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

• Published in: Cell genomics 2024-05, Vol.4 (5), p.100545, Article 100545
• Main Authors: Chen, Patrick B., Chen, Rachel, LaPierre, Nathan, Chen, Zeyuan, Mefford, Joel, Marcus, Emilie, Heffel, Matthew G., Soto, Daniela C., Ernst, Jason, Luo, Chongyuan, Flint, Jonathan
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - physiology; Chromosome Mapping; Fear - physiology; fear conditioning; Female; Genetic Complementation Test; inbred mouse strains; Male; Mice; Mice, Inbred C57BL; QTL mapping; quantitative complementation; Quantitative Trait Loci; single-nucleus ATAC-seq; single-nucleus RNA-seq
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2024.100545

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. [Display omitted] •Meta-analysis with 6,544 mice found 93 quantitative trait loci for fear-related behavior•Quantitative complementation testing identified six genes at six quantitative trait loci•Epigenetic analyses implicated excitatory neurons as mediating the genetic effects•Genetic variation occurs preferentially in excitatory versus inhibitory neuronal circuits Chen et al. use quantitative complementation to identify genes at six quantitative trait loci influencing fear-related behaviors. Epigenetic analysis indicated that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Creating CRISPR knockouts in inbred strains makes it possible to identify genes at QTLs in mice.