Study Maps the Average Human Genome
Researchers have characterized the average human genome for the first time, offering detailed insights into normal genetic variation and genetic disease risk according to research from the University of Exeter Medical School, as published in News Medical. The findings are also being presented at the American Society of Human Genetics annual meeting.
Researchers examined whole-genome sequences from nearly 900,000 adults housed in two major research repositories: the UK Biobank and the United States-based All of Us program. A typical individual genome differs from the standard reference sequence at approximately 4.3 million to 5.3 million sites. The majority of these differences are common across the population, reside outside of genes, and are unlikely to exert any measurable impact on health, while only about 1.5% of an individual’s variants are rare.
Categories of Genetic Variation
The study breaks down human genetic variation into several categories:
- Sequence alterations: About 10,000 variants alter gene sequences, producing positive, negative, or biologically neutral effects such as lactose intolerance or altered drug responses.
- Gene disruption: The average person carries roughly 229 variants predicted to disrupt gene function, though only about 72% of those predictions are considered high-confidence calls.
- Pathogenic variants: Among genes linked to inherited single-gene disorders, the average person carries one to three variants classified by the ClinVar database as pathogenic or likely pathogenic, mostly representing single copies of recessive conditions where the individual is a healthy carrier.
- Uncertain variants: Individuals carry about 50 rare variants of uncertain clinical relevance whose effects cannot yet be interpreted by science.
Using 2,334 parent-and-child trios, the research team estimated that each person is born with approximately 61 new mutations, supplemented by about two additional mutations arising early in development. Roughly 75% to 80% of these traceable new mutations originated from the father. Each added year of paternal age at conception correlated with about 1.2 additional new mutations, compared to about 0.4 extra mutations for each added year of maternal age.
Evaluating Polygenic Risk Scores
The research evaluated polygenic risk scores across 28 common conditions—including schizophrenia, cardiovascular disease, and diabetes—to estimate future disease likelihood by combining numerous small genetic factors. Investigators found that the average person would be categorized in the top 10% of genetic risk for approximately three of these conditions. About one in five participants of European ancestry scored in the top 1% for at least one condition, compared to about one in three participants of other ancestries.
People of African ancestry carried about one million more variants on average than other groups, a discrepancy researchers attribute partly to the fact that the reference genome was constructed primarily from individuals of European descent. Because the study did not investigate the health status of participants, many individuals flagged as high risk may not actually develop the diseases. Professor Caroline Wright from the University of Exeter, senior and corresponding author of the study, said: “For the first time, our study outlines what to expect in the average human genome, which can benefit clinicians and patients across the world in understanding, interpreting and contextualizing genomics.”
Professor Wright emphasized that because variation is the norm, professionals interpreting genetic testing results or commissioning screening programs must consider individual symptoms, family history, and environmental risk factors.