Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes.

David C Katz,Benedikt Hallgrímsson,Ralph S Marcucio,K Michael Pollard,Charles C Roseman,Stephen A Murray,Steven C Munger,James Cheverud,Wei Liu,J David Aponte,Christopher J Percival,Jessica M Mayeux,Daniel Pomp,Rebecca M Green

doi:10.1371/journal.pone.0233377

Abstract

The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in mouse), each characterized by 22 three-dimensional landmarks, 56,885 autosomal and X-chromosome markers, and sex and age classifiers. We identified 37 facial shape QTL across 20 shape principal components (PCs) using a mixed effects regression that accounts for kinship among observations. The QTL include some previously identified intervals as well as new regions that expand the list of potential targets for future experimental study. Three QTL characterized shape associations with size (allometry). Median support interval size was 3.5 Mb. Narrowing additional analysis to QTL for the five largest magnitude shape PCs, we found significant overrepresentation of genes with known roles in growth, skeletal and facial development, and sensory organ development. For most intervals, one or more of these genes lies within 0.25 Mb of the QTL’s peak. QTL effect sizes were small, with none explaining more than 0.5% of facial shape variation. Thus, our results are consistent with a model of facial diversity that is influenced by key genes in skeletal and facial development and, simultaneously, is highly polygenic.

Highlights

The facial skeleton is a complex morphology that serves a diverse set of critical roles
For each principal components (PCs) explaining more than 1% of shape variation, we identify statistically significant marker effects using a mixed effects regression model that simultaneously accounts for kinship among animals [50, 51]
Evidence for a quantitative trait loci (QTL) was evaluated by comparing logs odds (LOD) scores [53] at each marker to a distribution of maximum LOD scores obtained from quantifying marker effects over 1000 random permutations of GP assignments

Summary

Introduction

The facial skeleton is a complex morphology that serves a diverse set of critical roles. Structured differences (covariance) in facial shape, and between facial shape and size, depend upon variation in the biological processes that coordinate facial development [1,2,3,4,5,6,7] Understanding how these processes act and combine to build a facial skeleton requires interrogation at multiple levels of the genotype-phenotype (GP) map [8, 9]. Among the most fundamental of these inquiries is the search for genetic variants that contribute to facial shape variation These genetic variants are the basic building blocks of diversity and, within species, circumscribe the potential for short-term evolutionary change [10, 11]. The focus is typically on additive effects [12], though some recent work considers interactions among loci [4, 13, 14]

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Results

Conclusion