Academic journal article Genetics

High-Resolution Mapping of Complex Traits with a Four-Parent Advanced Intercross Yeast Population

Academic journal article Genetics

High-Resolution Mapping of Complex Traits with a Four-Parent Advanced Intercross Yeast Population

Article excerpt

ABSTRACT A large fraction of human complex trait heritability is due to a high number of variants with small marginal effects and their interactions with genotype and environment. Such alleles are more easily studied in model organisms, where environment, genetic makeup, and allele frequencies can be controlled. Here, we examine the effect of natural genetic variation on heritable traits in a very large pool of baker's yeast from a multiparent 12th generation intercross. We selected four representative founder strains to produce the Saccharomyces Genome Resequencing Project (SGRP)-4X mapping population and sequenced 192 segregants to generate an accurate genetic map. Using these individuals, we mapped 25 loci linked to growth traits under heat stress, arsenite, and paraquat, the majority of which were best explained by a diverging phenotype caused by a single allele in one condition. By sequencing pooled DNA from millions of segregants grown under heat stress, we further identified 34 and 39 regions selected in haploid and diploid pools, respectively, with most of the selection against a single allele. While the most parsimonious model for the majority of loci mapped using either approach was the effect of an allele private to one founder, we could validate examples of pleiotropic effects and complex allelic series at a locus. SGRP-4X is a deeply characterized resource that provides a framework for powerful and high-resolution genetic analysis of yeast phenotypes and serves as a test bed for testing avenues to attack human complex traits.

THE strong tendency for progeny to closely resemble their parents has turned out to be difficult to understand in detail. Nearly all traits, including lifetime risk for many common diseases, have a complex genetic basis that is determined by multiple quantitative trait loci (QTL) (Donnelly 2008; Manolio et al. 2009). The first step toward accurate models of trait variability, and a prerequisite for predicting and modulating them, is characterization of the underlying genetic factors in the context of rest of the genome and their external environment. Research in model systems has led the way in this effort and produced powerful experimental and computational approaches for genetic mapping (Nordborg and Weigel 2008; Flint and Mackay 2009; Mackay et al. 2009).

A traditional, well-controlled approach for finding the QTL underlying natural phenotypic variation is to analyze a large number of progenies from two-parent crosses (Brem et al. 2002; Simon et al. 2008). Studies using this design have improved our understanding of complex traits and provided concrete evidence of natural segregating variants (Mackay et al. 2009), but have been limited in their scope with regard to the extent of genetic variation between the two parents. Mapping populations of popular model organisms ranging from fruit flies (King et al. 2012) and mice (Churchill et al. 2004; Durrant et al. 2011) to plants (Kover et al. 2009; Gan et al. 2011; Huang et al. 2011) has recently expanded the genetic and phenotypic diversity available to study by incorporating a wider repertoire of founder lines. These panels are the forefront of complex trait research and bear close resemblance to natural populations in multiple ways. Beyond increased variation, multiple founders introduce the possibility of more than two independent alleles at a locus and a larger space of potential epistatic interactions (Huang et al. 2012), while additional outcrossing rounds break linkage to further mix alleles. Nevertheless, lack of complete genotype information and the extent of remaining linkage in these recombinant lines have limited the power to detect small-effect QTL and identify the causative loci.

A multiparent mapping population has notably been missing in the budding yeast Saccharomyces cerevisiae, perhaps themost powerful eukaryotic model organism (Liti and Louis 2012). Yeast is a powerhouse of quantitative genetics due to its small genome size and very high recombination rate and the potential for accurate quantitative phenotyping, ease of obtaining and maintaining large mapping populations, and the ability to manipulate the genome at a single-base resolution. …

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