Autism Spectrum Disorder is burdened by severely pathogenic
variations within core domains of CHD8 and its CHD7-binding motif
Ashitha S Niranjana Murthy, Suryanarayanan Thangalazhi Balakrishnan and
Nallur B Ramachandra*
Genetics and Genomics Laboratory, Department of Studies in Genetics and
Genomics, University of Mysore, Manasagangotri-570006, Karnataka, India
Ms. ASHITHA S NIRANJANA MURTHY, M.Sc.
Ph.D. Student
Genetics and Genomics Laboratory,
Department of Studies in Genetics and Genomics,
University of Mysore,
Manasagangotri- 570006,
Karnataka, India
ashitha@zoology.uni-mysore.ac.in
Mr. SURYANARAYANAN THANGALAZHI BALAKRISHNAN, M.Sc.
M.Sc. Student
Department of Zoology
St Aloysius College, Elthuruth, Thrissur
Kerala - 680611
suryantb1995@gmail.com
*Corresponding Author: Dr. NALLUR BASAPPA RAMACHANDRA
Emeritus Professor and Principal Investigator
Department of Studies in Genetics and Genomics,
University of Mysore,
Manasagangotri-570006,
Karnataka, India
nallurbr@gmail.com
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 inCHD8 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.
Keywords: Autism Spectrum Disorders (ASD); Chromodomain
Helicase DNA-binding protein 8 (CHD8); Intrinsically Disordered Protein
(IDP); Molecular Recognition Features (MoRFs);
Protein-protein-interaction (PPI) networks; Conformational dynamics.