Genetic Variability in Humans – Why Does It Matter?

Feb 20, 2018 | Trends

Genetic variability can be defined as the genetic differences that exist within or between populations of individuals, and explains the remarkable differences between humans, despite the fact that we share 99.5 % of our DNA with each other.

Genetic variability includes differences in both the coding and non-coding regions of our DNA and is brought about by variants. Simply put, variants are genotype alterations (e.g., mutations) that may or may not result in observable changes (e.g., a novel trait, disease). For any given gene or allele present in a population, a number of variants exist. Variants may be benign e.g., those governing hair and eye color, or pathogenic e.g., the variants associated with some types of cystic fibrosis, diabetes, high blood pressure, and hereditary cardiomyopathy, to name a few.  

The Many Faces of Genetic Variants

Single Nucleotide Polymorphisms

Single nucleotide polymorphisms (SNPs) make a significant contribution to genetic variability, and can be used to track the inheritance of disease genes within families. A SNP is defined as a single nucleotide difference that is found in at least 1 % of all members of a given population. SNPs occur approximately every 100 to 300 bases, and are the most common type of sequence variation in humans. A staggering 84.7 million SNPs were found in the 2,504 individuals characterized during the 1000 Genomes Project (1).

Structural Variants

Structural variants typically involve DNA regions of more than 50 bp* in length, and as their name suggests, they bring about structural changes to our chromosomes. Variants in this category include indels, chromosomal translocations, inversions, and duplications.


Indel, short for ‘insertion’ and ‘deletion, refers to the small-scale gain or loss of base pairs in a DNA sequence. Indels are generally less than 1 kb in length, and when they occur, they result in two alleles that differ in length. Indels are challenging to study, and since it is rarely known whether the size difference between two alleles was caused by an insertion or a deletion, the name of this variant reflects both possibilities.

Indels that occur within coding regions and are divisible by three are referred to as in-frame indels. Indels that occur in protein-coding regions and are not divisible by three constitute frameshift mutations. Frameshift indels often lead to premature stop codons and truncated proteins, and therefore have a more pronounced functional affect than in-frame indels. Diseases associated with insertions and deletions include Tay-Sachs disease and Duchenne muscular Dystrophy, respectively.

Trinucleotide repeats constitute one indel subtype that is important in human disease. Here, a repetitive stretch of the same three nucleotides (a  triplet) may be prone to further expansions as the number of repeats increases. One of the best-known trinucleotide repeat diseases is Huntington’s Disease, a fatal brain disease which manifests when more than 36 CAG repeats occur in the HTT gene (that encodes the Huntingtin protein).

*Indels are an exception to this rule. They can also involve single nucleotide bases.

Chromosomal Translocations

Chromosomal translocations occur when a fragmented chromosome is joined to a non-homologous chromosome. This causes movement of alleles, either to different loci on the same chromosome or to a different chromosome. This happens during meiosis as part of normal chromosomal crossover, but may also occur throughout life upon exposure to mutagenic factors e.g., radiation and carcinogens. Diseases associated with translocations include Burkitt’s lymphoma and cases of schizophrenia related to chromosome 11.


An inversion occurs when a broken chromosome segment is reversed and inserted back into the chromosome, so that the location is correct but the orientation is opposite to what it was originally. In a so-called ‘balanced’ inversion, the resulting chromosome contains all of the genes that are present in a normal chromosome, while unbalanced inversions result in new chromosomal variants where certain genes are deleted or duplicated during the inversion process. Balanced inversions are usually benign, whereas unbalanced inversions may be associated with abnormalities such as developmental delays, mental retardation, and birth defects. Other conditions caused by inversions include Hemophilia A and Hunter Syndrome (a severe X-linked lysosomal storage disease).


Genetic duplications include gene and chromosomal duplications, and may occur for several reasons, most often errors during DNA replication and repair. The duplication regions may remain adjacent to each other (tandem duplication), or they may be separated by non-duplicated regions (displaced duplication). Duplications in the gene encoding amyloid precursor protein (APP) are strongly associated with early-onset Alzheimer’s disease. Duplications of whole chromosomes result in polyploidy, of which the best-known example is Down syndrome (caused by trisomy of chromosome in 21).

Copy Number Variations

Copy number variations (CNVs) are differences in the copy number of specific genes in a genome. CNVs, most often the result of duplications, may lead to gene dosage imbalances, because the amount of a given protein is usually proportional to the number of gene copies present. Some genes that were traditionally believed to exist as two copies per genome have now been found as one, three, or more copies. CNVs are found in cases of autism and Autosomal dominant leukodystrophy with autonomic disease (ADLD).

Why Should We Care About Genetic Variability?

Most SNPs occur in the non-coding regions between genes and play no role in an individual’s health or development. However, SNPs that occur within genes and regulatory regions may play a direct role in cancer, metabolic disorders, heart disease, and others. Beyond that, research has found that SNPs might help to predict an individual’s response to drugs, susceptibility to environmental factors e.g., toxins, and susceptibility to particular diseases.  

Not surprisingly, copy number variations can result in disease, due to too much or too little activity of the respective protein. Indeed, SNPs have traditionally been viewed as the most important type of variant in the human genome, but this view is changing since research has revealed that the copy number of certain genes may be elevated cancer. It is also thought that CNVs may influence an individual’s response to particular drugs.

Understanding how individuals within and between populations differ from each other at the genetic level will allow us to address fundamental questions about human biology and disease. The fact that genetic variability contributes to disease susceptibility and our response to certain drugs and environmental factors presents opportunities for improved diagnostics, personalized treatments, and risk-mitigation strategies as our understanding progresses further.

The FDA’s approval of ivacaftor for the treatment of a small subset of cystic fibrosis (CF) patients in 2012 is an excellent example of how knowledge about genetic variability in disease can be exploited to create personalized treatments. Initially, ivacaftor was deemed suitable only for CF patients who had at least one copy of the G511D mutation in the CFDR gene. However, research since its initial approval has found at least 30 other forms of CF (based on the mutations involved) that are suitable for ivacaftor treatment, and the FDA has expanded its approval accordingly.

As well as harnessing our knowledge about genetic variability to improve health and disease, we shouldn’t forget that genetic variability lies at the heart of genetic fingerprinting and related techniques, which are widely used in forensics and paternity testing.


  1. Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68-74.

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Article by Karen O’Hanlon Cohrt PhD. Contact Karen at 

Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD,  Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.



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