Year: 2026
Type: article
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.
Source: Genome Medicine
Institution: University of Exeter
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,290
Awards: G1378233797, G3292477496, G340590750, Using whole genome sequencing to identify non-coding elements associated with diabetes and related traits across ancestries, Evaluating scientific and ethical approaches to newborn screening with whole genome sequencing using large-scale population cohorts, Deciphering the Non-Coding Genome using Millions of Diverse Whole-Genome Sequences
OpenAlex ID: W7223117946