Non-coding genetic variants in human disease

Abstract

Genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), in the non-coding regions of the human genome can play an important role in human traits and complex diseases. Most of the genome-wide association study (GWAS) signals map to non-coding regions and potentially point to non-coding variants, whereas their functional interpretation is challenging. In this review, we discuss the human non-coding variants and their contributions to human diseases in the following four parts. (i) Functional annotations of non-coding SNPs mapped by GWAS: we discuss recent progress revealing some of the molecular mechanisms for GWAS signals affecting gene function. (ii) Technical progress in interpretation of non-coding variants: we briefly describe some of the technologies for functional annotations of non-coding variants, including the methods for genome-wide mapping of chromatin interaction, computational tools for functional predictions and the new genome editing technologies useful for dissecting potential functional consequences of non-coding variants. (iii) Non-coding CNVs in human diseases: we review our emerging understanding the role of non-coding CNVs in human disease. (iv) Compound inheritance of large genomic deletions and non-coding variants: compound inheritance at a locus consisting of coding variants plus non-coding ones is described.

Figure 1.

(A) Functional CNVs in the gene-flanking regions are associated with human diseases (not to scale). References: POU3F4 (48), IRGM (49), NR0B1 (50), PMP22 (51,52), SHOX (53), PLP1 (54) and SOX9 (–58). (B) Various CNVs/SVs in the genomic region involving WNT6, IHH and PAX3 genes can cause different phenotypes of limb malformations (59). Deletion (del) is shown in green bar, duplication (dup) in red and inversion in blue.