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 QTL from two MPPs: the Collaborative Cross (CC) and the Drosophila Synthetic Population Resource (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.…”

A Bayesian model selection approach to mediation analysis

“…Modeling the allelic series of QTL with TIMBR We modeled the allelic series at the pQTL for to SNX4 and TUBG1 using a Bayesian hierarchical model as implemented in TIMBR [25]. The model is roughly equivalent to Equation 2, with the kinship effect excluded in order to make the computation feasible.…”

“…The haplotype effects of the Snx7 local pQTL and the Snx4 distal pQTL are highly correlated (r = 0.99) and reveal a complex haplotype effects pattern that cannot be explained by a single bi-allelic variant. We used the TIMBR software [25] to determine that the pQTL has as many as ≈5 distinct functional alleles (Figure S3a). Bi-allelic variants in the pQTL region with alleles shared by the B6 and 129 strains partially match the haplotype effects and thus have strong associations with both proteins.…”

Genetic architecture of variation in Arabidopsis thaliana rosettes

“…MAGIC allows haplotype reconstruction for markers alleles as founder-of-origin [ 89 – 91 ] tracking genetic variation back to parental sequence level [ 92 ]. Tailored bayesian models [ 93 , 94 ] improves parameter estimation and permutation-based procedures reduce False Discovery Rates [ 95 ].…”