Genetical genomics approaches for systems genetics

PhD ceremony: Mr. B.M. Tesson, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Genetical genomics approaches for systems genetics

Promotor(s): prof. R.C. Jansen, prof. R. Breitling

Faculty: Mathematics and Natural Sciences

Variation in DNA sequences is at the source of much phenotypic diversity. Understanding the biological mechanisms through which this variation affects tissues, organs or organisms is the aim of systems genetics. Genetical genomics uses quantitative genetics approaches to identify the naturally occurring allelic variants responsible for differential abundance of molecular traits such as messenger RNAs, proteins or metabolites. The thesisof Bruno Tesson explores the potential of genetical genomics to dissect the molecular interplay that gives rise to complex phenotypes (e.g. diseases) and thereby, contribute to the larger ambition of systems genetics.

The different steps of a genetical genomics study are detailed by Tesson, with such an analysis performed on transcriptomic data from mouse hematopoietic cells. The results demonstrate that the effects of natural DNA variation on gene expression are highly sensitive to cell differentiation stage, emphasizing the need for cellular targeting in systems genetics. A careful permutation strategy is advocated to guard against erroneous interpretation of expression quantitative trait loci (eQTL) hotspots as major genetic regulators.

Also a novel method is proposed by Tesson to study differential coexpression, offering complementary insights to classical differential expression analysis. Elucidating the role of individual genes, proteins or metabolites in the acquisition of specific phenotypes requires the ability to infer causal relationships between those traits. The potential and limitations of existing causal inference methods in genetical genomics is explored. Finally, current and future systems genetics challenges arising in experimental design, statistical significance and network reconstruction are discussed by him.