Mutational processes and impact of structural variants in somatic cells

Mutational processes that generate structural variants (SV) in human and other genomes are understudied and merit attention, and similarly so for the functional impact of the SVs on gene function and regulation.

SVs may explain some of the missing heritability in population studies, they may provide candidate pathogenic variants in pedigree studies of hereditary diseases, as well as constitute yet-undiscovered driver events that were anticipated from cancer genomics.

Reasons why the SV mutational processes and SV functional impact are understudied are both of a technical and a conceptual nature; both aspects will be addressed in the STRUCTOMATIC project.

We will study structural variation in human somatic cells by combining diverse computational and experimental approaches, drawing on a genomic resource of hundreds of tumors and healthy tissues sequenced using long-read WGS that we will generate.

We will further perform mutation accumulation and directed evolution experiments using cell line models of chromosomal instability, generating further genomic data that will support observational analyses of tumor genomes.

The project aims are: thoroughly cataloguing the diversity of SVs in multiple somatic cell types including those not detectable by short-read WGS, elucidating the underlying mutational mechanisms that generate SVs, their heterogeneity across the human chromosomes as well as their variation between individuals, and developing rigorous statistical methodologies for identifying positive and negative selection on SVs in human somatic cells.

Characterizing the landscape of somatic SVs is crucial for a more complete understanding of the genetic basis of carcinogenesis and of the variable cancer risk across tissues and individuals, and may also provide evidence for hypothesized roles of somatic genetic variation in aging-related pathologies more generally.