A systems genetics approach for sleep regulation

Sleep is a daily behavior important for health. Many people studied sleep with more or less sophisticated technologies over time, and yet it has not revealed all its mysteries. To help uncover the molecular consequences of sleep deprivation, the Franken group have assembled a systems genetics resource interrogating the BXD mouse panel. The genotypes and sleep-wake phenome were characterized, along with intermediate phenotypes: the transcriptome in brain and in liver, and the targeted metabolome in the blood plasma. I have used this rich multi-omics BXD dataset for computational investigation and development of analytical methods for data and knowledge integration to expand the current understanding of sleep regulation. First, in collaboration with Maxime Jan we used this real-world example of data and bioinformatic analysis management to highlight multi-omics challenges and solutions used to help internal or external reusability. This includes more details on the quality check and validations of the methods, the use of Rmarkdown reports for more higher levels parts of the analyses, a metadata workflow document illustrating and referencing the different code and data files, and a web site for exploration of the results. The robustness of the results was also assessed through the change to the newest version of the mouse genome reference assembly used. Then, the classical pipeline to analyse RNA-sequencing reads uses one mouse reference for all samples, irrespective of the strain of the samples, which is potentially creates a reference bias. Therefore, to improve the genetic-specificity of the read mapping, I customized the standard assembly based on one parental strain with variants from the BXD population. An important step was adding a tailored imputation of the population genetic variants using haplotypes blocks/regions to achieve a sufficient resolution for each line-specific reference. This strategy alleviated the reference bias and allowed to detect proportionally more eQTLs with the custom BXD-specific ...