A quadratic paradigm describes the relationship between phenotype severity and variation

Abigail Mumme-Monheit, Grace E. Gustafson, Colette A. Hopkins, Raisa Bailon-Zambrano, Juliana Sucharov, Michael J. Lippincott, Gregory P. Way, Kathryn L. Colborn and James T. Nichols ()
Additional contact information
Abigail Mumme-Monheit: University of Colorado Anschutz Medical Campus
Grace E. Gustafson: University of Colorado Anschutz Medical Campus
Colette A. Hopkins: University of Colorado Anschutz Medical Campus
Raisa Bailon-Zambrano: University of Colorado Anschutz Medical Campus
Juliana Sucharov: University of Colorado Anschutz Medical Campus
Michael J. Lippincott: University of Colorado Anschutz Medical Campus
Gregory P. Way: University of Colorado Anschutz Medical Campus
Kathryn L. Colborn: University of Colorado Anschutz Medical Campus
James T. Nichols: University of Colorado Anschutz Medical Campus

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract In 1942 Waddington observed that phenotype variation among mutant animals is greater than in wild types. Here we update this observation to depict unexpected relationships between phenotype severity and variation. Using a zebrafish mef2ca allelic series representing a range in craniofacial phenotype severity, we tested the straightforward hypothesis that as phenotype severity increases, variation increases. We found that severity and variation were positively correlated, but only to a point. Variation collapsed in the most severe conditions. Mathematically, we found that the best fit for the relationship between severity and variation is a quadratic function. Across both zebrafish craniofacial phenotypes and human genetic disease, wild-type conditions produced low variation, moderate severity was associated with high variation, and conditions of extreme severity resulted in low variation. We propose that the quadratic relationship between severity and variation is a universal principle of biology that until now has not been formally tested.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63316-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63316-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63316-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().