Exeter team describes the average human genome: 4.3–5.3 million variants versus the reference

Researchers at the University of Exeter Medical School have built the most complete description of an "average" human genome, ixbt.com reports. They analysed whole-genome sequencing data from almost 900 thousand adults in the UK Biobank and the US All of Us programme. A typical genome differs from the standard reference sequence at about 4.3–5.3 million positions. ixbt.comixbt.comixbt.comOpen source ↗

Variants and gene function

The vast majority of these variants are common in the population, lie outside genes and have no measurable effect on health. Only about 1.5% of all differences are rare.

On average a person carries about 229 variants that may disrupt gene function, though only 72% of them are confirmed with high confidence. Among genes linked to monogenic hereditary diseases, each person has from 1 to 3 variants that ClinVar, an international resource of clinically significant genetic changes, classifies as pathogenic or likely pathogenic. Most are a single copy in recessive conditions, so the person is a healthy carrier.

Each genome also holds about 50 variants of uncertain significance, whose effect cannot yet be interpreted. ixbt.comixbt.comixbt.comOpen source ↗

New mutations and risk scores

An analysis of 2334 parent-child pairs showed that each person receives about 61 new mutations, plus two more that arise in the early stages of embryo development. Between 75% and 80% of traceable new mutations come from the father. Each added year of paternal age at conception raises the count by about 1.2 mutations, while maternal age adds 0.4.

Polygenic risk scores, the combined probability of disease based on many small differences, showed a similar picture. Across 28 common diseases, the average participant fell in the top 10 percent for about three. About one in five people of European ancestry and one in three participants from other groups reached the top score for at least one disease. The authors link the gap mainly to the algorithms having been built on a European sample, not to real differences in risk.

People of African ancestry carry on average 1 million more variants, which is partly explained by bias in the reference genome itself, created mainly from European material. ixbt.comixbt.comixbt.comOpen source ↗

Professor Caroline Wright notes that genetic variation is the norm, and that carrying small sets of disease-associated variants does not guarantee they will manifest in a given person. Interpreting genetic test results and launching screening programmes requires accounting for symptoms, family history and other clinical factors.