On the use of whole-genome sequence data for across-breed genomic prediction and fine-scale mapping of QTL

Abstract

Background: Whole-genome sequence (WGS) data are increasingly available on large numbers of individuals in animal and plant breeding and in human genetics through second-generation resequencing technologies, 1000 genomes projects, and large-scale genotype imputation from lower marker densities. Here, we present a computationally fast implementation of a variable selection genomic prediction method, that could handle WGS data on more than 35,000 individuals, test its accuracy for across-breed predictions and assess its quantitative trait locus (QTL) mapping precision.

Methods: The Monte Carlo Markov chain (MCMC) variable selection model (Bayes GC) fits simultaneously a genomic best linear unbiased prediction (GBLUP) term, i.e. a polygenic effect whose correlations are described by a genomic relationship matrix (G), and a Bayes C term, i.e. a set of single nucleotide polymorphisms (SNPs) with large effects selected by the model. Computational speed is improved by a Metropolis-Hastings sampling that directs computations to the SNPs, which are, a priori, most likely to be included into the model. Speed is also improved by running many relatively short MCMC chains. Memory requirements are reduced by storing the genotype matrix in binary form. The model was tested on a WGS dataset containing Holstein, Jersey and Australian Red cattle. The data contained 4,809,520 genotypes on 35,549 individuals together with their milk, fat and protein yields, and fat and protein percentage traits.

Results: The prediction accuracies of the Jersey individuals improved by 1.5% when using across-breed GBLUP compared to within-breed predictions. Using WGS instead of 600 k SNP-chip data yielded on average a 3% accuracy improvement for Australian Red cows. QTL were fine-mapped by locating the SNP with the highest posterior probability of being included in the model. Various QTL known from the literature were rediscovered, and a new SNP affecting milk production was discovered on chromosome 20 at 34.501126 Mb. Due to the high mapping precision, it was clear that many of the discovered QTL were the same across the five dairy traits.

Conclusions: Across-breed Bayes GC genomic prediction improved prediction accuracies compared to GBLUP. The combination of across-breed WGS data and Bayesian genomic prediction proved remarkably effective for the fine-mapping of QTL.

Fig. 1

Manhattan plots of the variance of the local GEBV within 250-kb regions for fat percentage

Fig. 2

Manhattan plot of the variance of the local GEBV within 250-kb regions for fat percentage on BTA20

Fig. 3

Fine-scale map of the posterior probabilities of the SNPs for affecting fat percentage in the region between 30 and 35 Mb on BTA20. The blue bar denotes the 95% credibility interval for the QTL, and the red dot the position of the COJO SNP detected by [23]

Fig. 4

Fine-scale map of the posterior probabilities of the SNPs for affecting milk production in the region between 30 and 35 Mb on BTA20. The blue bar denotes the 95% credibility interval for the QTL