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

> **NIH NIH R01** · PACIFIC NORTHWEST RESEARCH INSTITUTE · 2021 · $684,046

## Abstract

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.

## Key facts

- **NIH application ID:** 10252936
- **Project number:** 5R01GM132589-03
- **Recipient organization:** PACIFIC NORTHWEST RESEARCH INSTITUTE
- **Principal Investigator:** Claudia Carvalho Fonseca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $684,046
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10252936

## Citation

> US National Institutes of Health, RePORTER application 10252936, Uncovering inversion formation in the human genome and its impact to disease. (5R01GM132589-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10252936. Licensed CC0.

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