Array-based genotyping in S.cerevisiae using semi-supervised clustering.

Abstract

Microarrays provide an accurate and cost-effective method for genotyping large numbers of individuals at high resolution. The resulting data permit the identification of loci at which genetic variation is associated with quantitative traits, or fine mapping of meiotic recombination, which is a key determinant of genetic diversity among individuals. Several issues inherent to short oligonucleotide arrays -- cross-hybridization, or variability in probe response to target -- have the potential to produce genotyping errors. There is a need for improved statistical methods for array-based genotyping. We developed ssGenotyping (ssG), a multivariate, semi-supervised approach for using microarrays to genotype haploid individuals at thousands of polymorphic sites. Using a meiotic recombination dataset, we show that ssG is more accurate than existing supervised classification methods, and that it produces denser marker coverage. The ssG algorithm is able to fit probe-specific affinity differences and to detect and filter spurious signal, permitting high-confidence genotyping at nucleotide resolution. We also demonstrate that oligonucleotide probe response depends significantly on genomic background, even when the probe's specific target sequence is unchanged. As a result, supervised classifiers trained on reference strains may not generalize well to diverged strains; ssG's semi-supervised approach, on the other hand, adapts automatically.