The average individual genome: a survey of nearly 1 million whole-genome sequences.

Inventory of per-genome variation (SNVs, indels, CNVs, de novo variants, runs of homozygosity, polygenic scores) in two biobanks

This study describes the variation carried by an "average" genome using genome sequences from 490,541 UK Biobank participants and 414,830 All of Us participants, across six genetically inferred ancestry groups. A genome contains about 4.3 to 5.3 million variants, about 1.5% of them rare (within-cohort frequency below 1%), about 67 autosomal deletions or duplications larger than 10 kb and, depending on parental age, about 63 de novo variants, 75-80% of paternal origin; a rare autosomal CNV larger than 1 Mb is present in about 1 in 41 individuals. In GenCC-curated monogenic disease genes, each genome carries about 1 to 3 rare ClinVar pathogenic or likely pathogenic variants, 2 to 5 high-confidence loss-of-function variants and about 50 ClinVar variants of uncertain significance; most pathogenic variants are heterozygous in recessive genes, consistent with carrier status. Applying polygenic scores for 28 common diseases in UK Biobank, the average person is in the top 10% for about 3 conditions, and about 1 in 5 people are in the top 1% for at least one score.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Useful orders of magnitude for counselling and for debates on population genomic screening: each genome carries a few ClinVar pathogenic variants and dozens of variants of uncertain significance in disease genes, a reminder that an isolated variant is not a diagnosis. The work is descriptive and brings no new data on a gene or on management; its value is that of a reference. Many populations remain underrepresented, a limitation stressed by the authors.

Analysis by Dr Thibaut Benquey