AI Article Synopsis
- Mutations (DNMs) play a significant role in Autism Spectrum Disorder (ASD), with whole genome sequencing revealing that 75.6% of germline DNMs come from fathers, particularly increasing with paternal age.
- Clustering of DNMs in ASD cases is more likely to originate from mothers and is often found near elevated mutation rates associated with copy number variations (CNVs).
- An analysis of DNM patterns shows a higher occurrence of damaging DNMs in ASD cases, including significant contributions from non-coding regions, suggesting that non-coding variants may influence the genetic landscape of ASD.
Article Abstract
mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10), but they could also be found adjacent to copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10; OR=1.84), of which 15.6% (p=4.3×10) and 22.5% (p=7.0×10) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes and Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980121 | PMC |
| http://dx.doi.org/10.1038/npjgenmed.2016.27 | DOI Listing |
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Article Synopsis
- De novo mutations (DNMs) are crucial in understanding genetic disorders but studying them is challenging due to technology limits in detecting rare mutations.
- Duplex Sequencing (DS) offers a highly accurate method, with a detection error of less than 1 in a billion base pairs, and was applied in this study to analyze DNA from blood and sperm of healthy young men.
- The results show a higher frequency of mutations in sperm than in blood, highlighting DS's capability to identify and quantify DNMs, which could help in understanding genetic diseases and hereditary risks.
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