Genetic Basis of Disease

Abstract

Differences between our individual genomes not only make us appear different from each other; these differences also play a key role in determining disease susceptibility. The effect of a single alteration in the DNA sequence may range from a certainty of severe disease to a slight predisposition that may become manifest in the presence of other genetic or environmental influences. The vast array of mechanisms by which genetic changes can lead to disease reflects the overall complexity of the underlying biological processes and the variety of ways in which these can be disrupted. Key Concepts Genetic disease can be due to a variety of different types of alteration in the human genome: extra or missing chromosomes, large chromosomal rearrangements, smaller deletions, insertions or substitutions of one or more nucleotides and even changes affecting the ability of genes to be switched on (epigenetics). Genetic variation is a normal characteristic of the human genome, and the effects of genetic variants range across a whole spectrum of substantial effect (complete loss of function or significant gain of function) to relatively minor or even zero effect on function. Genetic variants that are associated with disease are termed pathogenic, whilst variants that appear to have no significant effect upon health are termed benign. Recessive genetic disorders are a consequence of loss of function in both gene copies (i.e. both the maternally inherited and paternally inherited copies). Dominant genetic disorders are caused by either gain of function in one gene copy (either maternally or paternally inherited), or by loss of function in one gene copy in cases where the amount of gene product from a single gene copy is insufficient. Some genetic disorders are a consequence of alterations affecting the mitochondrial DNA. Although we inherit most of our genetic variants from our parents, we each have a number of de novo genetic changes, which may occasionally be associated with disease; some DNA sequences in our genome (e.g. triplet repeats) are particularly prone to new mutations. Cancer is a disease that is associated with the accumulation of multiple genetic changes that generally occur over the lifetime of the individual. Variants present in our genome make a contribution to virtually all human disease, sometimes as a consequence of cumulative effects of many variants across the genome which have small individual effects.