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The Inbred Long- and Short-Sleep (ILS, ISS) mouse lines were selected for differences in acute ethanol sensitivity using the loss of righting response (LORR) as the selection trait. The lines show an over tenfold difference in LORR and, along with a recombinant inbred panel derived from them (the LXS), have been widely used to dissect the genetic underpinnings of acute ethanol sensitivity. Here we have sequenced the genomes of the ILS and ISS to investigate the DNA variants that contribute to their sensitivity difference. We identified ~2.7 million high-confidence SNPs and small indels and ~7000 structural variants between the lines; variants were found to occur in 6382 annotated genes. Using a hidden Markov model, we were able to reconstruct the genome-wide ancestry patterns of the eight inbred progenitor strains from which the ILS and ISS were derived, and found that quantitative trait loci that have been mapped for LORR were slightly enriched for DNA variants. Finally, by mapping and quantifying RNA-seq reads from the ILS and ISS to their strain-specific genomes rather than to the reference genome, we found a substantial improvement in a differential expression analysis between the lines. This work will help in identifying and characterizing the DNA sequence variants that contribute to the difference in ethanol sensitivity between the ILS and ISS and will also aid in accurate quantification of RNA-seq data generated from the LXS RIs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-016-9663-6) contains supplementary material, which is available to authorized users.

The use of recombinant inbred strains in mice is a powerful tool for understanding the genetics of complex diseases, such as alcohol tolerance. In 1981, McClearn and Kakihana introduced the Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains that had been selectively bred from eight ancestor strains for their response to alcohol [3] . The study provides a rare framework for computational analysis as the lineages of the two strains are well documented and six of the eight ancestor mouse strains have been sequenced [2] . We have recently sequenced the complete genomes of the ILS and ISS strains to identify all single-nucleotide polymorphisms (SNPs), where individual nucleotides in the ILS and ISS genomes differ from the reference mouse genome (mm10).

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