Genetic variation describes the differences in DNA sequences among individuals within a species. While many genetic differences are common, a distinct category exists: rare variants. These less common genetic alterations are becoming increasingly significant in understanding human health and biological processes. This article explores what rare variants are, their importance in biology and disease, how scientists identify them, and the challenges in interpreting findings.
Understanding Rare Variants
Rare variants are defined by their low frequency within a population, typically occurring in less than 1% of individuals. This low prevalence distinguishes them from common genetic variants, such as single nucleotide polymorphisms (SNPs), which are found in a much larger percentage of the population. Unlike common variants, which are often ancient and widely distributed, rare variants can be more recent mutations unique to families or small groups. They represent a unique subset of genetic diversity, often arising from new mutations.
These genetic changes encompass various forms of DNA alterations. A common type involves single base changes, where one DNA building block is swapped for another, like an ‘A’ becoming a ‘G’. They can also include small insertions or deletions, where a few DNA bases are added into or removed from the genetic code. Even subtle changes in these sequences can alter the instructions for building proteins, potentially affecting their function or abundance.
Significance in Health and Biology
Rare variants hold importance in understanding human health, particularly inherited diseases. Many rare Mendelian diseases, caused by a single gene mutation, are directly linked to specific rare variants. For example, cystic fibrosis often results from a rare variant in the CFTR gene, while Huntington’s disease is caused by a rare expansion within the HTT gene. Identifying these variants allows for precise diagnoses and, in some cases, targeted therapies or genetic counseling.
Beyond single-gene disorders, rare variants are increasingly recognized for their contribution to more common, complex diseases. Conditions such as heart disease, diabetes, and certain cancers are influenced by multiple genetic and environmental factors. In these complex diseases, rare variants may exert a stronger effect than common variants, or they might act in combination with other genetic factors to increase disease susceptibility. Research suggests that an accumulation of several rare variants, each with a small effect, could collectively contribute to an individual’s risk for these conditions.
Rare variants also offer insights into human diversity and evolutionary processes. By studying these less common genetic differences across diverse populations, scientists can trace ancestral migration patterns and understand how human populations have adapted to different environments. These variants provide a molecular record of recent evolutionary events.
How Rare Variants Are Identified
The identification of rare variants has been revolutionized by advancements in modern DNA sequencing technologies. Whole-exome sequencing (WES) is a widely used method that focuses on the exome, the protein-coding portion of the genome. Although the exome constitutes only about 1-2% of the entire genome, it contains the vast majority of known disease-causing variants. WES involves selectively capturing and sequencing these protein-coding regions to search for disease-associated rare variants.
Whole-genome sequencing (WGS) involves reading the entire DNA sequence of an individual’s genome. Unlike WES, WGS covers both the coding and non-coding regions of DNA, providing a more comprehensive view of all genetic variations. This broader scope allows for the detection of rare variants in regions that regulate gene expression or have other functional roles. Both WES and WGS work by breaking DNA into small fragments, reading the sequence of these fragments, and then aligning them to a reference human genome to identify differences.
These high-throughput sequencing technologies have drastically reduced the cost and time to analyze an individual’s genetic makeup. The ability to rapidly sequence entire exomes or genomes has enabled large-scale studies, leading to the discovery of numerous rare variants linked to various health conditions.
Interpreting Rare Variant Findings
Identifying a rare variant in an individual’s genome is often the first step, but interpreting its significance presents challenges. A rare variant found through sequencing does not automatically imply it is the cause of a disease or has health implications. Many rare variants are benign, meaning they have no harmful effect, making it difficult to distinguish them from pathogenic ones. These uncertain findings are often termed variants of uncertain significance (VUS).
To determine the potential impact of a rare variant, scientists employ several validation strategies. Family studies are often conducted, examining whether the variant segregates with the disease within a family, meaning affected individuals carry the variant while unaffected relatives do not. Functional assays, which are laboratory experiments, can also be performed to assess if the variant alters protein function or gene expression. These experiments provide direct evidence of a variant’s biological effect.
Large population databases, such as gnomAD (Genome Aggregation Database), are routinely consulted to aid interpretation. These databases compile genetic data from tens of thousands of individuals, allowing researchers to check the frequency of a variant in a broad population. If a variant is found to be present in healthy individuals at a higher frequency than expected for a disease-causing mutation, it is more likely to be benign. The combination of these approaches helps geneticists understand its true clinical relevance.