Various types of variant: what is genomic variation?

The diversity of differences in our genomes and their complex relationship with health and disease

Every human is unique, but if we were to look at our genomes we would find that we are 99.9% the same, genetically speaking. It is the remaining 0.1% that is responsible for all the differences that make each one of us individual. Genomic variation describes the differences between our genomes, which can vary in size, and if they have an impact on our health or not.

Single nucleotide polymorphisms

The most common form of genetic variants among individuals are the smallest, known as single nucleotide polymorphisms (SNPs), describing a change in a single nucleotide anywhere in the genome. A nucleotide change is considered an SNP if the changes at a particular position are seen in more than 1% of the population.

As SNPs occur on average every 300 nucleotides, there will be approximately 10 million SNPs in a person’s genome. The majority of these are harmless and not disease causing, and can be used by scientists as biological markers when investigating genes associated with disease. However, some SNPs are the direct cause of a particular condition. For example, Achondroplasia, in the majority of cases, results from a specific single base change in the FGFR3 gene, which leads to a change in a protein involved with bone growth. To put this into perspective, this gene contains a total of 2,236 SNPs, with only a small fraction of these being pathogenic.

Copy number variants

Copy number variants (CNVs) are regions of our genome that vary in copy and number, either due to duplication or deletion. These are classed as structural changes and recent scientific research suggests that up to 9.5% of the human genome may consist of copy number variants.1 Like SNPs, some CNVs exist that have no phenotypic consequence and simply contribute to the genetic variation between two individuals, whereas others exist that are disease causing.

Huntington’s disease is caused by repetition of the three base pairs (known as a tri-nucleotide repeat) CAG in the HTT gene. In a healthy individual, these 3 bases are repeated between 10 and 35 times, but in an individual with Huntington’s the repeats can number from 36 up to 120.

CNVs are also used to describe repeats of a whole gene. The human alpha-amylase 1 gene AMY1A, which codes for an enzyme that breaks down starch into sugars, can be present multiple times in a person’s genome, with one study reporting 14 copies of the gene in one individual.2 Interestingly, the number of repeats of this gene was found to be higher in populations with high-starch diets.

Translocations

SNPs and CNVs can be studied using methods such as whole genome/exome sequencing and microarrays, but some variations in our genomes are so large they are visible when looking at an individual’s karyotype. Chromosomal translocation is genomic variation as a result of genetic rearrangements between different chromosomes, or within the same chromosome. In their simplest form, translocations can be balanced, meaning an even exchange between chromosomes resulting in no loss or gain of genetic information, or unbalanced, where the rearrangement results in extra or missing genetic information.

Balanced translocations are usually harmless and carriers are often unware they have one. However, unbalanced translocations can result in complications and are associated with numerous health problems, including developmental delay defects and several types of cancer. A rearrangement of genetic material between regions of chromosome 9 and 22 is common in patients with a form of leukaemia, as it was discovered this translocation created a fusion of two genes that resulted in increased cell division.

It is clear the influence that genetic variation can have on the health of an individual is complicated. Large changes to our genome can have no effect at all, whereas the change of a single nucleotide can have a huge impact. The advent of technologies like whole genome sequencing will undoubtedly generate new uncharacterised variants that may at first seem to make matters more complex, yet it will be this wealth of information that will begin to provide answers.

References

1. (Zarrei, et al, Nature Genetics, 2015)
2. (Perry et al, Nature Genetics, 2007)