Partitioning stable and unstable expression level variation in cell populations: A theoretical framework and its application to the T cell receptor.

Phenotypic variation in the copy number of gene products expressed by cells or tissues has been the focus of intense investigation. To what extent the observed differences in cellular expression levels are persistent or transient is an intriguing question. Here, we develop a quantitative framework that resolves the expression variation into stable and unstable components. The difference between the expression means in two cohorts isolated from any cell population is shown to converge to an asymptotic value, with a characteristic time, τT, that measures the timescale of the unstable dynamics. The asymptotic difference in the means, relative to the initial value, measures the stable proportion of the original population variance [Formula: see text]. Empowered by this insight, we analysed the T-cell receptor (TCR) expression variation in CD4 T cells. About 70% of TCR expression variance is stable in a diverse polyclonal population, while over 80% of the variance in an isogenic TCR transgenic population is volatile. In both populations the TCR levels fluctuate with a characteristic time of 32 hours. This systematic characterisation of the expression variation dynamics, relying on time series of cohorts' means, can be combined with technologies that measure gene or protein expression in single cells or in bulk.

Slower environmental change hinders adaptation from standing genetic variation.

Evolutionary responses to environmental change depend on the time available for adaptation before environmental degradation leads to extinction. Explicit tests of this relationship are limited to microbes where adaptation usually depends on the sequential fixation of de novo mutations, excluding standing variation for genotype-by-environment fitness interactions that should be key for most natural species. For natural species evolving from standing genetic variation, adaptation at slower rates of environmental change may be impeded since the best genotypes at the most extreme environments can be lost during evolution due to genetic drift or founder effects. To address this hypothesis, we perform experimental evolution with self-fertilizing populations of the nematode Caenorhabditis elegans and develop an inference model to describe natural selection on extant genotypes under environmental change. Under a sudden environmental change, we find that selection rapidly increases the frequency of genotypes with high fitness in the most extreme environment. In contrast, under a gradual environmental change selection first favors genotypes that are worse at the most extreme environment. We demonstrate with a second set of evolution experiments that, as a consequence of slower environmental change and thus longer periods to reach the most extreme environments, genetic drift and founder effects can lead to the loss of the most beneficial genotypes. We further find that maintenance of standing genetic variation can retard the fixation of the best genotypes in the most extreme environment because of interference between them. Taken together, these results show that slower environmental change can hamper adaptation from standing genetic variation and they support theoretical models indicating that standing variation for genotype-by-environment fitness interactions critically alters the pace and outcome of adaptation under environmental change.