Biology subjects

Parikshak, N.

Publications and source records attributed to Parikshak, N..

2 recordsLinked to original sources

bioRxiv2018

Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in postmortem human brain tissue.

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the cerebellum. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically-defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

genomics↗

bioRxiv2017

Sex Chromosome Dosage Effects On Gene Expression In Humans

A fundamental question in the biology of sex-differences has eluded direct study in humans: how does sex chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex chromosome aneuploidies (XO, XXX, XXY, XYY, XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity amongst evolutionarily preserved X-Y homologs, and update prevailing theoretical models for SCD compensation by detecting X-linked genes whose expression increases with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex chromosome genes regulate specific co-expression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. Our findings detail wide-ranging effects of SCD on genome function with implications for human phenotypic variation.\n\nSIGNIFICANCE STATEMENTSex chromosome dosage (SCD) effects on human gene expression are central to the biology of sex differences and sex chromosome aneuploidy syndromes, but challenging to study given the co-segregation of SCD and gonadal status. We address this obstacle by systematically modelling SCD effects on genome wide expression data from a large and rare cohort of individuals with diverse SCDs (XO, XX, XXX, XXXX, XY, XXY, XYY, XXYY, XXXXY). Our findings update current models of sex chromosome biology by (i) pinpointing a core set of X- and Y-linked genes with \"obligate\" SCD sensitivity, (ii) discovering several non-canonical modes of X-chromosome dosage compensation, and (iii) dissecting complex regulatory effects of X-chromosome dosage on large autosomal gene networks with key roles in cellular functioning.

genomics↗