Natural selection against a circadian clock gene mutation in mice

Abstract

Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.

Keywords: circadian rhythms; reproduction; resonance; survival; tau mutation.

Fig. 1.

Mutant tau allele frequency development in the six replicate populations. (A) The mean ± 1 SEM for all cohorts together. The drops in March, May, and September result from the inclusion of new mice after trapping. The dot on the right denotes final allele frequency after trapping all mice at the end of the experiment. (B) Mean frequency ±1 SEM for the cohorts separately. Horizontal lines (–4) indicate the four trapping intervals (see also Tables 1 and 3).

Fig. 2.

Effects of tau on daily activity in the laboratory and in the field. (A–C) Running-wheel activity in the laboratory (double-plot; i.e., x axis represents 48 h) of a wild-type (A), heterozygous (B), and homozygous (C) tau mutant mouse under LD 12:12 h and constant darkness (DD; day 15 onward; gray shade indicates darkness). tau/tau mice do not entrain; tau/+ mice entrain with a phase advance to the LD cycle. (D–I) Activity patterns recorded in outside enclosures for individual wild-type (D), heterozygote (E), and homozygote (F) tau mutant mice released on November 2, 2007, until last recorded; and composite actograms for all present wild-type (G), heterozygote (H), and homozygote (I) mice for the entire course of the experiment. Shaded: darkness from civil twilight (ct) at dusk to ct at dawn. (J) Diurnality Index D over the entire course of the experiment.

Fig. 3.

Variation in average daily feeding activity and average diurnality index between tau genotypes. Feeding activity, expressed in presence (in the number of 1-min bins per day per individual) at the feeders (no effect of genotype; ANOVA, F = 1.322, P = 0.25) (A) and the diurnality index D (B) estimates from a linear mixed effect model (LME) fitted with sex as fixed effect and date, individual, and enclosure as random effects (effect of genotype with both sexes combined, χ² = 94.7, df = 8, P < 0.0001).

Fig. 4.

Distribution of the first and second period in feeding behavior. For each individual, these two periods were defined as the highest and second highest peak in the average 14-d Lomb–Scargle (normalized) power spectrum. Each bar shows relative numbers of mice with their first (filled part of each bar) and the second (open part) most prominent rhythm at a specific period length (10-min resolution); n = 334/332 (first/second; +/+); n = 362/360 (tau/+); n = 85/81 (tau/tau).