Sex Inclusion in Transcriptome Studies of Daily Rhythms

Abstract

Biomedical research on mammals has traditionally neglected females, raising the concern that some scientific findings may generalize poorly to half the population. Although this lack of sex inclusion has been broadly documented, its extent within circadian genomics remains undescribed. To address this gap, we examined sex inclusion practices in a comprehensive collection of publicly available transcriptome studies on daily rhythms. Among 148 studies having samples from mammals in vivo, we found strong underrepresentation of females across organisms and tissues. Overall, only 23 of 123 studies in mice, 0 of 10 studies in rats, and 9 of 15 studies in humans included samples from females. In addition, studies having samples from both sexes tended to have more samples from males than from females. These trends appear to have changed little over time, including since 2016, when the US National Institutes of Health began requiring investigators to consider sex as a biological variable. Our findings highlight an opportunity to dramatically improve representation of females in circadian research and to explore sex differences in daily rhythms at the genome level.

Meta-analysis of Diurnal Transcriptomics in Mouse Liver Reveals Low Repeatability of Rhythm Analyses

“…Since these meta-analytic methods naturally account for differences between the individual studies, the inclusion of multiple study designs and conditions should not compromise the results. A further limitation is the small number of studies including female mice, which are known to be underused in circadian model animal studies ( Obodo et al, 2023 ).…”

“…Since these meta-analytic methods naturally account for differences between the individual studies, the inclusion of multiple study designs and conditions should not compromise the results. A further limitation is the small number of studies including female mice, which are known to be underused in circadian model animal studies (Obodo et al, 2023). cOncLuSIOn When a gene is found to be rhythmic in one data set and not in another, it can be due to technical factors that influence the statistical power to detect, or it can reflect the true biology-the gene in fact was rhythmic in one set of animals and not in the other.…”

Multi-omics profiling reveals rhythmic liver function shaped by meal timing

“…Notably, female mice exhibit a greater consolidation of diurnal rhythms of non-hepatic peripheral oscillators during DRF compared to males 7 , 11 , 14 . In the meanwhile, females are much less represented than males in circadian research 39 . Nevertheless, the liver clock and transcriptome exhibit comparable and complete entrainment to DRF from both sexes 7 , 11 , 14 .…”

Biological Sex Influences Daily Locomotor Rhythms in Mice Held Under Different Housing Conditions

“…Furthermore, estrus has been shown to modulate jetlag recovery (Pilorz et al, 2009), and unstaged female mice display larger photic resetting, accelerated jetlag recovery, and higher rates of light-induced arrhythmia (reviewed by Joye and Evans, 2022). These studies indicate that daily rhythms are influenced by sex and reproductive hormones, but little work has used both sexes at the behavioral (Lee et al, 2021), neurophysiological (Joye and Evans, 2022), and genetic levels (Obodo et al, 2023). Renewed interest in this topic provides exciting opportunities to investigate convergence and divergence of mammalian mechanisms driving circadian plasticity.…”