Properties of selected mutations and genotypic landscapes under Fisher's Geometric Model

The fitness landscape - the mapping between genotypes and fitness - determines properties of the process of adaptation. Several small genetic fitness landscapes have recently been built by selecting a handful of beneficial mutations and measuring fitness of all combinations of these mutations. Here we generate several testable predictions for the properties of these landscapes under Fisher's geometric model of adaptation (FGMA). When far from the fitness optimum, we analytically compute the fitness effect of beneficial mutations and their epistatic interactions. We show that epistasis may be negative or positive on average depending on the distance of the ancestral genotype to the optimum and whether mutations were independently selected or co-selected in an adaptive walk. Using simulations, we show that genetic landscapes built from FGMA are very close to an additive landscape when the ancestral strain is far from the optimum. However, when close to the optimum, a large diversity of landscape with substantial ruggedness and sign epistasis emerged. Strikingly, landscapes built from different realizations of stochastic adaptive walks in the same exact conditions were highly variable, suggesting that several realizations of small genetic landscapes are needed to gain information about the underlying architecture of the global adaptive landscape.Comment: 51 pages, 8 figure

Decomposing the site frequency spectrum: the impact of tree topology on neutrality tests

We investigate the dependence of the site frequency spectrum (SFS) on the topological structure of genealogical trees. We show that basic population genetic statistics - for instance estimators of $\theta$ or neutrality tests such as Tajima's $D$ - can be decomposed into components of waiting times between coalescent events and of tree topology. Our results clarify the relative impact of the two components on these statistics. We provide a rigorous interpretation of positive or negative values of an important class of neutrality tests in terms of the underlying tree shape. In particular, we show that values of Tajima's $D$ and Fay and Wu's $H$ depend in a direct way on a peculiar measure of tree balance which is mostly determined by the root balance of the tree. We present a new test for selection in the same class as Fay and Wu's $H$ and discuss its interpretation and power. Finally, we determine the trees corresponding to extreme expected values of these neutrality tests and present formulae for these extreme values as a function of sample size and number of segregating sites.Comment: 23 pages, 8 figure

Novel insights into RNAi off-target effects using C. elegans paralogs

<p>Abstract</p> <p>Background</p> <p>In the few years since its discovery, RNAi has turned into a very powerful tool for the study of gene function by allowing post-transcriptional gene silencing. The RNAi mechanism, which is based on the introduction of a double-stranded RNA (dsRNA) trigger whose sequence is similar to that of the targeted messenger RNA (mRNA), is subject to off-target cross-reaction.</p> <p>Results</p> <p>We use a novel strategy based on phenotypic analysis of paralogs and predict that, in <it>Caenorhabditis elegans</it>, off-target effects occur when an mRNA sequence shares more than 95% identity over 40 nucleotides with the dsRNA. Interestingly, our results suggest that the minimum length necessary of a high-similarity stretch between a dsRNA and its target in order to observe an efficient RNAi effect varies from 30 to 50 nucleotides rather than 22 nucleotides, which is the length of siRNAs in <it>C. elegans</it>.</p> <p>Conclusion</p> <p>Our predictive methods would improve the design of dsRNA and ultimately the use of RNAi as a therapeutic tool upon experimental verification.</p

The expected neutral frequency spectrum of linked sites

We present an exact, closed expression for the expected neutral Site Frequency Spectrum for two neutral sites, 2-SFS, without recombination. This spectrum is the immediate extension of the well known single site $\theta/f$ neutral SFS. Similar formulae are also provided for the case of the expected SFS of sites that are linked to a focal neutral mutation of known frequency. Formulae for finite samples are obtained by coalescent methods and remarkably simple expressions are derived for the SFS of a large population, which are also solutions of the multi-allelic Kolmogorov equations. Besides the general interest of these new spectra, they relate to interesting biological cases such as structural variants and introgressions. As an example, we present the expected neutral frequency spectrum of regions with a chromosomal inversion.Comment: 26 pages, 5 figure

Is convergence an evidence for positive selection?

International audienceA recommendation of the preprint: Frederic Bertels, Karin J Metzner, Roland R Regoes. Convergent evolution as an indicator for selection during acute HIV-1 infection (2018), bioRxiv, 168260, ver. 4 peer-reviewed and recommended by Peer Community in Evolutionary Biology. https://doi.org/10.1101/16826

Molecular evolution through the joint lens of genomic and population processes

International audienceA recommendation – based on reviews by Benoit Nabholz and one anonymous reviewer – of the article: Pouyet F, Gilbert KJ (2020) Towards an improved understanding of molecular evolution: the relative roles of selection, drift, and everything in between. arXiv:1909.11490 [q-bio]. ver. 4 peer-reviewed and recommended by PCI Evolutionary Biology. url: https://arxiv.org/abs/1909.1149

Pros and Cons of local adaptation scans

A recommendation – based on reviews by Lucas Gonçalves da Silva and one anonymous reviewer – of the article: Pratlong, M., Haguenauer, A., Brener, K., Mitta, G., Toulza, E., Garrabou, J., Bensoussan, N., Pontarotti P., and Aurelle, D. (2018). Separate the wheat from the chaff: genomic scan for local adaptation in the red coral Corallium rubrum. bioRxiv, 306456, ver. 3 peer-reviewed and recommended by PCI Evol Biol. . doi: 10.1101/30645

Frequency Spectrum Neutrality Tests: One for All and All for One

Neutrality tests based on the frequency spectrum (e.g., Tajima's D or Fu and Li's F) are commonly used by population geneticists as routine tests to assess the goodness-of-fit of the standard neutral model on their data sets. Here, I show that these neutrality tests are specific instances of a general model that encompasses them all. I illustrate how this general framework can be taken advantage of to devise new more powerful tests that better detect deviations from the standard model. Finally, I exemplify the usefulness of the framework on SNP data by showing how it supports the selection hypothesis in the lactase human gene by overcoming the ascertainment bias. The framework presented here paves the way for constructing novel tests optimized for specific violations of the standard model that ultimately will help to unravel scenarios of evolution

Testing for Neutrality in Samples With Sequencing Errors

Many data sets one could use for population genetics contain artifactual sites, i.e., sequencing errors. Here, we first explore the impact of such errors on several common summary statistics, assuming that sequencing errors are mostly singletons. We thus show that in the presence of those errors, estimators of θ can be strongly biased. We further show that even with a moderate number of sequencing errors, neutrality tests based on the frequency spectrum reject neutrality. This implies that analyses of data sets with such errors will systematically lead to wrong inferences of evolutionary scenarios. To avoid to these errors, we propose two new estimators of θ that ignore singletons as well as two new tests Y and Y* that can be used to test neutrality despite sequencing errors. All in all, we show that even though singletons are ignored, these new tests show some power to detect deviations from a standard neutral model. We therefore advise the use of these new tests to strengthen conclusions in suspicious data sets