21 januari 2015

Rat genome variation and complex traits

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Roel Hermsen has performed his research on rat genome variation and complex traits in the group of Edwin Cuppen at the Hubrecht Institute. Today he defended his thesis at the Utrecht University.

The relation between DNA variants (genotype) and their effect on traits (phenotype) is essential in understanding the mechanisms underlying human complex diseases such as hypertension and diabetes. Studying these type of diseases in human is difficult due to fluctuations in environmental influences and their heterozygous genomes. Therefore inbred rat lines are used here as models for human complex diseases to study the role of genomic variation in disease phenotypes. Technical advances in next-generation sequencing (NGS) make it now possible to determine the variation in DNA, RNA and nuclear 3D DNA organization.

The work that is described in this thesis assesses the use of NGS-based applications in rat functional genomic research as a tool to identify and molecularly characterize genomic variants in complex traits. Firstly, DNA variants were catalogued in more than 40 widely used rat inbred strains, which are models for a range of human complex diseases. Next this inventory was used to link these DNA variants to a broad range of complex phenotypes, including anxiety, heart disease and multiple sclerosis. In addition the effects of the noncoding variants from this inventory were studied to assess their role in molecular phenotypic variation. Finally, one specific complex trait, cancer, was studied in more detail on the genomic level using a rat Tp53 knockout model.

In this thesis multiple NGS techniques were used to dissect the intricate relationship between genomic variants and their role in complex traits in rat. This work is a basis for further fundamental research and reports multiple genome-wide resources, which are valuable for (not only) rat functional genomic research.