TY - JOUR
T1 - An evaluation of high-throughput approaches to QTL mapping in Saccharomyces cerevisiae
AU - Wilkening, Stefan
AU - Lin, Gen
AU - Fritsch, Emilie S.
AU - Tekkedil, Manu M.
AU - Anders, Simon
AU - Kuehn, Raquel
AU - Nguyen, Michelle
AU - Aiyar, Raeka S.
AU - Proctor, Michael
AU - Sakhanenko, Nikita A.
AU - Galas, David J.
AU - Gagneur, Julien
AU - Deutschbauer, Adam
AU - Steinmetz, Lars M.
PY - 2014/3
Y1 - 2014/3
N2 - Dissecting the molecular basis of quantitative traits is a significant challenge and is essential for understanding complex diseases. Even in model organisms, precisely determining causative genes and their interactions has remained elusive, due in part to difficulty in narrowing intervals to single genes and in detecting epistasis or linked quantitative trait loci. These difficulties are exacerbated by limitations in experimental design, such as low numbers of analyzed individuals or of polymorphisms between parental genomes. We address these challenges by applying three independent high-throughput approaches for QTL mapping to map the genetic variants underlying 11 phenotypes in two genetically distant Saccharomyces cerevisiae strains, namely (1) individual analysis of >700 meiotic segregants, (2) bulk segregant analysis, and (3) reciprocal hemizygosity scanning, a new genome-wide method that we developed. We reveal differences in the performance of each approach and, by combining them, identify eight polymorphic genes that affect eight different phenotypes: colony shape, flocculation, growth on two nonfermentable carbon sources, and resistance to two drugs, salt, and high temperature. Our results demonstrate the power of individual segregant analysis to dissect QTL and address the underestimated contribution of interactions between variants. We also reveal confounding factors like mutations and aneuploidy in pooled approaches, providing valuable lessons for future designs of complex trait mapping studies.
AB - Dissecting the molecular basis of quantitative traits is a significant challenge and is essential for understanding complex diseases. Even in model organisms, precisely determining causative genes and their interactions has remained elusive, due in part to difficulty in narrowing intervals to single genes and in detecting epistasis or linked quantitative trait loci. These difficulties are exacerbated by limitations in experimental design, such as low numbers of analyzed individuals or of polymorphisms between parental genomes. We address these challenges by applying three independent high-throughput approaches for QTL mapping to map the genetic variants underlying 11 phenotypes in two genetically distant Saccharomyces cerevisiae strains, namely (1) individual analysis of >700 meiotic segregants, (2) bulk segregant analysis, and (3) reciprocal hemizygosity scanning, a new genome-wide method that we developed. We reveal differences in the performance of each approach and, by combining them, identify eight polymorphic genes that affect eight different phenotypes: colony shape, flocculation, growth on two nonfermentable carbon sources, and resistance to two drugs, salt, and high temperature. Our results demonstrate the power of individual segregant analysis to dissect QTL and address the underestimated contribution of interactions between variants. We also reveal confounding factors like mutations and aneuploidy in pooled approaches, providing valuable lessons for future designs of complex trait mapping studies.
UR - http://www.scopus.com/inward/record.url?scp=84901361638&partnerID=8YFLogxK
U2 - 10.1534/genetics.113.160291
DO - 10.1534/genetics.113.160291
M3 - Article
C2 - 24374355
AN - SCOPUS:84901361638
SN - 0016-6731
VL - 196
SP - 853
EP - 865
JO - Genetics
JF - Genetics
IS - 3
ER -