ArticleGenetics2022
Local fitness and epistatic effects lead to distinct patterns of linkage disequilibrium in protein-coding genes.
Article in Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 23 citations in OpenAlex.
- Correlations between causal effect sizes of proximal SNPs vary with functional annotations and implicate stabilizing selection.Nature genetics · 2026Article
- Epistasis among clustered lineage-specific amino acid substitutions in the Drosophila Trio protein.PLoS genetics · 2026Article
- GENERAL MOMENT CLOSURE FOR THE NEUTRAL TWO-LOCUS WRIGHT-FISHER DYNAMICS.bioRxiv : the preprint server for biology · 2026Article
- A gene-based model of fitness and its implications for genetic variation: linkage disequilibrium.Genetics · 2025Article
- Epistasis among clustered lineage-specific adaptive amino acid substitutions in the Drosophila Trio protein.bioRxiv : the preprint server for biology · 2025Article
- A model for background selection in non-equilibrium populations.bioRxiv : the preprint server for biology · 2025Article
- A gene-based model of fitness and its implications for genetic variation: Linkage disequilibrium.bioRxiv : the preprint server for biology · 2025Article
- Article
- Linkage equilibrium between rare mutations.Genetics · 2024Article
- Constraining models of dominance for nonsynonymous mutations in the human genome.PLoS genetics · 2024Article
- Revisiting Dominance in Population Genetics.Genome biology and evolution · 2024Review
- A Path Integral Approach for Allele Frequency Dynamics Under Polygenic Selection.bioRxiv : the preprint server for biology · 2024Article
- Linkage equilibrium between rare mutations.bioRxiv : the preprint server for biology · 2024Article
- Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection.Research square · 2023Article
- Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection.medRxiv : the preprint server for health sciences · 2023Article
- Estimation of Genetic Correlation Between Rheumatoid Arthritis and Multiple Sclerosis Using Summary Statistics from Genome-Wide Association Studies.Journal of clinical practice and research · 2023Article
- Demographic modeling of admixed Latin American populations from whole genomes.American journal of human genetics · 2023Article
- Quantifying the fraction of new mutations that are recessive lethal.Evolution; international journal of organic evolution · 2023Article
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Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Selected mutations interfere and interact with evolutionary processes at nearby loci, distorting allele frequency trajectories and creating correlations between pairs of mutations. Recent studies have used patterns of linkage disequilibrium between selected variants to test for selective interference and epistatic interactions, with some disagreement over interpreting observations from data. Interpretation is hindered by a lack of analytic or even numerical expectations for patterns of variation between pairs of loci under the combined effects of selection, dominance, epistasis, and demography. Here, I develop a numerical approach to compute the expected two-locus sampling distribution under diploid selection with arbitrary epistasis and dominance, recombination, and variable population size. I use this to explore how epistasis and dominance affect expected signed linkage disequilibrium, including for nonsteady-state demography relevant to human populations. Using whole-genome sequencing data from humans, I explore genome-wide patterns of linkage disequilibrium within protein-coding genes. I show that positive linkage disequilibrium between missense mutations within genes is driven by strong positive allele-frequency correlations between mutations that fall within the same annotated conserved domain, pointing to compensatory mutations or antagonistic epistasis as the prevailing mode of interaction within conserved genic elements. Linkage disequilibrium between missense mutations is reduced outside of conserved domains, as expected under Hill-Robertson interference. This variation in both mutational fitness effects and selective interactions within protein-coding genes calls for more refined inferences of the joint distribution of fitness and interactive effects, and the methods presented here should prove useful in that pursuit.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.