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.
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).
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.
Metrics
-
- 1,605
- views
-
- 162
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape
eLife 10:e68623.
https://doi.org/10.7554/eLife.68623
Further reading
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Klebsiella pneumoniae is a global public health concern due to the rising myriad of hypervirulent and multidrug-resistant clones both alarmingly associated with high mortality. The molecular mechanisms underpinning these recalcitrant K. pneumoniae infection, and how virulence is coupled with the emergence of lineages resistant to nearly all present-day clinically important antimicrobials, are unclear. In this study, we performed a genome-wide screen in K. pneumoniae ECL8, a member of the endemic K2-ST375 pathotype most often reported in Asia, to define genes essential for growth in a nutrient-rich laboratory medium (Luria-Bertani [LB] medium), human urine, and serum. Through transposon directed insertion-site sequencing (TraDIS), a total of 427 genes were identified as essential for growth on LB agar, whereas transposon insertions in 11 and 144 genes decreased fitness for growth in either urine or serum, respectively. These studies not only provide further knowledge on the genetics of this pathogen but also provide a strong impetus for discovering new antimicrobial targets to improve current therapeutic options for K. pneumoniae infections.
-
- Developmental Biology
- Genetics and Genomics
New developmental programs can evolve through adaptive changes to gene expression. The annelid Streblospio benedicti has a developmental dimorphism, which provides a unique intraspecific framework for understanding the earliest genetic changes that take place during developmental divergence. Using comparative RNAseq through ontogeny, we find that only a small proportion of genes are differentially expressed at any time, despite major differences in larval development and life history. These genes shift expression profiles across morphs by either turning off any expression in one morph or changing the timing or amount of gene expression. We directly connect the contributions of these mechanisms to differences in developmental processes. We examine F1 offspring – using reciprocal crosses – to determine maternal mRNA inheritance and the regulatory architecture of gene expression. These results highlight the importance of both novel gene expression and heterochronic shifts in developmental evolution, as well as the trans-acting regulatory factors in initiating divergence.
