Complementation testing identifies genes mediating effects at quantitative trait loci underlying fear-related behavior

Patrick B Chen; Rachel Chen; Nathan LaPierre; Zeyuan Chen; Joel Mefford; Emilie Marcus; Matthew G Heffel; Daniela C Soto; Jason Ernst; Chongyuan Luo; Jonathan Flint

doi:10.1016/j.xgen.2024.100545

Complementation testing identifies genes mediating effects at quantitative trait loci underlying fear-related behavior

Cell Genom. 2024 May 8;4(5):100545. doi: 10.1016/j.xgen.2024.100545. Epub 2024 May 1.

Authors

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Computer Science, Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Computer Science, Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Computer Science, Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: jflint@mednet.ucla.edu.

Abstract

Knowing the genes involved in quantitative traits provides an entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six quantitative trait loci (QTLs) by quantitative complementation, and identified six genes. Four genes, Lamp, Ptprd, Nptx2, and Sh3gl, have known roles in synapse function; the fifth, Psip1, was not previously implicated in behavior; and the sixth is a long non-coding RNA, 4933413L06Rik, of unknown function. Variation in transcriptome and epigenetic modalities occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results relieve a bottleneck in using genetic mapping of QTLs to uncover biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.

Keywords: QTL mapping; fear conditioning; inbred mouse strains; quantitative complementation; single-nucleus ATAC-seq; single-nucleus RNA-seq.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / physiology
Chromosome Mapping
Fear* / physiology
Female
Genetic Complementation Test
Male
Mice
Mice, Inbred C57BL
Quantitative Trait Loci*