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Autism Spectrum Disorder is burdened by severely pathogenic variations within core domains of CHD8 and its CHD7-binding motif
  • Ashitha SNM,
  • Suryanarayanan Balakrishnan,
  • Ramachandra Nallur
Ashitha SNM
University of Mysore
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Suryanarayanan Balakrishnan
University of Mysore
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Ramachandra Nallur
University of Mysore
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Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder presented 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 gene that is a master regulator mediating the expression of genes controlling neuron functions. We collected 8,124 exonic SNPs in CHD8 from 4 databases representing the general and ASD populations; subjected them to multi-layered analyses on >20 computational tools. We observed that nsSNPs were common in the general population. Distinct hotspots for truncating and nsSNPs were identified within exons encoding the N and C terminals, respectively. Evolutionarily conserved regions involving CHD8 core domains: Helicase-C-terminal, Helicase-ATP-binding and SNF2_N domains, recorded the lowest density but severely pathogenic SNPs. Conversely, evolutionarily variable regions- CHD7-binding and BRK domains- hosted the highest SNPs, but were benign. Post-Translational-Modifications (PTMS) occurred on residues outside domains (P<0.01) i.e., non-conserved regions of CHD8 including the N and C terminals that were determined to be Intrinsically-Disordered-Protein-Regions (IDPRs) with 9 Molecular-Recognition-Features sites. Contrastingly, ASD population recorded significantly higher incidences of truncating SNPs than general population (P<0.0001). ASD-SNPs frequently occurring within core domains were severely damaging and accounted for >30% of all ASD variations. The CHD7-DNA-binding motif, with most PTMs, recorded the highest recurring truncating ASD-SNPs. The CHD8 PPIs effortlessly recapitulated the phenotypes presented by children with CHD8 mutations. 11/13 (84.6%) interacting molecules were IDPs. We identified 9 CHD8 nsSNPs that produced the strongest long-range disturbances, altering the modelled protein’s global conformational dynamics.

Peer review status:UNDER REVIEW

06 Aug 2020Submitted to PROTEINS: Structure, Function, and Bioinformatics
06 Aug 2020Assigned to Editor
06 Aug 2020Submission Checks Completed
14 Sep 2020Reviewer(s) Assigned