiac membranes from the parental strains showed a 21% reduction in B(max) in the WKY compared with the F344 strain, with no difference in K:(d). CONCLUSIONS: These data provide the first demonstration of a QTL linked to the RV response to hypoxia-induced pulmonary hypertension. The Ryr2 receptor gene lies within this QTL and merits further investigation as a candidate for this differential RV response.

Animals↗
PubMed2001

Using the mixed model for interval mapping of quantitative trait loci in outbred line crosses.

Interval mapping by simple regression is a powerful method for the detection of quantitative trait loci (QTLs) in line crosses such as F2 populations. Due to the ease of computation of the regression approach, relatively complex models with multiple fixed effects, interactions between QTLs or between QTLs and fixed effects can easily be accommodated. However, polygenic effects, which are not targeted in QTL analysis, cannot be treated as random effects in a least squares analysis. In a cross between true inbred lines this is of no consequence, as the polygenic effect contributes just to the residual variance. In a cross between outbred lines, however, if a trait has high polygenic heritability, the additive polygenic effect has a large influence on variation in the population. Here we extend the fixed model for the regression interval mapping method to a mixed model using an animal model. This makes it possible to use not only the observations from progeny (e.g. F2), but also those from the parents (F1) to evaluate QTLs and polygenic effects. We show how the animal model using parental observations can be applied to an outbred cross and so increase the power and accuracy of QTL analysis. Three estimation methods, i.e. regression and an animal model either with or without parental observations, are applied to simulated data. The animal model using parental observations is shown to have advantages in estimating QTL position and additive genotypic value, especially when the polygenic heritability is large and the number of progeny per parent is small.

Animals↗
PubMed2001

Selection and subsequent analysis of sib pair data for QTL detection.

Haseman and Elston (1972) developed a robust regression method for the detection of linkage between a marker and a quantitative trait locus (QTL) using sib pair data. The principle underlying this method is that the difference in phenotypes between pairs of sibs becomes larger as they share a decreasing number of alleles at a particular QTL identical by descent (IBD) from their parents. In this case, phenotypically very different sibs will also on average share a proportion of alleles IBD at any marker linked to the QTL that is lower than the expected value of 0.5. Thus, the deviation of the proportion of marker alleles IBD from the expected value in pairs of sibs selected to be phenotypically different (i.e. discordant) can provide a test for the presence of a QTL. A simple regression method for QTL detection in sib pairs selected for high phenotypic differences is presented here. The power of the analytical method was found to be greater than the power obtained using the standard analysis when samples of sib pairs with high phenotypic differences were used. However, the use of discordant sib pairs was found to be less powerful for QTL detection than alternative selective genotyping schemes based on the phenotypic values of the sibs except with intense selection, when its advantage was only marginal. The most effective selection scheme overall was the use of sib pairs from entire families selected on the basis of high within-family variance for the trait in question. There is little effect of selection on QTL position estimates, which are in good agreement with the simulated values. However, QTL variance estimates are biased to a greater or lesser degree, depending on the selection method.

Biological Evolution↗
PubMed2001

Genome-wide search for loci controlling serum IGF binding protein levels of mice.

A segregating F(2) pedigree based on two mouse lines (DU6i and DBA/2) with extremely different growth characteristics was generated to search for loci affecting serum levels of insulin-like growth factor (IGF) binding proteins (IGFBPs) and to estimate their effects on growth and body composition. DU6i is characterized by high body mass and obesity associated with hyperinsulinemia, hyperleptinemia, and elevated serum IGF-I concentrations. Furthermore, significantly elevated serum levels of IGFBP-2, IGFBP-3, and IGFBP-4 were found in DU6i vs. DBA/2 mice. Linkage analysis identified loci with major effects on the serum level of IGFBP-3 on Chromosome 5 at 58 cM (Igfbp3q1; F = 9.9) and on Chromosome 10 at 46 cM (Igfbp3q2; F = 33.8). A locus significantly influencing serum IGFBP-2 levels in males was found on Chromosome 7. Additional linkage was detected in males and females for IGFBP-2 on Chromosomes 8, 11, 14, 17, and X, and for IGFBP-4 on Chromosome 4. Additional loci affecting IGFBPs acted in a sex-specific manner. The identified loci coincide in part with chromosomal regions controlling growth and obesity. Thus, multiple genes or pleiotropic gene effects may be assumed for these chromosomal regions. The identification of quantitative trait loci for IGFBPs as subcomponents of growth regulation and differentiation will further improve the understanding of complex trait regulation.

Animals↗
PubMed2001

The porcine gonadotropin-releasing hormone receptor gene (GNRHR): genomic organization, polymorphisms, and association with the number of corpora lutea.

The interaction of gonadotropin-releasing hormone (GNRH) and its receptor (GNRHR) is critical in the endocrine regulation of reproduction. The gene (GNRHR) encoding the receptor has been mapped to porcine chromosome 8. There is evidence for three quantitative trait loci (QTL) influencing ovulation rate on this chromosome. We obtained an almost complete sequence (3993 bp, excluding intron 1) of the porcine GNRHR gene using PCR-based comparative genomic walking and inverse genomic walking approaches. Twelve polymorphisms were detected by sequencing of pooled DNA of Chinese Taihu and European Large White pigs, including 7 base substitutions and 5 insertions-deletions (indels). A F2 population of Meishan x European Large White pigs was genotyped for a TG indel in the promoter region, and a C/G substitution in the 3' UTR (untranslated region). A significant association of the C/G substitution with number of corpora lutea at first parity was observed.

3' Untranslated Regions↗
PubMed2001

Genetic and physical mapping, expression analysis and partial sequence of porcine PER1.

The porcine PER1 gene was mapped to chromosome 12q1.4-->q1.5 using fluorescence in situ hybridisation. A polymorphic microsatellite marker (S0601) was isolated from a BAC clone shown to contain the PER1 gene. Linkage analysis assigned S0601 distal to ALOX12 on SSC12, providing further evidence for the conservation of synteny between HSA17 and SSC12. RT-PCR analysis demonstrated the expression of PER1 in all 11 tissues tested, consistent with the data from other mammalian species. Part of the PER1 gene was sequenced, homologous to exons 2-14 of the human gene and encoding the N-terminus of porcine PER1. The predicted amino acid sequence of the partial pig PER1 protein shares over 96% identity with its human orthologue.

Animals↗
PubMed2000

Fine mapping of trypanosomiasis resistance loci in murine advanced intercross lines.

We have previously reported the results of genome-wide searches in two murine F(2) populations for QTLs that influence survival following Trypanosoma congolense infection. Three loci, Tir1, Tir2, and Tir3, were identified and mapped to mouse Chromosomes (Chrs) 17, 5, and 1 respectively, with confidence intervals (CIs) in the range 10-40 cM. The size of these CIs is to a large degree the consequence of limited numbers of recombination events in small chromosomal regions in F(2) populations. A number of population designs have been proposed to increase recombination levels in crosses, one of which is the advanced intercross line (AIL). Here we report fine mapping of Tir1, Tir2, and Tir3 in G6 populations of two independent murine AILs created by crossing the C57BL/6J strain with the A/J and BALB/cJ strains, respectively. Data were analyzed by two methods that gave equally informative and similar results. The three QTLs were confirmed in the A/J x C57BL/6J AIL and in the combined data set, but Tir2 was apparently lost from the BALB/cJ x C57BL/6J AIL. The reduction in CIs for the Tir loci ranged from 2.5 to more than ten-fold in G6 populations by comparison with CIs obtained previously in the equivalent F(2) generations. Mapping in the AILs also resolved the Tir3 locus into three trypanosomiasis resistance QTLs, revealing a degree of complexity not evident in extensive studies at the F(2) level.

Animals↗
PubMed2000

Combined analyses of data from quantitative trait loci mapping studies. Chromosome 4 effects on porcine growth and fatness.

For many species several similar QTL mapping populations have been produced and analyzed independently. Joint analysis of such data could be used to increase power to detect QTL and evaluate population differences. In this study, data were collated on almost 3000 pigs from seven different F(2) crosses between Western commercial breeds and either the European wild boar or the Chinese Meishan breed. Genotypes were available for 31 markers on chromosome 4 (on average 8.3 markers per population). Data from three traits common to all populations (birth weight, mean backfat depth at slaughter or end of test, and growth rate from birth to slaughter or end of test) were analyzed for individual populations and jointly. A QTL influencing birth weight was detected in one individual population and in the combined data, with no significant interaction of the QTL effect with population. A QTL affecting backfat that had a significantly greater effect in wild boar than in Meishan crosses was detected. Some evidence for a QTL affecting growth rate was detected in all populations, with no significant differences between populations. This study is the largest F(2) QTL analysis achieved in a livestock species and demonstrates the potential of joint analysis.

Adipose Tissue↗
PubMed2000

Multitrait least squares for quantitative trait loci detection.

A multiple-trait QTL mapping method using least squares is described. It is presented as an extension of a single-trait method for use with three-generation, outbred pedigrees. The multiple-trait framework allows formal testing of whether the same QTL affects more than one trait (i.e., a pleiotropic QTL) or whether more than one linked QTL are segregating. Several approaches to the testing procedure are presented and their suitability discussed. The performance of the method is investigated by simulation. As previously found, multitrait analyses increase the power to detect a pleiotropic QTL and the precision of its location estimate. With enough information, discrimination between alternative genetic models is possible.

Animals↗
PubMed2000

Mapping quantitative trait loci in complex pedigrees: a two-step variance component approach.

There is a growing need for the development of statistical techniques capable of mapping quantitative trait loci (QTL) in general outbred animal populations. Presently used variance component methods, which correctly account for the complex relationships that may exist between individuals, are challenged by the difficulties incurred through unknown marker genotypes, inbred individuals, partially or unknown marker phases, and multigenerational data. In this article, a two-step variance component approach that enables practitioners to routinely map QTL in populations with the aforementioned difficulties is explored. The performance of the QTL mapping methodology is assessed via its application to simulated data. The capacity of the technique to accurately estimate parameters is examined for a range of scenarios.

Animals↗
PubMed2000

Single QTL effects, epistasis, and pleiotropy account for two-thirds of the phenotypic F(2) variance of growth and obesity in DU6i x DBA/2 mice.

Genes influencing body weight and composition and serum concentrations of leptin, insulin, and insulin-like growth factor I (IGF-I) in nonfasting animals were mapped in an intercross of the extreme high-growth mouse line DU6i and the inbred line DBA/2. Significant loci with major effects (F > 7.07) for body weight, obesity, and muscle weight were found on chromosomes 1, 4, 5, 7, 11, 12, 13, and 17, for leptin on chromosome 14, for insulin on chromosome 4, and for IGF-I on chromosome 10 at the Igf1 gene locus itself and on chromosome 18. Significant interaction between different quantitative trait loci (QTL) positions was observed (P < 0.01). Evidence was found that loci having small direct effect on growth or obesity contribute to the obese phenotype by gene-gene interaction. The effects of QTLs, epistasis, and pleiotropy account for 64% and 63% of the phenotypic variance of body weight and fat accumulation and for over 32% of muscle weight and serum concentrations of leptin, and IGF-I in the F(2) population of DU6i x DBA/2 mice. [The quantitative trait loci described in this paper have been submitted to the Mouse Genome Database.]

Animals↗
PubMed1999

Discriminating among cattle breeds using genetic markers.

Genetic markers provide a potentially powerful means of identifying the breed of individual animals. In this study diallelic and microsatellite loci were compared for their efficiency in discriminating among cattle breeds. Data were simulated for seven European cattle breeds using allele frequencies estimated at 20 microsatellite and 30 diallelic markers. Animals were assigned to the breed for which their genotype had the highest probability, and the power of the method assessed by estimating the error rate or proportion of animals misclassified. The number of markers required for discriminating among pure, or both pure and crossbreed, animals was investigated using either randomly sampled markers or markers selected on individual error rate. The relationship between individual marker variability and discriminatory power was also investigated. Microsatellite markers were found to be more powerful than diallelic markers for distinguishing among the breeds. The most discriminatory markers were those with the highest average heterozygosity and observed number of alleles. The number of markers needed to achieve a particular error rate could be reduced by selecting markers with the lowest individual error rates. Discrimination among both crossbreeds and pure breeds required approximately three times as many markers as discrimination among pure breeds alone.

Animals↗
PubMed1999

Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats.

BACKGROUND: Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background. METHODS: Using a single homozygous TGRmRen2-27 male as transgene donor, we produced two F1 populations with (a) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH. RESULTS: Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 +/- 9.5 vs. 91.8 +/- 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH. CONCLUSIONS: Our study demonstrates the application of a transgene as a "major gene" to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.

Animals↗