Abstract
Pleiotropy (whereby one genetic polymorphism affects multiple traits) and epistasis (whereby non-linear interactions between genetic polymorphisms affect the same trait) are fundamental aspects of the genetic architecture of quantitative traits. Recent advances in the ability to characterize the effects of polymorphic variants on molecular and organismal phenotypes in human and model organism populations have revealed the prevalence of pleiotropy and unexpected shared molecular genetic bases among quantitative traits, including diseases. By contrast, epistasis is common between polymorphic loci associated with quantitative traits in model organisms, such that alleles at one locus have different effects in different genetic backgrounds, but is rarely observed for human quantitative traits and common diseases. Here, we review the concepts and recent inferences about pleiotropy and epistasis, and discuss factors that contribute to similarities and differences between the genetic architecture of quantitative traits in model organisms and humans.
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Both authors wrote the article. T.F.C.M. researched data for the article and wrote the first draft of the manuscript based on discussion of the content and organization with R.R.H.A. R.R.H.A. reviewed and edited the manuscript before submission.
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Glossary
- Additive effects
-
One half of the difference in mean phenotypes associated with homozygous genotypes at a biallelic locus affecting a quantitative trait.
- Additive genetic variance
-
The variance of breeding values.
- Deoxyribonuclease I (DNase I) hypersensitivity sites
-
Accessible nucleosome-free chromatin regions sensitive to cleavage by the DNase I enzyme; these regions are inferred to be involved in gene regulation.
- Dominance effects
-
The difference between the mean phenotype of the heterozygous genotype and the mean phenotype of the two homozygous genotypes at a biallelic locus affecting a quantitative trait
- Fitness
-
The contribution of offspring to the next generation, or reproductive success (viability and fertility) of an individual.
- Genetic architecture
-
The loci, genomic locations and additive, dominance, epistatic and pleiotropic effects and allele frequencies of causal variants affecting a quantitative trait.
- Haplotypes
-
Alleles at different loci on a chromosome that tend to be inherited together.
- Heritability
-
The ratio of the variance of additive genetic variance (narrow sense heritability) or the total genetic variance (broad sense heritability) to the total phenotypic variance.
- P-element
-
A Drosophila transposable element that can be mobilized to new genomic locations by simple genetic crosses.
- Shifting balance theory of evolution
-
A model of evolution proposed by Sewell Wright that assumes widespread epistasis for fitness, natural selection, genetic drift and differentiation among subpopulations, and migration.
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Mackay, T.F.C., Anholt, R.R.H. Pleiotropy, epistasis and the genetic architecture of quantitative traits. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00711-3
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DOI: https://doi.org/10.1038/s41576-024-00711-3
