Showing papers by "Chris Haley published in 2011"

EpiGPU: exhaustive pairwise epistasis scans parallelized on consumer level graphics cards

Abstract: Motivation: Hundreds of genome-wide association studies have been performed over the last decade, but as single nucleotide polymorphism (SNP) chip density has increased so has the computational burden to search for epistasis [for n SNPs the computational time resource is O(n(n-1)/2)]. While the theoretical contribution of epistasis toward phenotypes of medical and economic importance is widely discussed, empirical evidence is conspicuously absent because its analysis is often computationally prohibitive. To facilitate resolution in this field, tools must be made available that can render the search for epistasis universally viable in terms of hardware availability, cost and computational time. Results: By partitioning the 2D search grid across the multicore architecture of a modern consumer graphics processing unit (GPU), we report a 92× increase in the speed of an exhaustive pairwise epistasis scan for a quantitative phenotype, and we expect the speed to increase as graphics cards continue to improve. To achieve a comparable computational improvement without a graphics card would require a large compute-cluster, an option that is often financially non-viable. The implementation presented uses OpenCL—an open-source library designed to run on any commercially available GPU and on any operating system. Availability: The software is free, open-source, platformindependent and GPU-vendor independent. It can be downloaded from http://sourceforge.net/projects/epigpu/.

Quantitative trait loci for resistance to fish pasteurellosis in gilthead sea bream (Sparus aurata).

Abstract: Fish pasteurellosis is a bacterial disease causing important losses in farmed fish, including gilthead sea bream, a teleost fish of great relevance in marine aquaculture. We report in this study a QTL analysis for resistance to fish pasteurellosis in this species. An experimental population of 500 offspring originating from eight sires and six dams in a single mass-spawning event was subjected to a disease challenge with Photobacterium damselae subsp. piscicida (Phdp), the causative agent of fish pasteurellosis. A total of 151 microsatellite loci were genotyped in the experimental population, and half-sib regression QTL analysis was carried out on two continuous traits, body length at time of death and survival, and for two binary traits, survival at day 7 and survival at day 15, when the highest peaks of mortality were observed. Two significant QTLs were detected for disease resistance. The first one was located on linkage group LG3 affecting late survival (survival at day 15). The second one, for overall survival, was located on LG21, which allowed us to highlight a potential marker (Id13) linked to disease resistance. A significant QTL was also found for body length at death on LG6 explaining 5–8% of the phenotypic variation.

An empirical assessment of individual-based population genetic statistical techniques: application to British pig breeds.

Abstract: Recently developed Bayesian genotypic clustering methods for analysing genetic data offer a powerful tool to evaluate the genetic structure of domestic farm animal breeds. The unit of study with these approaches is the individual instead of the population. We aimed to empirically evaluate various individual-based population genetic statistical methods for characterization of genetic diversity and structure of livestock breeds. Eighteen British pig populations, comprising 819 individuals, were genotyped at 46 microsatellite markers. Three Bayesian genotypic clustering approaches, principle component analysis (PCA) and phylogenetic reconstruction were applied to individual multilocus genotypes to infer the genetic structure and diversity of the British pig breeds. Comparisons of the three Bayesian genotypic clustering methods (STRUCTURE, BAPS and STRUCTURAMA) revealed some broad similarities but also some notable differences. Overall, the methods agreed that majority of the British pig breeds are independent genetic units with little evidence of admixture. The three Bayesian genotypic clustering methods provided complementary, biologically credible clustering solutions but at different levels of resolution. BAPS detected finer genetic differentiation and in some cases, populations within breeds. Consequently, it estimated a greater number of underlying genetic populations (K, in the notation of Bayesian clustering methods). Two of the Bayesian methods (STRUCTURE and BAPS) and phylogenetic reconstruction provided similar success in assignment of individuals, supporting the use of these methods for breed assignment.

Characterisation of genome-wide association epistasis signals for serum uric acid in human population isolates.

Abstract: Genome-wide association (GWA) studies have identified a number of loci underlying variation in human serum uric acid (SUA) levels with the SLC2A9 gene having the largest effect identified so far. Gene-gene interactions (epistasis) are largely unexplored in these GWA studies. We performed a full pair-wise genome scan in the Italian MICROS population (n=1201) to characterise epistasis signals in SUA levels. In the resultant epistasis profile, no SNP pairs reached the Bonferroni adjusted threshold for the pair-wise genome-wide significance. However, SLC2A9 was found interacting with multiple loci across the genome, with NFIA - SLC2A9 and SLC2A9 - ESRRAP2 being significant based on a threshold derived for interactions between GWA significant SNPs and the genome and jointly explaining 8.0% of the phenotypic variance in SUA levels (3.4% by interaction components). Epistasis signal replication in a CROATIAN population (n=1772) was limited at the SNP level but improved dramatically at the gene ontology level. In addition, gene ontology terms enriched by the epistasis signals in each population support links between SUA levels and neurological disorders. We conclude that GWA epistasis analysis is useful despite relatively low power in small isolated populations.

A cornucopia of maize genes

Abstract: Two studies illustrate that with the appropriate resources and scale of study, most of the heritability of complex traits in maize is not missing, but can be located within the genome. Given that maize is one of the world's most important crop plants, this has implications for feeding a growing population with minimum carbon footprint as well as for understanding the genetics of complex traits in a range of species.

Mapping QTL in the porcine MHC region affecting fatness and growth traits in a Meishan/Large White composite population.

Abstract: Summary A number of studies have mapped QTL regulating porcine fatness and growth traits to the region of the major histocompatibility complex (MHC) on porcine chromosome 7 using various experimental crosses. The QTL results from crosses using the Chinese Meishan (MS) (slow growing and fat) are particularly interesting because the MS alleles have been found to be associated with increased growth rate and reduced backfat depth. We investigated these QTL further in a composite population derived previously over eight generations by intercrossing Meishan and the European Large White breeds. Genotype information from 32 markers in a 15cM target region was used in linkage and association analyses. A two-step variance component analysis identified QTL for three growth-related traits, explaining 19 ∼ 24% of the phenotypic variance with a confidence interval of 4 cM in the target region. SNP association analyses found that ss181128966 and ss181128924 within the QTL interval were strongly associated with the growth traits. Only weak signals for an effect on backfat depth were found in the association and linkage analyses, possibly because of past directional selection in the composite population.

Association analyses of the MAS-QTL data set using grammar, principal components and Bayesian network methodologies.

Abstract: Background It has been shown that if genetic relationships among individuals are not taken into account for genome wide association studies, this may lead to false positives. To address this problem, we used Genome-wide Rapid Association using Mixed Model and Regression and principal component stratification analyses. To account for linkage disequilibrium among the significant markers, principal components loadings obtained from top markers can be included as covariates. Estimation of Bayesian networks may also be useful to investigate linkage disequilibrium among SNPs and their relation with environmental variables. For the quantitative trait we first estimated residuals while taking polygenic effects into account. We then used a single SNP approach to detect the most significant SNPs based on the residuals and applied principal component regression to take linkage disequilibrium among these SNPs into account. For the categorical trait we used principal component stratification methodology to account for background effects. For correction of linkage disequilibrium we used principal component logit regression. Bayesian networks were estimated to investigate relationship among SNPs.

High throughput analyses of epistasis for swine body dimensions and organ weights.

Abstract: Summary High throughput analyses were performed to detect epistatic QTL in 17 body dimension and organ weight traits from a large F2 pig population derived from a White Duroc and Erhualian intercross. The analyses used a nested test framework to handle multiple tests and a combined search algorithm to map epistatic QTL with empirical genome-wide thresholds derived via prior permutation. Alternative statistical models (e.g. including vs. excluding carcass weight as a covariate) were tested to develop an in-depth understanding of the role of epistasis in these kinds of traits. Epistasis signals were detected in only two or three traits under each statistical model studied. The interaction component of each pair of epistatic QTL explained a small proportion (0.7 to 2.1%) of the phenotypic variance in general. About half of the detected epistatic QTL pairs involved one of the two major QTL on porcine chromosomes 7 and 4. In those traits, the Erhualian allele consistently increased the phenotypes for the chromosome 7 QTL but decreased them for the chromosome 4 QTL. Models including carcass weight as covariate detected epistasis in body dimension traits whereas those excluding carcass weight found epistasis in organ weight traits. In addition, the epistasis results suggested that a QTL on chromosome 14 could be important for a number of organ weight traits. Using the high-throughput analysis tool to examine different statistical models was essential for the generation of a complete picture of epistasis in a whole category of traits.

State of the genetic diversity, structure and admixture of British chicken breeds

Abstract: The characterisation of livestock genetic diversity can inform breed conservation initiatives. The state of genetic diversity and genetic structure in 24 British chicken breeds was assessed. A total of 239 alleles in 685 individual genotypes were found across 30 microsatellite loci with a mean number of 7.97 alleles per locus. Genetic differentiation between the phenotypically diverse British chicken breeds was high with an average FST value of 0.25. Genetic diversity was also high with an average expected heterozygosity of 0.49, ranging from 0.20 in Spanish to 0.62 in Araucana. However, the average observed heterozygote frequency was 0.39, ranging from 0.15 in Spanish to 0.49 in Cochin. A heterozygote deficit was observed in most breeds, with an average FIS value of 0.20. Individual-based clustering analyses revealed that most individuals clustered to breed origin. However, genetic subdivisions occurred in several breeds and this was predominantly associated with flock supplier and occasionally by morphological type. Overall, the levels of genetic diversity in British chicken breeds are comparable to those reported in mainland European chicken breeds, but the observed heterozygosity was considerably lower. It is likely that this was due to a Wahlund effect caused by sampling from subtly differentiated flocks, implying structure within breeds. It is proposed that gene flow amongst flocks within certain breeds should be enhanced to maintain the current levels of genetic diversity. Additionally, some breeds had low levels of both genetic diversity and uniqueness. Consideration is required for the conservation and preservation of these potentially vulnerable breeds.

Mapping and fine mapping of genes controlling differences in maternal behaviour

Abstract: Finding the genes that underlie variation in production and developmental traits has important economic applications. Incubation behaviour, also known as broodiness, results in lost production and can be a major problem in some breeds of chicken. Its expression is the consequence of sequential interaction of oestrogen, progesterone and prolactin acting centrally in the brain and peripherally(Sharp 2009). There are differences in the proclivity for maternal behaviour between chicken strains which is linked to their productivity (Vleck 2002). To study the genetics of the trait 280 F2 hens from 19 F1 families were created by crossing White leghorn (WL, 0 % incidence of incubation behaviour) and Silkie chickens (SLK, 100 % incidence of incubation behaviour). Broody phenotypes were recorded from hens placed in pens with nest boxes and were recorded each day for broodiness onset. Blood samples were collected for DNA genotyping. Phenotypes were regressed against 90 informative microsatellite markers genotypes in 23 autosomal linkage groups and the sex chromosome using the Grid QTL implementation of the Haley and Knott QTL mapping method(Haley and Knott 1992). Test statistics for broodiness showed that out of 276 birds studied for broodiness, 45% of birds showed full broodiness, 28% birds showed partial broodiness and 28 % birds showed no sign of broodiness. The evidence for a QTL affecting broody status on chromosome 5 at 79cM was significant at the genome-wide 1% level. The 95% Confidence Interval (C.I) for broody status however spanned a region around 95 cM. Standardized dominant effect represented 10.43 % of the trait standard deviation. TSHR is also found to be located at the same QTL position which is considered to be largest selective sweep associated with domestication of the chicken. Further fine mapping was done in this QTL region by adding 31 SNPs markers. Out of these, 15 SNPs markers were informative to fine map the loci which resulted in the CI reducing to 45cM and the most likely locus for the QTL remains at the TSHR. To further narrow down this loci, it is suggested to test this trait in other populations that segregate for the trait to increase the available recombinations. HALEY C.S. AND KNOTT S.A. (1992) A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69, 315-24. SHARP P.J. (2009) Broodiness and broody control. Biology of Breeding Poultry, (ed. P.M.Hocking), Abingdon, CAB International. VLECK M.C. (2002) Hormonal control of incubation behaviour. In: Avian Incubation: Behaviour, Enviornment, and Evolution (ed. by Deemig DC). Oxford Univeristy Press.