Principles and methods of in-silico prioritization of non-coding regulatory variants

Abstract

Over a decade of genome-wide association, studies have made great strides toward the detection of genes and genetic mechanisms underlying complex traits. However, the majority of associated loci reside in non-coding regions that are functionally uncharacterized in general. Now, the availability of large-scale tissue and cell type-specific transcriptome and epigenome data enables us to elucidate how non-coding genetic variants can affect gene expressions and are associated with phenotypic changes. Here, we provide an overview of this emerging field in human genomics, summarizing available data resources and state-of-the-art analytic methods to facilitate in-silico prioritization of non-coding regulatory mutations. We also highlight the limitations of current approaches and discuss the direction of much-needed future research.

Figure 1. Functional category of SNPs registered in the GWAS Catalog

The 3′ untranslated regions (3′ UTRs) of mRNAs contain binding sites for microRNAs and have a role in mRNA stability and translation. 5′ UTRs contain regulatory elements for both transcription and translation stages, such as the 5′‐cap structure, translation initiation motifs and internal ribosome entry sites.

Figure 2. Schematic model illustrating major regulatory elements

1) transcription factors interacting with RNA polymerase II and the promoter sequence to initiate the transcription of gene coding exons, 2) Co-activators binding to transcription factors to recruit enhancers, 3) histone modifications and DNA methylation, 4) silencers, repressors, and insulators, and 5) non-coding RNA.