Mobile element insertion detection in 89,874 clinical exomes

Torene, Rebecca; Galens, Kevin; Liu, Shuxi; Arvai, Kevin J.; Borroto, Carlos; Scuffins, Julie; Zhang, Zhancheng; Friedman, Bethany; Sroka, Hana; Heeley, Jennifer; Beaver, Erin; Clarke, Lorne; Neil, Sarah; Walia, Jagdeep S.; Hull, Danna; Juusola, Jane; Retterer, Kyle

doi:10.1038/s41436-020-0749-x

Cited by 46 publications

(54 citation statements)

References 21 publications

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“…Our study is limited in that only one tool was used to identify MEIs. Though the overall performance of MELT outperformed existing MEI discovery tools (Gardner et al 2017) and it has been successfully used in several large-scale studies (Gardner et al 2017(Gardner et al , 2019Feusier et al 2019;Werling et al 2018;Torene et al 2020), but the detection power could be compromised by modest sequencing depth and incompetence in complex genomic regions of short-read WGS etc. In addition, the overall genotyping accuracy by MELT v2 was 87.95% for non-reference Alus (not excluding MEIs in low complexity regions), when compared with PCR generated genotypes (Goubert et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of mobile element insertions in human genomes

Niu

Teng

et al. 2021

Preprint

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Mobile element insertions (MEIs) are a major class of structural variants (SVs) and have been linked to many human genetic disorders, including hemophilia, neurofibromatosis, and various cancers. However, human MEI resources from large-scale genome sequencing are still lacking compared to those for SNPs and SVs. Here, we report a comprehensive map of 36,699 non-reference MEIs constructed from 5,675 genomes, comprising 2,998 Chinese samples (∼26.2X, NyuWa) and 2,677 samples from the 1000 Genomes Project (∼7.4X, 1KGP). We discovered that LINE-1 insertions were highly enriched at centromere regions, implying the role of chromosome context in retroelement insertion. After functional annotation, we estimated that MEIs are responsible for about 9.3% of all protein-truncating events per genome. Finally, we built a companion database named HMEID for public use. This resource represents the latest and largest genomewide study on MEIs and will have broad utility for exploration of human MEI findings.

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Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of mobile element insertions in human genomes

Niu

Teng

et al. 2021

Preprint

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“…Since intronic TEIs can affect gene function through various mechanisms, such as altering RNA expression and splicing 1; 8 , TEIs contributing to ASD may present a phenotype different from known phenotypes caused by LoF coding mutations or large CNVs in these genes. Including TEIs and structural variants in standard clinical genetic analyses for ASD will continue to expand our knowledge of non-coding mutations and could increase the rates of genetic diagnoses 17 . Our work also presents important advances in scalable bioinformatic processing and identification of TEIs, which by their nature represent a challenging form of genomic variation to study.…”

Section: Main Textmentioning

confidence: 99%

Whole-genome analysis ofde novoand polymorphic retrotransposon insertions in Autism Spectrum Disorder

Monroy

Chu

Dias

et al. 2021

Preprint

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Retrotransposons are dynamic forces in evolutionary genomics and have been implicated as causes of Mendelian disease and hereditary cancer, but their role in Autism Spectrum Disorder (ASD) has never been systematically defined. Here, we report 86,154 polymorphic retrotransposon insertions including >60% not previously reported and 158 de novo retrotransposition events identified in whole genome sequencing (WGS) data of 2,288 families with ASD from the Simons Simplex Collection (SSC). As expected, the overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed more de novo L1 insertions than expected in ASD genes, and we also found de novo intronic retrotransposition events in known syndromic ASD genes in affected individuals but not in controls. Additionally, we observed exonic insertions in genes with a high probability of being loss-of-function intolerant, including a likely causative exonic insertion in CSDE1, only in ASD individuals. Although de novo retrotransposition occurs less frequently than single nucleotide and copy number variants, these findings suggest a modest, but important, impact of intronic and exonic retrotransposition mutations in ASD and highlight the utility of developing specific bioinformatic tools for high-throughput detection of transposable element insertions.

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“…The majority are Alu insertions 17 and only a few SVA (n = 16). Recently, large studies have evaluated the impact of MEI in patients between 0.04 and 0.15% of the cases 18,19 …”

Section: Discussionmentioning

confidence: 99%

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome

et al. 2020

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Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid‐specific SINE‐R/VNTR/Alu type F (SVA‐F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD‐SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient‐derived cell lines confirmed that the BBS1 SVA‐F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

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Mobile element insertion detection in 89,874 clinical exomes

Cited by 46 publications

References 21 publications

Genome-wide analysis of mobile element insertions in human genomes

Genome-wide analysis of mobile element insertions in human genomes

Whole-genome analysis ofde novoand polymorphic retrotransposon insertions in Autism Spectrum Disorder

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome

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