High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains

Abstract

Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders—80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.

Behavioral phenotypes revealed during reversal learning are linked with novel genetic loci in diversity outbred mice

“…This approach has revealed a novel QTL for reversal learning difference scores and a suggestive QTL for premature responding during reversal learning. Additional work is underway to characterize cocaine self-administration and other traits related cocaine use disorder in the DO/CC populations [ 34 , 61 , 62 ]. Future analysis will integrate data presented here with these additional studies to facilitate further discovery of the genetics that simultaneously influence impulsivity and SUD-related traits.…”

Reversal Learning Phenotypes are Linked with Novel Genetic Loci in Diversity Outbred Mice

“…This approach has revealed a novel QTL for reversal learning difference scores and a suggestive QTL for premature responding during reversal learning. Additional work is underway to characterize cocaine self-administration and other traits related cocaine use disorder in the DO/CC populations (Kim et al, 2021; Saul et al, 2020; Schoenrock et al, 2020). Future analysis will integrate data presented here with these additional studies to facilitate further discovery of the genetics that simultaneously influence impulsivity and SUD-related traits.…”

Targeting NR1D1 in organ injury: challenges and prospects

“…In addition, even cells originating from the same individual produce different rhythms over generations of inheritance. Kim et al [ 127 ] demonstrated that skin fibroblasts from diversity outbred (DO) mice underwent increased variations in circadian phenotypes over the course of inheritance. However, the mechanism by which NR1D1 regulates circadian rhythms in different species has not yet been clearly explored.…”