Our genetic code contains clues to health and disease, and the specialized field of rare variant analysis has gained prominence for uncovering powerful genetic signals. This approach shifts focus from common, widespread genetic markers to the unique and infrequent changes that can have profound consequences for an individual. By homing in on these uncommon genetic events, researchers and clinicians are unlocking new understandings of human biology and disease.
Defining Genetic Variants
The human genome is composed of billions of DNA letters, and while largely identical from person to person, it contains variation. A genetic variant is a difference in this DNA sequence, akin to a different spelling of a word. These variants are the basis of human diversity, influencing everything from eye color to health predispositions. When these changes are widespread, found in more than 1-5% of the population, they are considered “common variants.”
In contrast, a “rare variant” is a genetic alteration that appears infrequently in the human population. Scientists define these as variants with a minor allele frequency (MAF) of less than 1%. A rare variant is like a unique typo found in only a handful of books out of thousands. While any single rare variant is uncommon, they collectively account for the vast majority of all genetic variations in the human genome.
The Goal of Rare Variant Analysis
The primary motivation for studying rare variants is their potential to exert a much stronger effect on health than common variants. While common variants are often associated with a small change in risk for complex diseases, a single rare variant can have a large and direct impact. This is particularly true for single-gene disorders, called Mendelian diseases, where inheriting a specific rare variant is often sufficient to cause the condition.
This strong effect size is a consequence of natural selection. Variants that are highly detrimental are unlikely to become common because individuals who carry them may have lower survival or reproductive rates, a process known as purifying selection. Therefore, impactful, disease-causing variants are kept at low frequencies. By focusing on this class of variants, researchers aim to explain a portion of the “missing heritability”—the gap between known genetic risk factors and what is estimated from family studies.
Methods for Identification and Analysis
Identifying rare variants requires technology capable of reading DNA with high resolution, such as Next-Generation Sequencing (NGS). The primary methods are Whole Exome Sequencing (WES), which reads the protein-coding regions of the genome, and Whole Genome Sequencing (WGS), which reads the entire DNA sequence. WES is a cost-effective first choice as the exome contains most known disease-causing mutations, while WGS offers a more comprehensive view.
Because any single rare variant is present in so few individuals, testing each one for a disease association lacks statistical power. To overcome this, scientists use “aggregation” or “burden” tests. These methods group together all the rare variants found within a specific gene or region. The analysis then tests whether the collective “burden” of these variants is higher in individuals with a disease compared to healthy controls.
This approach differs from Genome-Wide Association Studies (GWAS), which are designed to find common variants and test them one by one. Aggregation methods instead ask if an excess of rare mutations within a gene is associated with a disease. More advanced techniques, like variance-component tests, offer a flexible alternative by assessing the cumulative effect of variants without assuming they all have the same directional impact.
Clinical and Research Applications
Rare variant analysis has significant real-world impacts on medical care and scientific discovery. One application is in diagnostics for individuals on a “diagnostic odyssey.” Many children with complex developmental disorders spend years undergoing tests without a diagnosis. Rare variant analysis, often through WES, can pinpoint the genetic cause, providing answers and a path toward management or treatment.
Beyond diagnosing rare disorders, this analysis sheds light on common, complex diseases. Researchers are discovering that an accumulation of rare variants in certain genes can contribute to conditions like schizophrenia, heart disease, or cancer. This reveals new biological pathways underlying these diseases. Identifying a gene where rare variants lead to a lower risk of heart disease can provide a clue for developing new drugs.
This also applies to drug development. When rare variant analysis links a gene to a disease, that gene and its protein become a target for therapeutic intervention. Pharmaceutical companies can design drugs that mimic the protective effect of a rare variant or block the harmful effect of a disease-causing one. This approach accelerates the journey from genetic discovery to novel medicines.