Genetic Complexity of the Human Genome in Health and Disease: Basic Concepts

Abstract

Determination of the DNA sequence of the human genome, revealing extensive genetic variation, and the mapping of the genes and the various regulatory elements of genome function within the genomic DNA, has revolutionized the way we view the states of health and disease in our time. Genetic complexity of the genome is manifested on different levels. The first level refers to the expression of protein coding genes, as regulated by their individual promoter in linear proximity. The next level of genetic complexity involves long distance action by far away enhancers, interacting with promoters through DNA looping. This 3-dimensional (3D) regulation is further developing by chromosome folding into the so called transcription factories, for fully physiological expression. Chromosome folding, mediated by specific genetic elements – insulators – is adding to the genetic complexity by facilitating movements of chromatin of specific genomic regions – the so-called topologically associated domains (TAD) in support of transcription and other cellular functions. Further genetic complexity has emerged with the finding that over 75% of the genome is transcribed and except of the coding genes, a plethora of RNA transcripts are produced – the non-coding RNA – that has important regulatory roles in the gene expression context. The great variation of genome sequence and regulatory elements of the genome architecture are exploited in studies of genome-wide association with disease, in the framework of Precision Medicine and in general of Genomic Medicine.