Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape

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 unde...

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Autores principales:	Jose D Aponte, David C Katz, Daniela M Roth, Marta Vidal-García, Wei Liu, Fernando Andrade, Charles C Roseman, Steven A Murray, James Cheverud, Daniel Graf, Ralph S Marcucio, Benedikt Hallgrímsson
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	multivariate genotype-phenotype map complex traits craniofacial mouse diversity outcross genetics Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/88b99fdbe9bf4745aa04504d6544da97
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spelling	oai:doaj.org-article:88b99fdbe9bf4745aa04504d6544da972021-11-30T12:07:01ZRelating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape10.7554/eLife.686232050-084Xe68623https://doaj.org/article/88b99fdbe9bf4745aa04504d6544da972021-11-01T00:00:00Zhttps://elifesciences.org/articles/68623https://doaj.org/toc/2050-084XRealistic 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.Jose D AponteDavid C KatzDaniela M RothMarta Vidal-GarcíaWei LiuFernando AndradeCharles C RosemanSteven A MurrayJames CheverudDaniel GrafRalph S MarcucioBenedikt HallgrímssoneLife Sciences Publications Ltdarticlemultivariate genotype-phenotype mapcomplex traitscraniofacialmousediversity outcrossgeneticsMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	multivariate genotype-phenotype map complex traits craniofacial mouse diversity outcross genetics Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	multivariate genotype-phenotype map complex traits craniofacial mouse diversity outcross genetics Medicine R Science Q Biology (General) QH301-705.5 Jose D Aponte David C Katz Daniela M Roth Marta Vidal-García Wei Liu Fernando Andrade Charles C Roseman Steven A Murray James Cheverud Daniel Graf Ralph S Marcucio Benedikt Hallgrímsson Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
description	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.
format	article
author	Jose D Aponte David C Katz Daniela M Roth Marta Vidal-García Wei Liu Fernando Andrade Charles C Roseman Steven A Murray James Cheverud Daniel Graf Ralph S Marcucio Benedikt Hallgrímsson
author_facet	Jose D Aponte David C Katz Daniela M Roth Marta Vidal-García Wei Liu Fernando Andrade Charles C Roseman Steven A Murray James Cheverud Daniel Graf Ralph S Marcucio Benedikt Hallgrímsson
author_sort	Jose D Aponte
title	Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
title_short	Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
title_full	Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
title_fullStr	Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
title_full_unstemmed	Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
title_sort	relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/88b99fdbe9bf4745aa04504d6544da97
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Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape

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