Evidence map›Paper›PMID 40890102›Full record

ArticleNature communications2025

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, James T Nichols

Abstract read
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Early ultraviolet exposure disrupts late dorsal fin skeletal development in zebrafish.Developmental dynamics : an official publication of the American Association of Anatomists · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Abigail Mumme-MonheitDepartment of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0003-0090-1418
Grace E GustafsonDepartment of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0001-8343-4493
Colette A HopkinsDepartment of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-1206-455X
Raisa Bailon-ZambranoDepartment of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-5848-3952
Juliana SucharovDepartment of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Michael J LippincottDepartment of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-8637-1448
Gregory P WayDepartment of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-0503-9348
Kathryn L ColbornDepartment of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
James T NicholsDepartment of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. james.nichols@cuanschutz.edu.ORCID http://orcid.org/0000-0002-7263-1704

Funding

Mechanisms of developmental bufferingR01DE029193 · NIDCR · UNIVERSITY OF COLORADO DENVER · PI NICHOLS, JAMES TUCKER · 2021 to 2025
$2.1M
National Science Foundation (NSF) GRFP 1938058National Science Foundation (NSF) GRFP 2439026NIDCR NIH HHS R01 DE029193U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR) DE029193
6 · The paper itself

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.

Indexed as

Craniofacial AbnormalitiesPhenotypeZebrafishAllelesAnimalsHumansMutationZebrafish ProteinsZebrafish Proteins

Identifiers

PMID40890102
PMCPMC12402270

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

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.