Abstract
BackgroundExperimental intercrosses between outbred founder populations are powerful resources for mapping loci that contribute to complex traits i.e. quantitative trait loci (QTL). Here, we present an approach and its accompanying software for high-resolution reconstruction of founder mosaic genotypes in the intercross offspring from such populations using whole-genome high-coverage sequence data on founder individuals (~ 30×) and very low-coverage sequence data on intercross individuals (< 0.5×). Sets of founder-line informative markers were selected for each full-sib family and used to infer the founder mosaic genotypes of the intercross individuals. The application of this approach and the quality of the estimated genome-wide genotypes are illustrated in a large F2 pedigree between two divergently selected lines of chickens.ResultsWe describe how we obtained whole-genome genotype data for hundreds of individuals in a cost- and time-efficient manner by using a Tn5-based library preparation protocol and an imputation algorithm that was optimized for this application. In total, 7.6 million markers segregated in this pedigree and, within each full-sib family, between 10.0 and 13.7% of these were fully informative, i.e. fixed for alternative alleles in the founders from the divergent lines, and were used for reconstruction of the offspring mosaic genotypes. The genotypes that were estimated based on the low-coverage sequence data were highly consistent (> 95% agreement) with those obtained using individual single nucleotide polymorphism (SNP) genotyping. The estimated resolution of the inferred recombination breakpoints was relatively high, with 50% of them being defined on regions shorter than 10 kb.ConclusionsA method and software for inferring founder mosaic genotypes in intercross offspring from low-coverage whole-genome sequencing in pedigrees from heterozygous founders are described. They provide high-quality, high-resolution genotypes in a time- and cost-efficient manner. The software is freely available at https://github.com/CarlborgGenomics/Stripes.
Highlights
Experimental intercrosses between outbred founder populations are powerful resources for mapping loci that contribute to complex traits i.e. quantitative trait loci (QTL)
Sequencing, marker selection, read mapping and inference of founder mosaic genotypes Step 1–2: Founder sequencing and identification of markers that are informative within a full‐sib family High coverage (~ 30×) individual sequence data detected 7,608,483 single nucleotide polymorphism (SNP) among the HWS and LWS founders (nHWS = 27 and nLWS = 29) that contributed to the F2 individuals
Quality of imputed founder mosaic genotypes Overall, the founder mosaic genotypes that were estimated with our method were in good agreement with the available SNP genotypes
Summary
Experimental intercrosses between outbred founder populations are powerful resources for mapping loci that contribute to complex traits i.e. quantitative trait loci (QTL). Genotyping by next-generation sequencing has emerged as a rapid, high-throughput approach to obtain high-density genotypes in large populations [1, 2] The downside of this approach is that confident assignment of individual genotypes requires costly deep sequencing, which restricts its application for large association panels. Multiple methods and software exist for analyses of such ultra-low coverage sequencing data in intercrosses between pairs of inbred founders, including FSFHap [4], LB-impute [6], and TIGER [7] This principle has been successfully extended to populations that are founded by multiple inbred parents, with implementations in software such as Mpimpute [16] and Reconstruct [17]
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