Researchers at the University of Exeter Medical School have produced the most comprehensive portrait to date of the ‘average’ human genome, drawn from the whole-genome sequences of nearly 900,000 adults in two large research biobanks: UK Biobank and the US-based All of Us program.
The average human genome contains 4.3-5.3 million variants, of which 1.5% are rare. Image credit: Wright et al., doi: 10.1186/s13073-026-01792-x.
“Whole genome sequencing has become such an important tool in diagnosing genetic disease, and we’re increasingly moving towards genetic screening for predicting disease,” said Professor Caroline Wright, corresponding author of the study.
“Yet most people are unaware of just how much genetic variation is present in every genome.”
“Actually, variation is the norm. For the first time, our study outlines what to expect in the average human genome, which can benefit clinicians and patients across the word in understanding, interpreting and contextualizing genomics.”
Professor Wright and her colleagues found that a typical person’s genome differs from the standard reference sequence at roughly 4.3 to 5.3 million sites.
Most of those differences are common in the population and lie outside genes, and are unlikely to have any measurable effect on health. Only about 1.5% of an individual’s variants are rare.
People with African ancestry carried about a million more variants than other groups on average. The authors attribute part of the gap to the reference genome, which was built mostly from people of European descent.
The study also found that the average person carries about 229 variants predicted to disrupt a gene’s function, though only about 72% of those were high-confidence calls.
Among genes linked to inherited single-gene diseases, the average person has roughly one to three variants that the ClinVar database classifies as pathogenic or likely pathogenic.
Most are single copies of recessive conditions, meaning the person is a healthy carrier.
They also carry about 50 rare ‘variants of uncertain significance,’ whose effects scientists cannot yet interpret.
Using 2,334 parent-and-child trios, the researchers estimated that each person is born with about 61 new mutations in their DNA, plus about two more that arise early in development. Roughly 75 to 80% of the new mutations that could be traced came from the father.
Each added year of paternal age at conception was associated with about 1.2 more new mutations, compared with about 0.4 for each added year of maternal age.
Polygenic risk scores, which tally the combined effect of many small variants to estimate disease risk, produced a similar message.
Across 28 common conditions, the average person ranked in the top 10% for about three.
About one in five participants of European ancestry scored in the top 1% for at least one condition, as did about one in three of the other participants. The gap probably reflects the poor performance of scores developed mainly in Europeans rather than real differences in risk.
“We found that everyone carries a small number of genetic variants linked to disease, although many of these will not actually cause disease in that individual,”
“It is therefore crucial to consider context when interpreting findings from genetic testing, including symptoms or family history of disease as well as other clinical and environmental risk factors.”
“Our findings also provide important context for professionals who are interpreting genetic testing results or commissioning genetic screening programs.”
The team’s results appear today in the journal Genome Medicine.
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H.I.W. Wright et al. 2026. The average individual genome: a survey of nearly 1 million whole-genome sequences. Genome Med 18, 160; doi: 10.1186/s13073-026-01792-x
