Understanding Neurodevelopmental Disorders: The Promise of Regulatory Variation in the 3′UTRome

Abstract

Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1% to 2% of the human genome. With the advent of whole genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and noncoding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of noncoding variants identified per individual can be overwhelming, making it prudent to focus on noncoding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3'UTRome is a region of the noncoding genome that perfectly fulfills these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3'UTRome as binding sites for microRNAs or RNA binding proteins, or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3'UTRome will lead to the identification of new risk factors, new candidate disease genes, and a better understanding of the molecular mechanisms contributing to neurodevelopmental disorders.

Electroacupuncture Promoted Nerve Repair After Peripheral Nerve Injury by Regulating miR-1b and Its Target Brain-Derived Neurotrophic Factor

“…MicroRNAs (miRNAs) account for 2–3% of the total number of human genes, which mainly mediate gene silencing by binding to the 3′ untranslated regions (3′ UTR) of target miRNAs ( Wanke et al, 2018 ), make up an important and significant fraction of the regulation of various signaling pathways and biological processes in the repair of PNI ( Treiber et al, 2019 ). Recent researches suggested that miRNAs play an important role in PNI; hence, they have attracted increasing interest in peripheral nerve regeneration field ( Yu et al, 2015 ).…”

Genome-wide investigation of an ID cohort reveals de novo 3′UTR variants affecting gene expression

“…Variants that affect non-coding regulatory regions of the genome may influence brain development and function via their critical role in regulating gene expression, and have been previously implicated in neurodevelopmental disorders (Wanke et al 2018 ). In this study, we hypothesised that de novo variation in 3′UTR regulatory regions may be a possible mechanism through which non-coding mutations contribute to ID.…”

A Point Mutation in the RNA Recognition Motif of CSTF2 Associated with Intellectual Disability in Humans Causes Defects in 3′ End Processing

“…Comparable issues may arise with CSTF2's role in histone mRNA processing efficiency, affecting the cell cycle (Romeo et al, 2014;. These C/P changes subsequently affect post-transcriptional regulation of key mRNAs by changing 3 UTR regulation by revealing miRNA or RNA-binding protein sites, or by changing targeted localization of mRNAs to neural projections (Ciolli Mattioli et al, 2019;Fontes et al, 2017;Hafner et al, 2019;Jereb et al, 2018;Nazim et al, 2017;Taliaferro et al, 2016;Wanke et al, 2018).…”

“…Similarly, mutations in mRNA processing genes encoding decapping enzymes (Ahmed et al, 2015;Ng et al, 2015), the polyglutamine binding protein 1 (PQBP1, Kalscheuer et al, 2003), spliceosomal proteins (Carroll et al, 2017), hnRNA-binding proteins (Bain et al, 2016), mRNA surveillance proteins (Tarpey et al, 2007), and cleavage and polyadenylation factors (Gennarino et al, 2015) cause intellectual disabilities. These disorders are associated with changes in the mRNA processing landscape, especially 3 end cleavage and polyadenylation (C/P), highlighting the importance of RNA processing in controlling neuronal function (Fontes et al, 2017;MacDonald, 2019;Szkop et al, 2017;Wanke et al, 2018).…”