Complementation testing identifies causal genes at quantitative trait loci underlying fear related behavior

Abstract

ABSTRACTKnowing the genes involved in quantitative traits provides a critical 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. Here we address a key step towards that goal by deploying a test that directly queries whether a gene mediates the effect of a quantitative trait locus (QTL). To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six QTLs, and identified six genes. Four genes,Lsamp, Ptprd, Nptx2andSh3gl,have known roles in synapse function; the fifth gene,Psip1,is a transcriptional co-activator not previously implicated in behavior; the sixth is a long non-coding RNA4933413L06Rikwith no known function. Single nucleus transcriptomic and epigenetic analyses implicated excitatory neurons as likely mediating the genetic effects. Surprisingly, variation in transcriptome and epigenetic modalities between inbred strains occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results open a bottleneck in using genetic mapping of QTLs to find novel biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.