Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
- University of Calgary, Canada
- University of Alberta, Canada
- Loyola University Chicago, United States
- Jackson Laboratory, United States
- University of California, San Francisco, United States
Abstract
Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait-craniofacial shape - in a sample of n = 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (process MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.
Data availability
All diversity outcross microCT scan and QTL data have been deposited with Facebase (https://doi.org/10.25550/1-731C).Scripts are available at github.com/j0vid and the associated online tool is available at genopheno.ucalgary.ca/MGP.
Article and author information
Author details
Benedikt Hallgrimsson
Funding
National Institutes of Health (2R01DE019638)
- Benedikt Hallgrimsson
Natural Sciences and Engineering Research Council of Canada (238992-17)
- Benedikt Hallgrimsson
Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-06311)
- Benedikt Hallgrimsson
Canadian Institutes of Health Research (159920)
- Benedikt Hallgrimsson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
Ethics
Animal experimentation: The work performed accordinging to protocols approvaed and reviewed by animal care committees at the University of Calgary (AC13-0268) and the University of Alberta (AUP1149).
Version history
- Preprint posted: November 12, 2020 (view preprint)
- Received: March 21, 2021
- Accepted: November 12, 2021
- Accepted Manuscript published: November 15, 2021 (version 1)
- Version of Record published: November 30, 2021 (version 2)
Copyright
© 2021, Aponte et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
eLife 10:e68623.
https://doi.org/10.7554/eLife.68623
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