Inferring the Allelic Series at QTL in Multiparental Populations

Abstract

Multiparental populations (MPPs) are experimental populations in which the genome of every individual is a mosaic of known founder haplotypes. These populations are useful for detecting quantitative trait loci (QTL) because tests of association can leverage inferred founder haplotype descent. It is difficult, however, to determine how haplotypes at a locus group into distinct functional alleles, termed the allelic series. The allelic series is important because it provides information about the number of causal variants at a QTL and their combined effects. In this study, we introduce a fully-Bayesian model selection framework for inferring the allelic series. This framework accounts for sources of uncertainty found in typical MPPs, including the number and composition of functional alleles. Our prior distribution for the allelic series is based on the Chinese restaurant process, a relative of the Dirichlet process, and we leverage its connection to the coalescent to introduce additional prior information about haplotype relatedness via a phylogenetic tree. We evaluate our approach via simulation and apply it to real QTL from two MPPs: the Collaborative Cross (CC) and the Drosophila Genetic Reference Population (DSPR). We find that, although posterior inference of the exact allelic series is often uncertain, we are able to distinguish biallelic QTL from more complex multiallelic cases. Additionally, our allele-based approach improves haplotype effect estimation when the true number of functional alleles is small. Our method, Tree-Based Inference of Multiallelism via Bayesian Regression (TIMBR), provides new insight into the genetic architecture of QTL in MPPs.

QTLViewer: An interactive webtool for genetic analysis in the Collaborative Cross and Diversity Outbred mouse populations

“…These effects can be used to distinguish which founder strains likely possess the causal genetic variants. They also highlight QTL that are multi-allelic (Crouse et al 2020) – a unique feature of MPPs like the CC and DO.…”

“…Promising candidates will significantly reduce or drop the initial QTL LOD score and be encoded on the genome near the QTL. This “LOD-drop” method of mediation is a powerful tool to identify candidate mediators, but it is also susceptible to false positive detection of linked independent effects (Chick et al 2016; Crouse et al 2020). Mediation can be performed against different datasets by changing the selection in the Mediate Against box.…”

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

“…More broadly speaking, scaling with respect to variation in the sample population will increase the QTL effect for deviations from balanced homozygous allele frequencies at the QTL, which will occur when there are heterozygous animals rather than homozygous, alleles that are rare, and even imbalanced allelic series, i . e ., how the QTL’s functional alleles are distributed among the founder strains (Crouse et al . 2020).…”

QTL Mapping in Outbred Tetraploid (and Diploid) Diallel Populations

“…At present, a user of our software is limited to hypothesizing that haplotypes with similar effect carry the same allele. One direction for future research would be to incorporate methods to formally test such hypotheses (Jannink and Wu 2003;Crouse et al 2020).…”