Variant

In humans, if the genomes of two individuals were compared, on average they would be between 99.8%–99.9% similar. It is the remaining small variation that accounts for all the differences seen between individuals. Although this may seem a tiny fraction, when applied to the 3 billion letters that make up the human genome, the numbers are significant: 0.1% represents three million individual changes.

Some genomic variants are harmless and will have no impact on health, whereas others account for physical differences or predisposition to specific health conditions.

Variants can either be inherited from a parent or they can occur de novo.

De novo variants are new variants that have arisen for the first time in the individual rather than being inherited from a parent. De novo variants can be caused by chance, impaired DNA repair, or increased mutation of the genome due to mutagens such as radiation and particular chemicals. As with all variants, de novo variants may, or may not, have functional consequences.

There are many different types of variant. Broadly these are either sequence changes, structural changes, or epigenetic changes.

Sequence changes occur when one base is changed for another. These are single nucleotide variants (SNVs). When a SNV occurs at a rate of more than about 1% in the population it is often called a single nucleotide polymorphism (SNP).

Structural changes to the genome can also change its sequence. Structural variants occur when sections of the genome are added (insertions), removed (deletions), rearranged (translocations) and duplicated (duplications). They can affect short sections only a few bases long, or large tracts several kilobases long. Whole chromosomes can also be duplicated or deleted. Deletions and duplications are copy number variants, they change the number of copies of that part of the genome that are present.

Epigenetic changes are changes to the DNA structure that do not alter the DNA sequence but can affect gene expression and an individual’s phenotype.

Variants that don’t just change one base for another might result in a frameshift variant. This changes the way that the genetic code is read during the process of creating an amino acid sequence. This can have severe implications on the production of the protein.

Nonsense variants occur when a DNA variant changes an amino acid coding codon to a stop codon. This results in a shorter, often non-functional protein.

Not all variants have an impact on phenotype, and those that do are not always pathogenic. When a variant does impact on phenotype this can be the result of a gain of function variant or a loss of function variant.

The size of the genomic variant is not reflective of the impact it will have, if any, on the individual. Large variants in the genome can have no effect, while smaller changes can.

Among all cases of achondroplasia, 99% are caused by a single base change in a particular gene that codes for a protein involved in the regulation of bone growth. This is an example of how a tiny change in a person’s genome can have a significant effect.

Conversely, studies have shown that large variants may have no effect at all on the individual. One study reported an individual who had a 9 million base-pair region missing from chromosome 4 and seemed unaffected. It should be noted, however, that the effect that any variant will have on an individual will depend on where in the genome it occurs.

• If the genomes of two individuals were compared they would be 99.8%–99.9% similar. All variation occurs in the remaining 0.1%–0.2%.
• Variants in our genome account not only for our physical traits, such as height, but can also impact on our health.
• The size of variants in the genome does not reflect the impact they will have on the individual.

For clinicians

• NHS England Genomics Education Programme: Genomics 101: From Genes to Genome course

References:

• Bateman MS, Mehta SG,  Willatt L and others. ‘A de novo 4q34 interstitial deletion of at least 9.3 Mb with no discernible phenotypic effect‘. American Journal of Medical Genetics 2010: volume 152A, issue 7, pages 1,764–1,769. DOI: 10.1002/ajmg.a.33426
• Nowakowska, B. ‘Clinical interpretation of copy number variants in the human genome‘. Journal of Applied Genetics 2017: volume 58, issue 4, pages 449–457. DOI: 10.1007/s13353-017-0407-4