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Start Over Descriptor "Gene insertion" Journal cell reports
2 results on '"Gene insertion"'

1. Conserved and divergent DNA recognition specificities and functions of R2 retrotransposon N-terminal domains.

Author

Lee, Rosa, Horton, Connor, Van Treeck, Briana, McIntyre, Jeremy, and Collins, Kathleen

Subjects
CP: Molecular biology, DNA-binding specificity, Myb domain, R2 retrotransposon, gene insertion, gene therapy, genome engineering, non-LTR retrotransposon, protein-DNA interaction, zinc finger, Retroelements, Humans, DNA, Zinc Fingers, Protein Domains, Protein Binding
Abstract

R2 non-long terminal repeat (non-LTR) retrotransposons are among the most extensively distributed mobile genetic elements in multicellular eukaryotes and show promise for applications in transgene supplementation of the human genome. They insert new gene copies into a conserved site in 28S ribosomal DNA with exquisite specificity. R2 clades are defined by the number of zinc fingers (ZFs) at the N terminus of the retrotransposon-encoded protein, postulated to additively confer DNA site specificity. Here, we illuminate general principles of DNA recognition by R2 N-terminal domains across and between clades, with extensive, specific recognition requiring only one or two compact domains. DNA-binding and protection assays demonstrate broadly shared as well as clade-specific DNA interactions. Gene insertion assays in cells identify the N-terminal domains sufficient for target-site insertion and reveal roles in second-strand cleavage or synthesis for clade-specific ZFs. Our results have implications for understanding evolutionary diversification of non-LTR retrotransposon insertion mechanisms and the design of retrotransposon-based gene therapies.

Published
2024

2. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

Author

Nicholas M. DiLullo, Nicholas Carriero, Bernie Devlin, Adam Yongxin Ye, Stephen Sanders, Vanessa H. Bal, Shan Dong, Michael F. Walker, Liping Wei, Stephanie Frahm, John F. Keaney, Jeanselle Dea, Kathryn Roeder, Nicole A. Teran, A. Jeremy Willsey, Michael Sheldon, Rehab O. Khalil, Sinem M. Sertel, Abha R. Gupta, Jake Gockley, Zafer Yüksel, Jeffrey D. Mandell, Catherine A.W. Sullivan, Zainulabedin Waqar, Luis E. Gonzalez, A. Gulhan Ercan-Sencicek, Matthew W. State, Michael DiCola, Andrew Brooks, John D. Overton, and Shrikant Mane

Subjects
Proband, Male, Mutation rate, frameshift mutation, genetic association, Medical Physiology, genetic identification, paternalism, animal cell, genetic risk, open reading frame, Fragile X Mental Retardation Protein, single nucleotide polymorphism, synapse, genetic variability, 2.1 Biological and endogenous factors, Aetiology, indel mutation, Child, Frameshift Mutation, lcsh:QH301-705.5, PHF3 gene, Sequence Deletion, Genetics, Pediatric, chromatin structure, food and beverages, regulating synaptic exocytosis 1, Phenotype, unclassified drug, Pedigree, DNA-Binding Proteins, Mental Health, female, Autism spectrum disorder, protein protein interaction, fragile X mental retardation protein, sequence alignment, KMT2E gene, Female, gene insertion, parental age, RIMS1 gene, Child Development Disorders, Intellectual and Developmental Disabilities (IDD), sex difference, CHD2 gene, autism, Nerve Tissue Proteins, mixed lineage leukemia protein 5, gene sequence, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Frameshift mutation, animal tissue, Sex Factors, male, GTP-Binding Proteins, mental disorders, medicine, Humans, controlled study, human, cell protein, Indel, gene, Gene, mouse, Pervasive, nonhuman, gene deletion, human cell, intellectual impairment, missense mutation, Human Genome, Chromosome, DNA, medicine.disease, major clinical study, human tissue, Brain Disorders, lcsh:Biology (General), Child Development Disorders, Pervasive, mixed lineage leukemia protein, Biochemistry and Cell Biology, exome
Abstract

Summary: Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0–2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10−9), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. : Insertions and deletions (indels) have proven especially difficult to detect in exome sequencing data. Dong et al. now identify indels in exome data for 787 autism spectrum disorder (ASD) families. They demonstrate association between de novo indels that alter the reading frame and ASD. Furthermore, by observing clustering of indels in unrelated probands, they uncover two additional ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

Published
2014
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