Chapter 11 - The regulatory genome and defects in monogenic diseases

Abstract

The emergence of whole genome sequencing and increased information on gene regulation have led to discoveries indicating that defects in transcriptional enhancer elements can lead to specific disorders. Furthermore, evidence has emerged that transcriptional enhancer element changes can play roles in Mendelian single-gene disorders and in polygenic disorders. Identification of specific epigenetic modifications has been useful in the identification of active enhancer elements. Chromatin conformation capture analyses and chromatin looping data can identify enhancer–promoter contacts. Impaired enhancer interaction with the Sonic Hedgehog gene, SHH, was shown to lead to the defects in preaxial polydactyly. In 10 different families with a history of pancreatic disorder, a defect was found in an enhancer element approximately 25kb downstream of the PTF1A gene that encodes a product that impacts pancreas development. Comprehensive analyses of genomic sites have led to the identification of variants that impact levels of expression of genes. Some of the sites are labeled as expression quantitative Trait Loci Factors that determine homeostasis in certain processes are increasingly being analyzed. Homeostasis is also dependent on autophagic processes involved in the removal of damaged proteins or organelles and removal of abnormal accumulations of certain substances e.g., iron. New studies have shed light on roles of the regulatory genome in neurodevelopment.