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Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
- Source :
- eLife, Vol 10 (2021), eLife
- Publication Year :
- 2021
- Publisher :
- eLife Sciences Publications, Ltd, 2021.
-
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 = 1145 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 that 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.
- Subjects :
- Multivariate statistics
QH301-705.5
Science
Gene regulatory network
Genomics
Computational biology
Biology
craniofacial
multivariate genotype-phenotype map
General Biochemistry, Genetics and Molecular Biology
complex traits
03 medical and health sciences
0302 clinical medicine
genetics
Biology (General)
Craniofacial
Set (psychology)
Gene
mouse
030304 developmental biology
0303 health sciences
General Immunology and Microbiology
General Neuroscience
Skull
Genetics and Genomics
diversity outcross
General Medicine
Phenotype
Variation (linguistics)
Face
Multivariate Analysis
Medicine
030217 neurology & neurosurgery
Research Article
Subjects
Details
- ISSN :
- 2050084X
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....030d2f0e95e95bf7f01a5449d25d43e3
- Full Text :
- https://doi.org/10.7554/elife.68623