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De novo Germline Mutation and Autism: A Global View of Mutability on Human Diseases

De novo Germline Mutation and Autism: A Global View of Mutability on Human Diseases

In an article entitled, “Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation,” published on 21st Dec 2012 issue of Cell (151:1431–1442), the lead author Jacob J. Michaelson with twenty-seven other associates from thirteen research groups have reported the results of their latest investigation on de novo germline mutation by whole genome sequencing in autism patients. This study provides a global view of the landscape of mutability and its influence on genetic diversity and susceptibility to autism and its implications on other human diseases. The results  shed new light on a deeper understanding of the mechanisms underlying genome evolution and human diseases. They investigated global patterns of germ-line mutation by whole genome sequencing of 10 monozygotic (MZ) twins concordant for autism spectrum disorders (ASD) and their parents, and examined the genetic association of genes and nucleotide substitution hotspots with disease in independent data sets. A total of 581 germ-line de novo mutations (DNMs) were detected in 10 MZ twin pairs and DNMs displayed a remarkably non-random positioning in the genome (P < 10-10). They applied a simple statistical approach to clustering mutations and defined > 20 regions where DNMs occur at a significantly high density. Notably, some hotspots included genes that have been previously implicated in ASD. Five of the 26 genes found in their study were impacted by mutations in an independent data set from recent exome (the part of the genome formed by exons) sequencing studies of ASD (7 DNMs in cases and 0 in controls), a higher degree of gene overlap than would be expected by chance (P=10-7). In addition, ASD cases showed a 3-fold enrichment of DNMs in hotspots compared to controls. The observed distribution of DNMs could be explained in part by intrinsic properties of the genome. On the whole, DNMs were biased toward regions with reduced GC-content, low nucleosome occupancy, and the researchers observed a weak bias toward late-replicating, heterochromatic regions. However, DNMs were also enriched within certain high-GC features, including recombination hotspots and transcribed sequences. Their findings suggest that rates of nucleotide substitution vary widely throughout the genome as a function of DNA sequence elements and their chromatin status. They also found that there was a significant relationship between human diseases and individual genetic variation model shaped by DNMs derived regional hyper-mutability. Furthermore, the finding of a large number of novel autism vulnerability genes will set a solid basis for the early diagnosis and an effective treatment of autism. [Summarized by BMB,DU graduate student, Samsad Razzaque]

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