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This preprint study examines how rare genetic mutations contribute to variation in disease susceptibility among humans. Researchers modeled mutation-selection-drift balance and found that two humans typically differ in ancestral fitness by 17-33% due to deleterious mutations, with most variation coming from rare variants (below 1% frequency) and ultra-rare variants (below 0.01% frequency). The findings suggest that the total human deleterious mutation rate exceeds 3.8 mutations per generation, higher than previous estimates based on sequence constraint alone.
Why it matters
This research could explain part of the "missing heritability" problem in genetics, where pedigree studies show higher disease heritability than genome-wide association studies detect. The results suggest that analyzing rare and ultra-rare variants through whole-genome sequencing, rather than relying solely on polygenic risk scores, could better identify individuals at high risk for genetic diseases.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
It is an open question whether variation in the genetic load of unconditionally deleterious mutations contributes substantially to the variability in human disease. Here, we solve for mutation-selection-drift balance and predict variation in genetic load given a realistic human genome-wide deleterious mutation rate, U, and a distribution of fitness effects (DFE). Empirical estimates of U come from sequence constraint, which fails to count slightly deleterious mutations that nevertheless fix. We use the inferred DFE to correct for this and conclude that total human U>3.8. Two humans typically differ in ancestral fitness by 17-33% given uncertainty in U, or by 6-49% when we consider a broad range of alternative DFEs. Results are similar for other species with larger mean selection coefficients, such as other mammals. Most variation in load comes from rare variants with frequencies below 1%, with a substantial fraction coming from ultra-rare variants below 0.01%. This could help explain why some of the heritability observed in pedigree studies is missing from genome-wide association studies. Accounting for rare and ultra-rare variants, e.g., via variant-effect prediction of unique mutations from whole-genome sequencing rather than via polygenic risk scores, could help identify individuals at high risk of disease.
Source: Rare variants drive high variance in human ancestral fitness at mutation-selection-drift balance