Network-Based Functional Prediction Augments Genetic Association To Predict Candidate Genes for Histamine Hypersensitivity in Mice.

Document Type

Article

Publication Date

12-2019

Keywords

JMG

JAX Source

G3 (Bethesda) 2019 Dec; 9:4223-4233

Volume

9

Issue

12

First Page

4223

Last Page

4233

ISSN

2160-1836

PMID

31645420

DOI

https://doi.org/10.1534/g3.119.400740

Grant

LM012615

Abstract

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often ad hoc and biased by previous findings. Here we present a technique for prioritizing positional candidates based on computationally inferred gene function. Our method uses machine learning with functional genomic networks, whose links encode functional associations among genes, to identify network-based signatures of functional association to a trait of interest. We demonstrate the method by functionally ranking positional candidates in a large locus on mouse Chr 6 (45.9 Mb to 127.8 Mb) associated with histamine hypersensitivity (Histh). Histh is characterized by systemic vascular leakage and edema in response to histamine challenge, which can lead to multiple organ failure and death. Although Histh risk is strongly influenced by genetics, little is known about its underlying molecular or genetic causes, due to genetic and physiological complexity of the trait. To dissect this complexity, we ranked genes in the Histh locus by predicting functional association with multiple Histh-related processes. We integrated these predictions with new single nucleotide polymorphism (SNP) association data derived from a survey of 23 inbred mouse strains and congenic mapping data. The top-ranked genes included Cxcl12, Ret, Cacna1c, and Cntn3, all of which had strong functional associations and were proximal to SNPs segregating with Histh. These results demonstrate the power of network-based computational methods to nominate highly plausible quantitative trait genes even in challenging cases involving large QTL and extreme trait complexity.

Comments

We thank Laura Cort for supervising students during genotyping of congenic mice.

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