Poster #5 - Simon Chu

Contribution of de novo retroelements to birth defects and childhood cancers in 3244 trios

Chu, Chong, PhD¹,²; Tran, Antuan¹; Ljungström, Viktor, PhD¹,³; Sexton, Corinne¹; Jin, Hu, PhD¹; Hamilton, Kayla V., MD⁴; Kamihara, Junne, MD, PhD⁴; Ting, David T., MD⁵; Park, Peter J., PhD¹* ¹ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA ² The Wistar Institute, Philadelphia, PA, USA ³ Department of Immunology, Genetics and Pathology, Uppsala University, Sweden ⁴ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA ⁵ Mass General Cancer Center, Harvard Medical School, Charlestown, MA, USA *Correspondence: Peter J. Park, PhD, Email: peter_park@hms.harvard.edu

Insertion of active retroelements-¬L1s, Alus, and SVAs-can disrupt proper genome function and lead to various disorders. However, the role of de novo retroelements (DNRTs) in birth defects and childhood cancers has not been well characterized due to limited data and a lack of efficient computational tools. Here, we analyzed whole-genome sequencing data from 3,244 trios across 12 birth defect and childhood cancer cohorts in the Gabriella Miller Kids First Pediatric Research Program. Using an improved version of our tool xTea (x-Transposable element analyzer) that incorporates a deep-learning module, we identified 162 DNRTs, as well as 2 pseudogene insertions. Several variants are likely to be causal, such as a de novo Alu insertion that resulted in the deletion of an entire exon in the NF1 gene in a proband with a brain tumor. We observed a high burden of de novo SVA insertions in both high-intolerance loss-of-function genes and exons, as well as a higher frequency of de novo Alu insertions of paternal origin. We also identified potential mosaic DNRTs from embryonic stages. Our study reveals the important roles of DNRTs in causing birth defects and predisposing children to cancers.