A single human genome is not a near-copy of the reference sequence with a few typos. It differs from it at 4.3 to 5.3 million sites, according to the largest effort yet to describe what an ordinary genome looks like.
Researchers at the University of Exeter Medical School built the picture from whole-genome sequences of nearly 900,000 adults in two biobanks, UK Biobank and the US All of Us programme. The results appear in Genome Medicine.
Variation is the normal case
Most of those millions of differences are common in the population, sit outside genes, and are unlikely to have any measurable effect on health. Only about 1.5 percent of an individual's variants are rare.
The average person carries about 229 variants predicted to disrupt a gene's function, though only about 72 percent of those calls are high confidence. Among genes linked to inherited single-gene disease, the typical genome holds one to three variants that the ClinVar database classes as pathogenic or likely pathogenic. Most are single copies of recessive conditions, which makes the person a healthy carrier rather than a patient. A further 50 or so are variants of uncertain significance, where science cannot yet say what the change does.
New mutations and the father's age
Using 2,334 parent-and-child trios, the team estimated that each person is born with about 61 new mutations, plus about two more that arise early in development. Between 75 and 80 percent of the traceable new mutations came from the father. Each additional year of paternal age at conception was linked to about 1.2 more new mutations, against roughly 0.4 for each year of maternal age.
What it means for screening
The numbers matter as genetic testing moves from diagnosing rare disease to predicting common ones. Polygenic risk scores, which combine many small effects, placed the average person in the top 10 percent of risk for about three of 28 common conditions. Without a baseline for what normal looks like, a high score is easy to misread.
One bias stands out. People with African ancestry carried about a million more variants on average, partly because the reference genome was built mostly from people of European descent. As screening expands, that gap becomes a technical problem, not just a historical one.