Long Read Genome Sequencing Elucidates Diverse Functional Consequences of Structural and Repeat Variation in Autism
Mortazavi, M.; Guevara, J.; Diaz, J.; Tran, S.; Ziaei Jam, H.; Batalov, S.; Bainbridge, M.; Besterman, A. D.; Gymrek, M.; Palmer, A. A.; Sebat, J.
Show abstract
Long-read whole genome sequencing (LR-WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR-WGS on 267 individuals from 63 ASD families and generated an integrated call set combining long- and short-read data. LR-WGS increased detection of gene-disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication-deletion events. By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes, and demonstrated the effect of intermediate TR expansions (35-54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% CI: 2.7-17%) of the heritability of ASD. These findings demonstrate how LR-WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature 97%
- Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder 97%
- Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation 97%
Similar papers in this journal
- Rare coding variation illuminates the allelic architecture, risk genes, cellular expression patterns, and phenotypic context of autism 98%
- The impact of rare protein coding genetic variation on adult cognitive function 96%
- Comprehensive multiomic profiling of somatic mutations in malformations of cortical development 96%
Similar papers in this journal
Similar papers in this journal
- A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project. 95%
- Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination 95%
- Defining and Reducing Variant Classification Disparities 94%
Similar papers in this journal
- Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes 97%
- Variant-resolved prediction of context-specific isoform variation with a graph-based attention model 96%
- Polymorphic short tandem repeats make widespread contributions to blood and serum traits 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.