Informace o publikaci

High-throughput sleep phenotyping produces robust and heritable traits in Diversity Outbred mice and their founder strains



Rok publikování 2020
Druh Článek v odborném periodiku
Časopis / Zdroj SLEEP
Fakulta / Pracoviště MU

Středoevropský technologický institut

Klíčová slova genetics; high-throughput phenotyping; Diversity Outbred mice; sleep latency in new environment; modified Murine Multiple Sleep Latency Test; circadian period; sleep
Popis Study Objectives: This study describes high-throughput phenotyping strategies for sleep and circadian behavior in mice, including examinations of robustness, reliability, and heritability among Diversity Outbred (DO) mice and their eight founder strains. Methods: We performed high-throughput sleep and circadian phenotyping in male mice from the DO population (n = 338) and their eight founder strains: A/J (n = 6), C57BL/6J (n = 14), 129S1/SvlmJ (n = 6), NOD/LtJ (n = 6), NZO/H1LtJ (n = 6), CAST/EiJ (n = 8), PWK/PhJ (n = 8), and WSB/EiJ (n = 6). Using infrared beam break systems, we defined sleep as at least 40 s of continuous inactivity and quantified sleep-wake amounts and bout characteristics. We developed assays to measure sleep latency in a new environment and during a modified Murine Multiple Sleep Latency Test, and estimated circadian period from wheel-running experiments. For each trait, broad-sense heritability (proportion of variability explained by all genetic factors) was derived in founder strains, while narrow-sense heritability (proportion of variability explained by additive genetic effects) was calculated in DO mice. Results: Phenotypes were robust to different inactivity durations to define sleep. Differences across founder strains and moderate/high broad-sense heritability were observed for most traits. There was large phenotypic variability among DO mice, and phenotypes were reliable, although estimates of heritability were lower than in founder mice. This likely reflects important nonadditive genetic effects. Conclusions: A high-throughput phenotyping strategy in mice, based primarily on monitoring of activity patterns, provides reliable and heritable estimates of sleep and circadian traits. This approach is suitable for discovery analyses in DO mice, where genetic factors explain some proportion of phenotypic variation. Statement of Significance Diversity Outbred (DO) mice are an increasingly used resource for genetic discovery, with unique advantages. However, genetic analyses using this resource require a robust and high-throughput phenotyping strategy. This study describes such a strategy for sleep and circadian behaviors. Using DO mice and mice from their eight founder strains, we demonstrate that measures of sleep architecture, latency to sleep, sleep drive, and circadian period derived through monitoring of activity patterns are robust to the specific inactivity duration used to define sleep, are reliable in DO mice, and are significantly influenced by complex genetic effects (e.g. heritable). This phenotyping strategy can be used in future studies leveraging DO mice to discover individual or combinations of genes affecting sleep and circadian behavior.

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