Thousands of induced germline mutations affecting immune cells identified by automated meiotic mapping coupled with machine learning.

Journal: Proceedings of the National Academy of Sciences of the United States of America
PMID: 34260399

Abstract

Forward genetic studies use meiotic mapping to adduce evidence that a particular mutation, normally induced by a germline mutagen, is causative of a particular phenotype. Particularly in small pedigrees, cosegregation of multiple mutations, occasional unawareness of mutations, and paucity of homozygotes may lead to erroneous declarations of cause and effect. We sought to improve the identification of mutations causing immune phenotypes in mice by creating Candidate Explorer (CE), a machine-learning software program that integrates 67 features of genetic mapping data into a single numeric score, mathematically convertible to the probability of verification of any putative mutation-phenotype association. At this time, CE has evaluated putative mutation-phenotype associations arising from screening damaging mutations in ∼55% of mouse genes for effects on flow cytometry measurements of immune cells in the blood. CE has therefore identified more than half of genes within which mutations can be causative of flow cytometric phenovariation in The majority of these genes were not previously known to support immune function or homeostasis. Mouse geneticists will find CE data informative in identifying causative mutations within quantitative trait loci, while clinical geneticists may use CE to help connect causative variants with rare heritable diseases of immunity, even in the absence of linkage information. CE displays integrated mutation, phenotype, and linkage data, and is freely available for query online.

Authors

  • Darui Xu
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Stephen Lyon
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Chun Hui Bu
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Sara Hildebrand
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Jin Huk Choi
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Xue Zhong
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Aijie Liu
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Emre E Turer
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Zhao Zhang
  • Jamie Russell
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Sara Ludwig
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Elena Mahrt
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Evan Nair-Gill
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Hexin Shi
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Ying Wang
    Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi 710062, China.
  • Duanwu Zhang
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Tao Yue
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Kuan-Wen Wang
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Jeffrey A SoRelle
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Lijing Su
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Takuma Misawa
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • William McAlpine
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Lei Sun
    1Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT 84322-4105 USA.
  • Jianhui Wang
  • Xiaoming Zhan
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Mihwa Choi
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Roxana Farokhnia
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Andrew Sakla
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Sara Schneider
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Hannah Coco
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Gabrielle Coolbaugh
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Braden Hayse
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Sara Mazal
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Dawson Medler
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Brandon Nguyen
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Edward Rodriguez
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Andrew Wadley
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Miao Tang
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Xiaohong Li
    College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
  • Priscilla Anderton
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Katie Keller
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Amanda Press
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Lindsay Scott
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Jiexia Quan
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Sydney Cooper
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Tiffany Collie
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Baifang Qin
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Jennifer Cardin
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Rochelle Simpson
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Meron Tadesse
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Qihua Sun
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Carol A Wise
    Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219.
  • Jonathan J Rios
    Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219.
  • Eva Marie Y Moresco
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • Bruce Beutler
    Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu.

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