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1. A Multigenerational Turing Model Reproduces Transgressive Petal Spot Phenotypes in Hybrid Mimulus

   Simmons, E.S.; Cooley, A.M.; Puzey, J.R.; Conradi-Smith, G.D. (November 2023, Bulletin of mathematical biology)

   The origin of phenotypic novelty is a perennial question of genetics and evolution. To date, few studies of biological pattern formation specifically address multi-generational aspects of inheritance and phenotypic novelty. For quantitative traits influenced by many segregating alleles, offspring phenotypes are often intermediate to parental values. In other cases, offspring phenotypes can be transgressive to parental values. For example, in the model organism Mimulus (monkeyflower), the offspring of parents with solid-colored petals exhibit novel spotted petal phenotypes. These patterns are controlled by an activator-inhibitor gene regulatory network with a small number of loci. Here we develop and analyze a model of hybridization and pattern formation that accounts for the inheritance of a diploid gene regulatory network composed of either homozygous or heterozygous alleles. We find that the resulting model of multi-generational Turing-type pattern formation can reproduce transgressive petal phenotypes similar to those observed in Mimulus. The model gives insight into how non-patterned parent phenotypes can yield phenotypically transgressive, patterned offspring, aiding in the development of empirically testable hypotheses. 

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2. A Multigenerational Turing Model Reproduces Transgressive Petal Spot Phenotypes in Hybrid Mimulus

   https://doi.org/10.1007/s11538-023-01223-7  

   Simmons, Emily S. G.; Cooley, Arielle M.; Puzey, Joshua R.; ConradiSmith, Gregory D. (November 2023, Bulletin of Mathematical Biology)

   Abstract The origin of phenotypic novelty is a perennial question of genetics and evolution. To date, few studies of biological pattern formation specifically address multi-generational aspects of inheritance and phenotypic novelty. For quantitative traits influenced by many segregating alleles, offspring phenotypes are often intermediate to parental values. In other cases, offspring phenotypes can be transgressive to parental values. For example, in the model organismMimulus(monkeyflower), the offspring of parents with solid-colored petals exhibit novel spotted petal phenotypes. These patterns are controlled by an activator-inhibitor gene regulatory network with a small number of loci. Here we develop and analyze a model of hybridization and pattern formation that accounts for the inheritance of a diploid gene regulatory network composed of either homozygous or heterozygous alleles. We find that the resulting model of multi-generational Turing-type pattern formation can reproduce transgressive petal phenotypes similar to those observed inMimulus. The model gives insight into how non-patterned parent phenotypes can yield phenotypically transgressive, patterned offspring, aiding in the development of empirically testable hypotheses. 

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3. The regulatory network for petal anthocyanin pigmentation is shaped by the MYB5a/NEGAN transcription factor in Mimulus

   https://doi.org/10.1093/genetics/iyaa036  

   Zheng, Xingyu; Om, Kuenzang; Stanton, Kimmy A; Thomas, Daniel; Cheng, Philip A; Eggert, Allison; Simmons, Emily; Yuan, Yao-Wu; Conradi Smith, Gregory D; Puzey, Joshua R; et al (February 2021, Genetics)

   Bomblies, K (Ed.)

   Abstract Much of the visual diversity of angiosperms is due to the frequent evolution of novel pigmentation patterns in flowers. The gene network responsible for anthocyanin pigmentation, in particular, has become a model for investigating how genetic changes give rise to phenotypic innovation. In the monkeyflower genus Mimulus, an evolutionarily recent gain of petal lobe anthocyanin pigmentation in M. luteus var. variegatus was previously mapped to genomic region pla2. Here, we use sequence and expression analysis, followed by transgenic manipulation of gene expression, to identify MYB5a—orthologous to the NEGAN transcriptional activator from M. lewisii—as the gene responsible for the transition to anthocyanin-pigmented petals in M. l. variegatus. In other monkeyflower taxa, MYB5a/NEGAN is part of a reaction-diffusion network that produces semi-repeating spotting patterns, such as the array of spots in the nectar guides of both M. lewisii and M. guttatus. Its co-option for the evolution of an apparently non-patterned trait—the solid petal lobe pigmentation of M. l. variegatus—illustrates how reaction-diffusion can contribute to evolutionary novelty in non-obvious ways. Transcriptome sequencing of a MYB5a RNAi line of M. l. variegatus reveals that this genetically simple change, which we hypothesize to be a regulatory mutation in cis to MYB5a, has cascading effects on gene expression, not only on the enzyme-encoding genes traditionally thought of as the targets of MYB5a but also on all of its known partners in the anthocyanin regulatory network. 

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4. Cryptic variation fuels plant phenotypic change through hierarchical epistasis

   https://doi.org/10.1038/s41586-025-09243-0  

   Zebell, Sophia G; Martí-Gómez, Carlos; Fitzgerald, Blaine; Cunha, Camila P; Lach, Michael; Seman, Brooke M; Hendelman, Anat; Sretenovic, Simon; Qi, Yiping; Bartlett, Madelaine; et al (July 2025, Nature)

   Abstract Cryptic genetic variants exert minimal phenotypic effects alone but are hypothesized to form a vast reservoir of genetic diversity driving trait evolvability through epistatic interactions^1–3. This classical theory has been reinvigorated by pan-genomics, which is revealing pervasive variation within gene families,cis-regulatory regions and regulatory networks^4–6. Testing the ability of cryptic variation to fuel phenotypic diversification has been hindered by intractable genetics, limited allelic diversity and inadequate phenotypic resolution. Here, guided by natural and engineeredcis-regulatory cryptic variants in a paralogous gene pair, we identified additional redundanttransregulators, establishing a regulatory network controlling tomato inflorescence architecture. By combining coding mutations withcis-regulatory alleles in populations segregating for all four network genes, we generated 216 genotypes spanning a wide spectrum of inflorescence complexity and quantified branching in over 35,000 inflorescences. Analysis of this high-resolution genotype–phenotype map using a hierarchical model of epistasis revealed a layer of dose-dependent interactions within paralogue pairs enhancing branching, culminating in strong, synergistic effects. However, we also identified a layer of antagonism between paralogue pairs, whereby 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 paralogue diversification converge to shape phenotypic space, producing the potential for both strongly buffered phenotypes and sudden bursts of phenotypic change. 

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5. Engineering Quantitative Trait Variation for Crop Improvement by Genome Editing

   https://doi.org/doi: 10.1016/j.cell.2017.08.030  

   Rodriguez-Leal, D; Lemmon, Z; Man, J; Bartlett, M; Lippman, Z. (January 2017, Cell)

   Major advances in crop yields are needed in the coming decades. However, plant breeding is currently limited by incremental improvements in quantitative traits that often rely on laborious selection of rare naturally occurring mutations in gene-regulatory regions. Here, we demonstrate that CRISPR/Cas9 genome editing of promoters generates diverse cis-regulatory alleles that provide beneficial quantitative variation for breeding. We devised a simple genetic scheme, which exploits trans-generational heritability of Cas9 activity in heterozygous loss-of-function mutant backgrounds, to rapidly evaluate the phenotypic impact of numerous promoter variants for genes regulating three major productivity traits in tomato: fruit size, inflorescence branching, and plant architecture. Our approach allows immediate selection and fixation of novel alleles in transgene-free plants and fine manipulation of yield components. Beyond a platform to enhance variation for diverse agricultural traits, our findings provide a foundation for dissecting complex relationships between gene-regulatory changes and control of quantitative traits. 

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