title: Quantitative trait Loci association mapping by imputation of strain origins in multifounder crosses.
abstract: Although mapping quantitative traits in inbred strains is simpler than mapping the analogous traits in humans, classical inbred crosses suffer from reduced genetic diversity compared to experimental designs involving outbred animal populations. Multiple crosses, for example the Complex Trait Consortium's eight-way cross, circumvent these difficulties. However, complex mating schemes and systematic inbreeding raise substantial computational difficulties. Here we present a method for locally imputing the strain origins of each genotyped animal along its genome. Imputed origins then serve as mean effects in a multivariate Gaussian model for testing association between trait levels and local genomic variation. Imputation is a combinatorial process that assigns the maternal and paternal strain origin of each animal on the basis of observed genotypes and prior pedigree information. Without smoothing, imputation is likely to be ill-defined or jump erratically from one strain to another as an animal's genome is traversed. In practice, one expects to see long stretches where strain origins are invariant. Smoothing can be achieved by penalizing strain changes from one marker to the next. A dynamic programming algorithm then solves the strain imputation process in one quick pass through the genome of an animal. Imputation accuracy exceeds 99% in practical examples and leads to high-resolution mapping in simulated and real data. The previous fastest quantitative trait loci (QTL) mapping software for dense genome scans reduced compute times to hours. Our implementation further reduces compute times from hours to minutes with no loss in statistical power. Indeed, power is enhanced for full pedigree data.
authors.affiliation: Department of Biostatistics, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: Jin J
authors.initials: JJ
authors.lastname: Zhou
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sobel
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lange
mesh_terms: D000465:Algorithms; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D003198:Computer Simulation; D003433:Crosses, Genetic; D005838:Genotype; D007178:Inbreeding; D051379:Mice; D008957:Models, Genetic; D015233:Models, Statistical; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results