Integrated in silico functional analysis predicts autism spectrum disorders to be burdened by deleterious variations within CHD8 core domains and its CHD7-binding motif

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder presenting with social and communication deficits, restricted, repetitive behaviours and interest. Several recurrently mutated genetic risk factors have been implicated in ASD manifestation.Chromodomain helicase remodeller(CHD8) is one such master regulator mediating the expression of genes controlling neuron functions. We collected 8124 exonic SNPs inCHD8 from four databases representing the general and ASD populations and subjected them to multi-layered analyses on  >  25 computational tools. We observed that nsSNPs were common in the general population. Contrastingly, the ASD population recorded significantly higher incidences of truncating SNPs than the general population (P <  0.0001). Distinct hotspots for truncating and nsSNPs were identified within exons encoding CHD8’s N and C terminals, respectively. The evolutionarily conserved CHD8 core domains—helicase C-terminal, helicase ATP-binding and SNF2_N domains—recorded the lowest density of SNPs that were predic ted to be severely damaging. Conversely, the evolutionarily variable regions—CHD7-binding and BRK domains—that hosted the highest aggregate of SNPs were largely benign. Post-translational modifications (PTMS) occurred frequently on residues outside the CHD8 domains (P <  0.01); i.e. on non-conserved regions including the N and C terminals, which were also predicted to be intrinsically disordered protein regions...
Source: Network Modeling Analysis in Health Informatics and Bioinformatics - Category: Bioinformatics Source Type: research