Mutations: A larger target leads to faster evolution
The speed at which a cell fate decision in nematode worms evolves is due to the number of genes that control the decision, rather than to a high mutation rate.
- Section of Ecology, Behavior and Evolution, Division of Biological Sciences, University of California, San Diego, United States
Evolution is a two-step process: first, variation is generated, for example through random mutations; and then events such as natural selection determine whether specific traits become more or less common in a population. Some traits evolve faster than others, and different explanations for this emphasize the relative importance of one or the other of the two steps. For example, a fast-evolving trait could be under sustained and intense selection pressure, so that when a favorable new variant arises, it quickly spreads throughout the population. Alternatively, mutations might affect certain traits more than others, leading to more variation in these traits. Since variation is the fuel of evolution, this could make the affected traits change faster.
At the molecular level, two mechanisms can bias which traits are more likely to be affected by mutations. On one hand, the genes that affect a particular trait could be located in genomic areas with high mutation rates, known as ‘mutational hotspots’ (Fondon and Garner, 2004; Xie et al., 2019); on the other, a phenotype could depend on a large number genes, increasing the ‘mutational target size’ (Boyle et al., 2017).
Caenorhabditis elegans and C. briggsae worms have two sexes – males, which are very rare, and hermaphrodites. In hermaphrodites, the cell divisions and fate decisions that occur during development are nearly identical for individuals within a species. However, a cell called P3.p, which is involved in the development of the vulva, sometimes divides and sometimes does not, even among worms with the same genome (Sulston and Horvitz, 1977). A decade ago Marie-Anne Félix and colleagues reported that the frequency of this binary decision evolves more quickly than the cell fate decisions made by other early vulval cells, and that this fast evolution was probably due more to mutational biases – either hotspots or large target size – than selection effects (Braendle et al., 2010). Now, in eLife, Fabrice Besnard, Joao Picao-Osorio, Clément Dubois and Félix – who are based at laboratories in Lyon and Paris – report that this mutational bias is caused by a large mutational target size (Besnard et al., 2020).
To show this, Besnard et al. used mutation accumulation lines of either C. elegans or the closely related C. briggsae. These lines started from the offspring of a single individual and were bred in parallel. All of the lines were inbred: in each line a single selfing hermaphrodite was the parent of the next generation. This meant that if the parent had a new mutation, there would be a good chance that its offspring would inherit it. In this environment, the effects of natural selection were minimized because the only requirement for a line to endure was that a single hermaphrodite from that line survived and reproduced. After many generations, each line accumulated its own constellation of new mutations. Since the lines all started out genetically identical and selection was minimal, any differences in traits between the lines were be due to the different mutations.
The mutation accumulation lines used in these experiments were evolved for 250 generations (Baer et al., 2005), after which Besnard et al. chose to look at five lines in which the P3.p cell fate changed the most. By combining genomic sequencing and gene modification through CRISPR technology, they identified one gene in each line that was responsible for the change and showed that: (i) none of the genes are in a mutational hotspot in the genome; and (ii) only one of these genes was known to have a role specifically in vulval development. This suggests that the mutational target for P3.p cell fate is much broader than previously thought (Figure 1).
Figure 1
Fast evolution of a cell-fate decision in C. elegans and C. briggsae.
The vulva in Caenorhabditis worms develops from six precursor cells. In some individuals, the most anterior of these cells (called P3.p) divides during development; in other worms it does not (left). The chance of it dividing differs between species. Cell division in the other five vulval precursor cells (VPCs; left) does not vary. This faster evolution of P3.p may be due due to mutational hotspots (if the genes that regulate this decision have a relatively high mutation rate) or to a large target size (if there are relatively more genes that affect this decision). Besnard et al. used a mutation accumulation (MA) approach in two species – C. elegans and C. briggsae – to distinguish between the two explanations (right). They examined the MA lines in which the decision frequency differed the most from the ancestor (shown by the vertical grey, orange and blue bars in the graph) and identified the genes responsible (shown by the horizontal grey, orange and blue bars at the bottom of the figure). They found that none of these genes appear to be in a mutational hotspot and that they have a range of different biological roles. In this case, fast evolution is due to a large mutational target size.
This broad mutational target is consistent with many genome-wide association studies and genetic mapping studies (Manolio et al., 2009; Shi et al., 2016). These experiments suggest that trait evolution tends not to be caused by one or two mutations with very large effects: rather, tens (or even hundreds) of genes carrying mutations with small effects seem to be responsible. These previous studies also suggest, rather unexpectedly, that a large fraction of the genes that underlie trait variation often have very little or no previously known functional relationships to the traits, and this is also the case in the work of Besnard et al. Therefore, there is a discrepancy between genetic pathways that have been described in the last century as being responsible for specific traits and the genes whose variation apparently fuels evolution.
The use of Caenorhabditis species in this work reinforces the power of this model system in research on developmental and evolutionary biology. Because so much is known about worm cell fates, Besnard et al. were able to go beyond identifying genes and pose testable hypotheses for why this particular cell was more variable than other vulval precursors. For example, they point out that the P3.p cell is at the far end of a gradient of cell fate-inducing molecules that are secreted from the tail end of the animal. The Félix lab previously showed that P3.p cell division is much more sensitive to variations in the dose of these molecules than cells closer to the source of the gradient (Pénigault and Félix, 2011). This suggests that the decision by P3.p to divide or not operates close to a concentration threshold for these molecules. This in turn means that mutations with small effects on the shape of the gradient, or on the responsiveness of P3.p to the molecules, could have large effects on the fate of the P3.p cell.
Developmental processes are responsible for generating the effects of many mutations. Therefore, to fully understand how mutations influence evolution, we must first understand the developmental context in which they occur.
References
-
Evolution of a system sensitive to stochastic noise: p3.p cell fate in CaenorhabditisDevelopmental Biology 357:419–427.https://doi.org/10.1016/j.ydbio.2011.05.675
-
Contrasting the genetic architecture of 30 complex traits from summary association dataThe American Journal of Human Genetics 99:139–153.https://doi.org/10.1016/j.ajhg.2016.05.013
-
Post-embryonic cell lineages of the nematode, Caenorhabditis elegansDevelopmental Biology 56:110–156.https://doi.org/10.1016/0012-1606(77)90158-0
Article and author information
Author details
Publication history
- Version of Record published: October 14, 2020 (version 1)
Copyright
© 2020, Yang and Rifkin
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,413
- views
-
- 112
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Mutations: A larger target leads to faster evolution
eLife 9:e62689.
https://doi.org/10.7554/eLife.62689
Further reading
-
- Evolutionary Biology
The RNA world hypothesis proposes that during the early evolution of life, primordial genomes of the first self-propagating evolutionary units existed in the form of RNA-like polymers. Autonomous, non-enzymatic, and sustained replication of such information carriers presents a problem, because product formation and hybridization between template and copy strands reduces replication speed. Kinetics of growth is then parabolic with the benefit of entailing competitive coexistence, thereby maintaining diversity. Here, we test the information-maintaining ability of parabolic growth in stochastic multispecies population models under the constraints of constant total population size and chemostat conditions. We find that large population sizes and small differences in the replication rates favor the stable coexistence of the vast majority of replicator species (‘genes’), while the error threshold problem is alleviated relative to exponential amplification. In addition, sequence properties (GC content) and the strength of resource competition mediated by the rate of resource inflow determine the number of coexisting variants, suggesting that fluctuations in building block availability favored repeated cycles of exploration and exploitation. Stochastic parabolic growth could thus have played a pivotal role in preserving viable sequences generated by random abiotic synthesis and providing diverse genetic raw material to the early evolution of functional ribozymes.
-
- Ecology
- Evolutionary Biology
Seasonal animal dormancy is widely interpreted as a physiological response for surviving energetic challenges during the harshest times of the year (the physiological constraint hypothesis). However, there are other mutually non-exclusive hypotheses to explain the timing of animal dormancy, that is, entry into and emergence from hibernation (i.e. dormancy phenology). Survival advantages of dormancy that have been proposed are reduced risks of predation and competition (the ‘life-history’ hypothesis), but comparative tests across animal species are few. Using the phylogenetic comparative method applied to more than 20 hibernating mammalian species, we found support for both hypotheses as explanations for the phenology of dormancy. In accordance with the life-history hypotheses, sex differences in hibernation emergence and immergence were favored by the sex difference in reproductive effort. In addition, physiological constraint may influence the trade-off between survival and reproduction such that low temperatures and precipitation, as well as smaller body mass, influence sex differences in phenology. We also compiled initial evidence that ectotherm dormancy may be (1) less temperature dependent than previously thought and (2) associated with trade-offs consistent with the life-history hypothesis. Thus, dormancy during non-life-threatening periods that are unfavorable for reproduction may be more widespread than previously thought.
