Genotype-free individual genome reconstruction of Multiparental Population Models by RNA sequencing data

Abstract Multi-parent populations (MPPs), genetically segregating model systems derived from two or more inbred founder strains, are widely used in biomedical and agricultural research. Gene expression profiling by direct RNA sequencing (RNA-Seq) is commonly applied to MPPs to investigate gene expression regulation and to identify candidate genes. In genetically diverse populations, including most MPPs, quantification of gene expression is improved when the RNA-Seq reads are aligned to individualized transcriptomes that incorporate known polymorphic loci. However, the process of constructing and analyzing individual genomes can be computationally demanding and error prone. We propose a new approach, genome reconstruction by RNA-Seq (GBRS), that relies on simultaneous alignment of RNA-Seq reads to the founder strain transcriptomes. GBRS can reconstruct the diploid genome of each individual and quantify both total and allele-specific gene expression. We demonstrate that GBRS performs as well as methods that rely on high-density genotyping arrays to reconstruct the founder haplotype mosaic of MPP individuals. Using GBRS in addition to other genotyping methods provides quality control for detecting sample mix-ups and improves power to detect expression quantitative trait loci. GBRS software is freely available at https://github.com/churchill-lab/gbrs .