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

Area of Science:

• Genetics and Genomics
• Developmental Biology
• Quantitative Trait Genetics

Background:

• Morphological traits result from complex, multivariate gene interactions.
• Current genetic studies often focus on single genes, overlooking coordinated effects.
• High-dimensional phenotypic data, like craniofacial shape, are underutilized in genetic analyses.

Purpose of the Study:

• To develop and apply a process-centered, multivariate genotype-phenotype (process MGP) approach.
• To model the joint effects of biologically coherent gene collections on craniofacial shape variation.
• To investigate the contributions of specific biological processes to complex trait variation.

Main Methods:

• Utilized Gene Ontology (GO) annotations to define gene sets for skeletal and facial development.
• Applied a multivariate statistical framework to analyze genotype-phenotype relationships in 1145 Diversity Outbred (DO) mice.
• Solved for axes of shape variation that maximally covary with gene set marker variation.

Main Results:

• Identified specific biological processes contributing to craniofacial variation.
• Characterized the correspondence between gene set variation and multivariate axes of shape.
• Demonstrated the ability to predict phenotypic effects of mutations based on pathway associations.

Conclusions:

• The process MGP approach effectively links collections of genes to complex morphological phenotypes.
• This method advances our understanding of coordinated gene action in development and evolution.
• The approach is broadly applicable to various continuously varying phenotypes in complex trait genetics.