Genome wide association analysis in a mouse advanced intercross line

Abstract

Genome wide association analyses (GWAS) in model organisms have numerous advantages compared 2 to human GWAS, including the ability to use populations with well-defined genetic diversity, the ability to 3 collect tissue for gene expression analysis and the ability to perform experimental manipulations. We 4 examined behavioral, physiological, and gene expression traits in 1,063 male and female mice from a 5 50-generation intercross between two inbred strains (LG/J and SM/J). We used genotyping by 6 sequencing in conjunction with whole genome sequence data from the two founder strains to obtain 7 genotypes at 4.3 million SNPs. As expected, all alleles were common (mean MAF=0.35) and linkage 8 disequilibrium degraded rapidly, providing excellent power and sub-megabase mapping precision. We 9 identified 126 genome-wide significant loci for 50 traits and integrated this information with 7,081 cis-10 eQTLs and 1,476 trans-eQTLs identified in hippocampus, striatum and prefrontal cortex. We replicated 11 several loci that were identified using an earlier generation of this intercross, including an association 12 between locomotor activity and a locus containing a single gene, Csmd1. We also showed that Csmd1 13 mutant mice recapitulated the locomotor phenotype. Our results demonstrate the utility of this population, 14 identify numerous novel associations, and provide examples of replication in an independent cohort, 15 which is customary in human genetics, and replication by experimental manipulation, which is a unique 16 advantage of model organisms.

Mapping QTL for Resistance to New Virulent Races of Wheat Stripe Rust from Two Argentinean Wheat Cultivars

“…Infection type and severity were analyzed independently for each year, using the mean of the two replications as the response variable. In addition, LOCO-LMM models reduce potential overestimations of Type I and Type II error rates, compared with linear mixed models with a single kinship matrix (Yang et al, 2014;Gonzales et al, 2017). Interval mapping was conducted using a "leave-onechromosome-out" linear mixed model (LOCO-LMM), with a 1-cM step.…”

“…Interval mapping was conducted using a "leave-onechromosome-out" linear mixed model (LOCO-LMM), with a 1-cM step. Linear mixed models account for potential polygenic effects by modeling the covariance between phenotypes and genotypes as a random effect (Gonzales et al, 2017). In addition, LOCO-LMM models reduce potential overestimations of Type I and Type II error rates, compared with linear mixed models with a single kinship matrix (Yang et al, 2014;Gonzales et al, 2017).…”

“…Linear mixed models account for potential polygenic effects by modeling the covariance between phenotypes and genotypes as a random effect (Gonzales et al, 2017). In addition, LOCO-LMM models reduce potential overestimations of Type I and Type II error rates, compared with linear mixed models with a single kinship matrix (Yang et al, 2014;Gonzales et al, 2017). Twenty-one kinship matrices were calculated, each one excluding a different chromosome, and each chromosome was evaluated using the kinship matrix constructed with the remaining chromosomes only.…”

Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: evidence for “polygenic epistasis”

“…The second cohort consists of 1,063 animals from the F50 -F56 generation of an advanced intercross line (AIL) created by crossing the LG/J and SM/J inbred mouse strains 12 . Unlike the RI strains from the HMDP, AILs are maintained in a manner that minimizes inbreeding.…”

“…The GxƟ test successfully distinguishes between effects dependent only on SNP or ancestry and effects which arise from their interaction. We then applied the test to two different populations of mice: recombinant inbred (RI) lines that are a subset of the Hybrid Mouse Diversity Panel (HMDP) 11 , and a 50 th generation intercross between the inbred LG/J and SM/J mouse strains 12 , whose ancestry proportions can be clearly and precisely determined 12 Next, we conducted a replication study demonstrating that our approach is able to replicate findings across similar populations.…”