Genetic Basis of Disease


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.

Keywords: genetics; genome; disease; variant; recessive; dominant; mutation; epigenetics; complex disorders; cancer

Figure 1. Some chromosomal rearrangements. (a) Reciprocal translocations involve the exchange of segments between any two chromosomes. As illustrated here, these are often balanced, that is no genetic material is lost or gained. (b) Robertsonian translocations involve the long arms of two acrocentric chromosomes (13, 14, 15, 21, 22). While the long arms join together, the short arms are lost; however, this loss does not result in phenotypic consequences due to the fact that the genetic material found here is similar in all acrocentrics. (c) Inversions occur when part of a chromosome ‘flips’ within the chromosome and may include the centromere (pericentric inversion) as illustrated or not include the centromere (paracentric inversion).
Figure 2. DNA variants may affect many different aspects of gene function. Some examples of coding sequence variants are depicted. Note that frameshift may be caused by insertions or deletions of any number of nucleotides that is not a multiple of three. In‐frame deletions and in‐frame insertions may lead to alteration of codons at the site of the change, as in the example, where deletion of GGT has generated a histidine codon from the adjacent sequences, but downstream sequences are unaltered.
Figure 3. The overall active level of each gene product will vary depending on number of gene copies and any variants within each copy that affect activity of the product. Due to variants within genes, different individuals may make different levels of the gene product and/or versions of the gene product with more or less activity. A wide range of levels of a gene product may lead to a healthy overall phenotype. However, for some genes, there will be an upper and/or lower threshold beyond which a disease state is likely to ensue. For autosomal recessive disorders, the amount of product from one ‘normal’ gene is enough, whereas some autosomal dominant diseases are a consequence of the requirement for two ‘normal’ copies of the gene. Microdeletions, microduplications and aneuploidies may affect activity levels of several key gene products.
Figure 4. New mutations can have different consequences depending on when they occur. (a) A new mutation occurring during development can lead to gonadal mosaicism, whereby multiple gametes may carry a mutation. Therefore, more than one offspring may carry a mutation that is not detectable in parental blood samples. (b) A new mutation occurring in one gamete will generate a child who carries that mutation. (c) A new mutation occurring in the embryo will generate a mosaic offspring. For scenarios b and c, it is very unlikely that the same mutation would affect future offspring of the original couple. Note that gonadal mosaicism may also occur in females, and new mutations may also occur in oocytes.


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Further Reading

Jackson M, Marks L, May GHW and Wilson J (2018) The genetic basis of disease. Essays in Biochemistry 62: 643–723.

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Jackson, Maria, and Marks, Leah(Nov 2019) Genetic Basis of Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028790]