The Role of Noncoding Variants in Heritable Disease

A large proportion of the noncoding genome is functional and can harbor genetic variants that are causally related to Mendelian disorders or act to influence complex traits. Noncoding variants can influence gene expression or function through diverse functional units including untranslated regions, DNA regulatory elements, and noncoding RNAs. The current challenges for the interpretation of noncoding genetic variants include identifying the disease-relevant cell type, predicting and evaluating the underlying mechanisms, and the lack of appropriate in vivo models. A comprehensive understanding of the mechanisms and impact of noncoding genetic variation in human disease will assist future genetic diagnoses and selective targeting as a therapeutic strategy. The genetic basis of disease has largely focused on coding regions. However, it has become clear that a large proportion of the noncoding genome is functional and harbors genetic variants that contribute to disease etiology. Here, we review recent examples of inherited noncoding alterations that are responsible for Mendelian disorders or act to influence complex traits. We explore both rare and common genetic variants and discuss the wide range of mechanisms by which they affect gene regulation to promote disease. We also debate the challenges and progress associated with identifying and interpreting the functional and clinical significance of genetic variation in the context of the noncoding regulatory landscape. The genetic basis of disease has largely focused on coding regions. However, it has become clear that a large proportion of the noncoding genome is functional and harbors genetic variants that contribute to disease etiology. Here, we review recent examples of inherited noncoding alterations that are responsible for Mendelian disorders or act to influence complex traits. We explore both rare and common genetic variants and discuss the wide range of mechanisms by which they affect gene regulation to promote disease. We also debate the challenges and progress associated with identifying and interpreting the functional and clinical significance of genetic variation in the context of the noncoding regulatory landscape. a method that measures the frequency with which two DNA fragments interact within the 3D nuclear space. noncoding DNA sequences that regulate the transcription of nearby genes. a freely accessible public archive of reports that list information about genomic variation and human health. (clustered regularly interspaced short palindromic repeats) a technology that allows precise editing of DNA in the genome. nucleotide sequences that code information for protein synthesis. associations between genetic variants and gene expression. includes SNPs, small indels (fewer than 50 base pairs in length), and large structural variants. Structural variants (greater than 50 base pairs) can be copy-number variations, such as deletions and duplications, copy-number neutral, such as inversions and translocations, or often a combination of these. used to identify common genetic variants in different individuals associated with a particular disease or trait. a high-throughput 3C method that quantifies chromatin interactions between all possible pairs of DNA fragments simultaneously. nucleotide sequences within a gene that do not code information for protein synthesis. a class of regulatory ncRNAs (>200 nucleotides) that are involved in diverse cellular functions. a class of small ncRNAs (20–25 nucleotides) that inhibit target gene expression by binding to the 3′UTRs of target mRNAs to induce mRNA degradation and translational repression. a single-stranded RNA molecule transcribed from the DNA of a gene that carries the genetic information needed to make proteins. RNA molecules that are transcribed from DNA but not translated into proteins. a computationally derived number that reflects a person’s inherited risk for a particular disease or trait. a pyrimidine-rich region of the pre-mRNA that directs intron removal in pre-mRNA splicing. proteins that bind to RNA in cells and change the fate or function of the bound RNAs. a class of small ncRNAs (150 nucleotides) involved in the splicing of introns from pre-mRNA in the nucleus. associations between genetic variants and alternative splicing of pre-mRNAs. short DNA sequences (usually one to six nucleotides in length) that are repeated multiple times and lie adjacent to each other on the chromosome. defined as local domains within which genomic loci interact more frequently with one another than with surrounding regions. sequence-specific DNA-binding proteins that help to regulate gene transcription. DNA sequences that move from one location on the genome to another. regulatory regions of DNA located at the 5′ and 3′ ends of genes that are transcribed into mRNA but not translated into protein.