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ABSTRACT Cryptic genetic variants exert minimal or no phenotypic effects alone but have long been hypothesized to form a vast, hidden reservoir of genetic diversity that drives trait evolvability through epistatic interactions. This classical theory has been reinvigorated by pan-genome sequencing, which has revealed pervasive variation within gene families and regulatory networks, including extensive cis-regulatory changes, gene duplication, and divergence between paralogs. Nevertheless, empirical testing of cryptic variation’s capacity to fuel phenotypic diversification has been hindered by intractable genetics, limited allelic diversity, and inadequate phenotypic resolution. Here, guided by natural and engineered cis-regulatory cryptic variants in a recently evolved paralogous gene pair, we identified an additional pair of redundant trans regulators, establishing a regulatory network that controls tomato inflorescence architecture. By combining coding mutations with a cis-regulatory allelic series in populations segregating for all four network genes, we systematically constructed a collection of 216 genotypes spanning the full spectrum of inflorescence complexity and quantified branching in over 27,000 inflorescences. Analysis of the resulting high-resolution genotype-phenotype map revealed a layer of dose-dependent interactions within paralog pairs that enhances branching, culminating in strong, synergistic effects. However, we also uncovered an unexpected layer of antagonism between paralog pairs, where accumulating mutations in one pair progressively diminished the effects of mutations in the other. Our results demonstrate how gene regulatory network architecture and complex dosage effects from paralog diversification converge to shape phenotypic space under a hierarchical model of epistatic interactions. Given the prevalence of paralog evolution in genomes, we propose that paralogous cryptic variation within regulatory networks elicits hierarchies of epistatic interactions, catalyzing bursts of phenotypic change. Keyword:cryptic mutations, paralogs, redundancy, cis-regulatory, tomato, inflorescence, gene regulatory network, modeling, epistasis
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A supergene-linked estrogen receptor drives alternative phenotypes in a polymorphic songbird
Behavioral evolution relies on genetic changes, yet few behaviors can be traced to specific genetic sequences in vertebrates. Here we provide experimental evidence showing that differentiation of a single gene has contributed to the evolution of divergent behavioral phenotypes in the white-throated sparrow, a common backyard songbird. In this species, a series of chromosomal inversions has formed a supergene that segregates with an aggressive phenotype. The supergene has capturedESR1, the gene that encodes estrogen receptor α (ERα); as a result, this gene is accumulating changes that now distinguish the supergene allele from the standard allele. Our results show that in birds of the more aggressive phenotype, ERα knockdown caused a phenotypic change to that of the less aggressive phenotype. We next showed that in a free-living population, aggression is predicted by allelic imbalance favoring the supergene allele. Finally, we identifiedcis-regulatory features, both genetic and epigenetic, that explain the allelic imbalance. This work provides a rare illustration of how genotypic divergence has led to behavioral phenotypic divergence in a vertebrate.
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- Award ID(s):
- 1656247
- PAR ID:
- 10184680
- Publisher / Repository:
- Proceedings of the National Academy of Sciences
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 117
- Issue:
- 35
- ISSN:
- 0027-8424
- Page Range / eLocation ID:
- p. 21673-21680
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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