Coding and noncoding: The dual function of DNA sequences and their role in human diseases

Most of our genome comprises noncoding sequences that include diverse transcriptional regulatory elements, such as enhancers, while only ~1.5% of the genome codes for proteins. Nevertheless, DNA sequences that code for protein (exons) can also function as enhancers that regulate transcription. Mutations in exonic-enhancers can lead to multiple phenotypes due to their dual function. Here, we show that structural variants of protein coding genes can lead to craniofacial disorders due to disruption of exonic- enhancers of the nearby gene/s. Moreover, the prevalence of protein-coding sequences that possess transcriptional regulatory function and the consequences of their mutations are not well described. Using advanced sequencing technologies and in vivo functional assays, protein-coding sequences were analyzed for their potential regulatory function in mammalian cells and found to be overrepresented in the genome (>6%). Dissection of the enhancer activity of exons at single nucleotide resolution has demonstrated that: (1) most nucleotide changes with high impact effect are deleterious; (2) deleterious enhancer mutations are correlated with the location of transcription factor-binding sites; (3) synonymous and non-synonymous mutations have similar effects on enhancer activity; and (4) the transcription factor repertoire that controls the activity of enhancers differs across cell types, indicating differences in deleterious mutation profiles. Thus, exonic-enhancer mutations can disrupt both protein structure and enhancer activity with differential effect across cell types, suggesting that mutations in genes could cause phenotypes that have nothing to do with their protein-coding function but are due to their additional hidden regulatory function.