Uncovering inversion formation in the human genome and its impact to disease.

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1. Project Summary The relevance of inversions for disease causation, speciation and adaptation, is broadly and prominently recognized although the prevalence is unknown. In humans, de novo inversions are associated with congenital anomalies in ~9.6% of patients. Yet, despite the biological relevance of inversions, their molecular features, formation mechanism, impact to the genomic structure in carriers, as well as their contribution to clinical phenotypes, have not been further explored. Inversions are typically classified as a balanced reciprocal event generated by ectopic recombination, although recent studies reveal a distinct picture whereby inversions originate from mechanisms that concomitantly generate copy number variants (CNVs). Surprisingly, those complex inversions underlie as much as 30% of neurodevelopmental defect-associated CNVs. The hypothesis of this application are: i. inversions are often generated de novo by mechanisms other than ectopic recombination; ii. a relevant fraction of inversions are associated with complex genomic rearrangements (CGRs) often overlooked in sporadic diseases, and iii. inversions are a “hidden” type of structural variation for which contribution to a clinical phenotype has been under assessed due to the lack of appropriate detection tools. These hypotheses will be tested by virtue of the following specific aims: i) to define the relative contributions of distinct DNA repair mechanisms to the formation of inversions; ii) to establish whether CGRs are genomic signature of inversions; and iii) to investigate the scale of contribution of de novo inversions to sporadic diseases. To overcome the limitations of each methodology, a combined strategy of multiple genomic tools will be applied to characterize inversions and associated genomic alterations, consisting of whole genome sequencing (WGS) short-and long-reads, genome mapping classical cytogenetics, array CGH and/or SNP arrays. The results obtained in this application will lead to a more broadly definition for the term inversion, enable estimate of the contribution of mitotic and meiotic DNA repair mechanisms of their formation and reveal the frequency of origin and underlying genomic architecture. Moreover, it will identify candidate genes affected by that structural variant for further genetic and functional validation. In summary, this application will strongly impact our understanding of human biological processes and disease mechanisms associated with inversions with broad implications for diagnosis of birth defects, human development, infertility and cancer. This application will also establish common grounds to bridge studies of rare and common diseases, human evolution and population genetics.