Looking beyond the genes: the role of non-coding variants in human disease

Abstract

Over the past decades the search for disease causing variants has been focusing exclusively on the coding genome. This highly selective approach has been extremely successful resulting in the identification of thousands of disease genes, but ignores the functional and therefore disease relevance of the rest of the genome. Dropping sequencing costs and new high-throughput technologies such as ChIP-seq and chromosome conformation capture have opened new possibilities for the systematic investigation of the non-coding genome. These data have revealed the importance of non-coding DNA in fundamental processes such as gene regulation and 3D chromatin folding. Research into the principles of chromatin folding has revealed a domain structure of the genome, called topologically associated domains that provide a scaffold for enhancer promoter contacts. Non-coding mutations that affect regulatory elements can affect gene regulation by a loss of function, resulting in reduced gene expression, or a gain of function resulting in gene mis- or overexpression. Structural variations such as deletions, inversions or duplications have the potential to disturb normal chromatin folding. This may lead to the repositioning or disruption of topological associating domains and the relocation of enhancer elements with consecutive gene misexpression. Several recent studies highlight this as important disease mechanisms in developmental disorders and cancer. Therefore, the regulatory landscape of the genome has to be taken into consideration when investigating the pathology of human disease. In this review, we will discuss the recent discoveries in the field of non-coding variation, gene regulation, 3D genome architecture, and their implications for human genetics.

The Role of Copy Number Variants in Disorders of Sex Development

“…Regulatory elements associate with genes within their local topologically associating domains (TADs) which, in turn, are influenced by the overall 3D structure of the chromatin in the nucleus. CNVs can alter this interaction between regulatory elements and their promoters [Franke et al, 2016;Spielmann and Mundlos, 2016]. Consequently, CNVs that alter transcription factor binding to noncoding elements, such as enhancers, may be responsible for a significant proportion of previously undiagnosed DSD.…”

A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula

“…Moreover, mutations may reside outside genes. For example, structural variations and point mutations may disturb normal chromatin folding with consecutive gene misexpression, a disease mechanism known from developmental disorders and cancer 17 . Finally, the recent identification of mutations in CEP78 in patients with an Usher-like phenotype 18 illustrates that novel disease genes have to be taken into account even in mutation-negative Usher syndrome patients.…”

Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach

“…This cis - acting effect of non-coding variations has been recently demonstrated for a SNP in a distal enhancer element regulating the expression of SNCA (Soldner et al 2016). Some representative pictures about the mechanisms of non-coding variants and their implication in human genetics are reported in a number of excellent reviews (Spielmann and Mundlos 2016; Lupianez et al 2016; Spielmann and Mundlos 2013), which the reader is referred to.…”