The average individual genome: a survey of nearly 1 million whole-genome sequences.
- 1Department of Clinical and Biomedical Sciences, University of Exeter Medical School, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK.
- 2Department of Clinical and Biomedical Sciences, University of Exeter Medical School, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK. [email protected].
Abstract
Background
As whole-genome sequencing (WGS) is increasingly used in clinical and public health contexts, clearer expectations regarding the amount of variation present in the "average" human genome are required to contextualise findings.Methods
We analysed WGS data from two large population cohorts: 490,541 individuals in UK Biobank (UKB) and 414,830 individuals in All of Us. Following variant and genotype QC, we aimed to assess the range of neutral and disease-associated variation across six genetically-inferred ancestry groups.Results
The "average" genome contains ~4.3-5.3 million variants, of which ~1.5% are rare (within-cohort allele frequency < 1%). This includes ~67 autosomal deletions/duplications > 10,000 basepairs per genome, and rare autosomal copy number variants > 1 Mb present in ~ 1 in 41 (2.5%) individuals. On average, ~32-42% of variants per person are homozygous and individuals have ~4 unique runs of homozygosity > 1.5 Mb, with marked variation observed across ancestry groups. Of the ~21- 26,000 SNVs/indels per person in coding exons of MANE Select transcripts, ~48% are predicted to alter the protein, of which ~0.8% are high-confidence loss-of-function and ~0.1% have REVEL score > 0.7 suggestive of pathogenicity. Depending upon parental age, the average genome contains ~63 de novo variants, of which ~75-80% are paternal in origin. Considering only rare variants in GenCC-curated monogenic disease-associated genes, the average genome contains ~1-3 ClinVar pathogenic or likely pathogenic variants, ~2-5 high-confidence loss-of-function variants, and ~50 ClinVar variants of uncertain significance. Most ClinVar pathogenic variants are heterozygous in recessive disease genes, consistent with carrier status, and have multiple ClinVar submitters. Finally, applying polygenic scores (PGS) for 28 common diseases within UKB, we estimate that the average person is in the top 10% for ~3 conditions, and around 1 in 5 people are in the top 1% for at least one PGS.Conclusions
The ubiquity of genetic variation in individuals has important implications for policy-makers considering genomic screening and clinicians counselling families. The continued underrepresentation of many global populations reflects a broader limitation of contemporary genomic research, underscoring the need for more inclusive datasets worldwide in order to enable equitable precision medicine.
Related
- Small Average Error, Wide Individual Error: General-Purpose LLMs Estimating Energy Intake from Meal Photos in a Feeding Trial
- Five hundred million years of methylation: tracing the mutational origins of vertebrate genome composition
- Complete genome sequences of three biocalcifying bacterial strains, Lysinibacillus fusiformis LBL1, Peribacillus frigoritolerans PBL6, and Planococcus glaciei PCL1, isolated from Lebanese calcareous soil
- Complete Genome Sequences of four DE4 cluster phages isolated using Gordonia terrae 3612.
- Muscari commutatum genome sequences reveal genetic basis of flower pigmentation
BibTeX
@article{wright2026average,
title = {{The average individual genome: a survey of nearly 1 million whole-genome sequences.}},
author = {Harrison I W Wright and Robin N Beaumont and James Fasham and Joseph S Leslie and V Kartik Chundru and Timothy S Hall and Stuart J Cannon and Alistair T Pagnamenta and Emma L Baple and Andrew R Wood and Anna Murray and Leigh Jackson and Michael N Weedon and Kashyap Patel and Gareth Hawkes and Caroline F Wright},
journal = {Genome medicine},
year = {2026},
month = oct,
doi = {10.1186/s13073-026-01792-x},
url = {https://europepmc.org/article/MED/42907903},
note = {CC BY},
}
RIS
TY - JOUR
TI - The average individual genome: a survey of nearly 1 million whole-genome sequences.
AU - Harrison I W Wright
AU - Robin N Beaumont
AU - James Fasham
AU - Joseph S Leslie
AU - V Kartik Chundru
AU - Timothy S Hall
AU - Stuart J Cannon
AU - Alistair T Pagnamenta
AU - Emma L Baple
AU - Andrew R Wood
AU - Anna Murray
AU - Leigh Jackson
AU - Michael N Weedon
AU - Kashyap Patel
AU - Gareth Hawkes
AU - Caroline F Wright
PY - 2026
DA - 2026/10/22
JO - Genome medicine
DO - 10.1186/s13073-026-01792-x
UR - https://europepmc.org/article/MED/42907903
AB - Background As whole-genome sequencing (WGS) is increasingly used in clinical and public health contexts, clearer expectations regarding the amount of variation present in the "average" human genome are required to contextualise findings.Methods We analysed WGS data from two large population cohorts: 490,541 individuals in UK Biobank (UKB) and 414,830 individuals in All of Us. Following variant and genotype QC, we aimed to assess the range of neutral and disease-associated variation across six genetically-inferred ancestry groups.Results The "average" genome contains ~4.3-5.3 million variants, of which ~1.5% are rare (within-cohort allele frequency < 1%). This includes ~67 autosomal deletions/duplications > 10,000 basepairs per genome, and rare autosomal copy number variants > 1 Mb present in ~ 1 in 41 (2.5%) individuals. On average, ~32-42% of variants per person are homozygous and individuals have ~4 unique runs of homozygosity > 1.5 Mb, with marked variation observed across ancestry groups. Of the ~21- 26,000 SNVs/indels per person in coding exons of MANE Select transcripts, ~48% are predicted to alter the protein, of which ~0.8% are high-confidence loss-of-function and ~0.1% have REVEL score > 0.7 suggestive of pathogenicity. Depending upon parental age, the average genome contains ~63 de novo variants, of which ~75-80% are paternal in origin. Considering only rare variants in GenCC-curated monogenic disease-associated genes, the average genome contains ~1-3 ClinVar pathogenic or likely pathogenic variants, ~2-5 high-confidence loss-of-function variants, and ~50 ClinVar variants of uncertain significance. Most ClinVar pathogenic variants are heterozygous in recessive disease genes, consistent with carrier status, and have multiple ClinVar submitters. Finally, applying polygenic scores (PGS) for 28 common diseases within UKB, we estimate that the average person is in the top 10% for ~3 conditions, and around 1 in 5 people are in the top 1% for at least one PGS.Conclusions The ubiquity of genetic variation in individuals has important implications for policy-makers considering genomic screening and clinicians counselling families. The continued underrepresentation of many global populations reflects a broader limitation of contemporary genomic research, underscoring the need for more inclusive datasets worldwide in order to enable equitable precision medicine.
SN - 1756-994X
ER -