A systematic approach to the study of GC-biased gene conversion in mammals
Fine-scale quantification of GC-biased gene conversion intensity in mammals
The role of GC-biased gene conversion (gBGC) in molecular evolution has interested scientists for the last two decades since its discovery in 1999 (Eyre-Walker 1999; Galtier et al. 2001). gBGC is a process that is associated with meiotic recombination, and is characterized by a transmission distortion in favor of G and C over A and T alleles at GC/AT heterozygous sites that occur in the vicinity of recombination-inducing double-strand breaks (Duret and Galtier 2009; Mugal et al. 2015). This transmission distortion results in a fixation bias of G and C alleles, equivalent to directional selection for G and C (Nagylaki 1983). The fixation bias subsequently leads to a correlation between recombination rate and GC content across the genome, which has served as indirect evidence for the prevalence of gBGC in many organisms. The fixation bias also produces shifts in the allele frequency spectrum (AFS) towards higher frequencies of G and C alleles.
These molecular signatures of gBGC provide a means to quantify the strength of gBGC and study its variation among species and across the genome. Following this idea, first Lartillot (2013) and Capra et al. (2013) developed phylogenetic methodology to quantify gBGC based on substitutions, and De Maio et al. (2013) combined information on polymorphism into a phylogenetic setting. Complementary to the phylogenetic methods, later Glemin et al. (2015) developed a method that draws information solely from polymorphism data and the shape of the AFS. Application of these methods to primates (Capra et al. 2013; De Maio et al. 2013; Glemin et al. 2015) and mammals (Lartillot 2013) supported the notion that variation in the strength of gBGC across the genome reflects the dynamics of the recombination landscape, while variation among species correlates with proxies of the effective population size. However, application of the polymorphism-based method by Glemin et al. (2015) to distantly related Metazoa did not confirm the correlation with effective population size (Galtier et al. 2018).
Here, Galtier (2021) introduces a novel phylogenetic approach applicable to the study of closely related species. Specifically, Galtier introduces a statistical framework that enables the systematic study of variation in the strength of gBGC among species and among genes. In addition, Galtier assesses fine-scale variation of gBGC across the genome by means of spatial autocorrelation analysis. This puts Galtier in a position to study variation in the strength of gBGC at three different scales, i) among species, ii) among genes, and iii) within genes. Galtier applies his method to four families of mammals, Hominidae, Cercopithecidae, Bovidae, and Muridae and provides a thorough discussion of his findings and methodology.
Galtier found that the strength of gBGC correlates with proxies of the effective population size (Ne), but that the slope of the relationship differs among the four families of mammals. Given the relationship between the population-scaled strength of gBGC B = 4Neb, this finding suggests that the conversion bias (b) could vary among mammalian species. Variation in b could either result from differences in the strength of the transmission distortion (Galtier et al. 2018) or evolutionary changes in the rate of recombination (Boman et al. 2021). Alternatively, Galtier suggests that also systematic variation in proxies of Ne could lead to similar observations. Finally, the present study reports intriguing inter-species differences between the extent of variation in the strength of gBGC among and within genes, which are interpreted in consideration of the recombination dynamics in mammals.
Boman J, Mugal CF, Backström N (2021) The Effects of GC-Biased Gene Conversion on Patterns of Genetic Diversity among and across Butterfly Genomes. Genome Biology and Evolution, 13. https://doi.org/10.1093/gbe/evab064
Capra JA, Hubisz MJ, Kostka D, Pollard KS, Siepel A (2013) A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes. PLOS Genetics, 9, e1003684. https://doi.org/10.1371/journal.pgen.1003684
De Maio N, Schlötterer C, Kosiol C (2013) Linking Great Apes Genome Evolution across Time Scales Using Polymorphism-Aware Phylogenetic Models. Molecular Biology and Evolution, 30, 2249–2262. https://doi.org/10.1093/molbev/mst131
Duret L, Galtier N (2009) Biased Gene Conversion and the Evolution of Mammalian Genomic Landscapes. Annual Review of Genomics and Human Genetics, 10, 285–311. https://doi.org/10.1146/annurev-genom-082908-150001
Eyre-Walker A (1999) Evidence of Selection on Silent Site Base Composition in Mammals: Potential Implications for the Evolution of Isochores and Junk DNA. Genetics, 152, 675–683. https://doi.org/10.1093/genetics/152.2.675
Galtier N (2021) Fine-scale quantification of GC-biased gene conversion intensity in mammals. bioRxiv, 2021.05.05.442789, ver. 5 peer-reviewed and recommended by Peer Community in Genomics. https://doi.org/10.1101/2021.05.05.442789
Galtier N, Piganeau G, Mouchiroud D, Duret L (2001) GC-Content Evolution in Mammalian Genomes: The Biased Gene Conversion Hypothesis. Genetics, 159, 907–911. https://doi.org/10.1093/genetics/159.2.907
Galtier N, Roux C, Rousselle M, Romiguier J, Figuet E, Glémin S, Bierne N, Duret L (2018) Codon Usage Bias in Animals: Disentangling the Effects of Natural Selection, Effective Population Size, and GC-Biased Gene Conversion. Molecular Biology and Evolution, 35, 1092–1103. https://doi.org/10.1093/molbev/msy015
Glémin S, Arndt PF, Messer PW, Petrov D, Galtier N, Duret L (2015) Quantification of GC-biased gene conversion in the human genome. Genome Research, 25, 1215–1228. https://doi.org/10.1101/gr.185488.114
Lartillot N (2013) Phylogenetic Patterns of GC-Biased Gene Conversion in Placental Mammals and the Evolutionary Dynamics of Recombination Landscapes. Molecular Biology and Evolution, 30, 489–502. https://doi.org/10.1093/molbev/mss239
Mugal CF, Weber CC, Ellegren H (2015) GC-biased gene conversion links the recombination landscape and demography to genomic base composition. BioEssays, 37, 1317–1326. https://doi.org/10.1002/bies.201500058
Nagylaki T (1983) Evolution of a finite population under gene conversion. Proceedings of the National Academy of Sciences, 80, 6278–6281. https://doi.org/10.1073/pnas.80.20.6278
Carina Farah Mugal (2021) A systematic approach to the study of GC-biased gene conversion in mammals. Peer Community in Genomics, 100012. https://doi.org/10.24072/pci.genomics.100012
Evaluation round #2
DOI or URL of the preprint: https://www.biorxiv.org/content/10.1101/2021.05.05.442789v4
Version of the preprint: 4
Author's Reply, 15 Sep 2021
Decision by Carina Farah Mugal, 15 Sep 2021
Dear Nicolas Galtier,
I am pleased to inform you that all three reviewers and I found that your revisions address all the earlier concerns and that your revised manuscript is in principle ready for recommendation. Only one reviewer has some very minor suggestions, which I think will be straight forward to address.
Carina Farah Mugal
Reviewed by Fanny Pouyet , 08 Sep 2021
Reviewed by anonymous reviewer, 24 Aug 2021
Reviewed by David Castellano, 01 Sep 2021
Evaluation round #1
DOI or URL of the preprint: https://www.biorxiv.org/content/10.1101/2021.05.05.442789v3
Version of the preprint: 3
Author's Reply, None
Decision by Carina Farah Mugal, 11 Jul 2021
Dear Nicolas Galtier,
Three reviewers have now read your manuscript "Fine-scale quantification of GC-biased gene conversion intensity in mammals". All three reviewers and I find the manuscript well-written, and results and method-contribution relevant and interesting. Nevertheless, all three reviewers also provide valuable suggestions for improvement, which I think will help to improve the quality and clarity of the study. Briefly,
(1) All three reviewers ask for more clarity of Method and Figure description. You will find specific comments and suggestions in the respective review reports.
(2) Reviewer #3 suggests an alternative hypothesis to explain the weak clustering of WS substitutions within Hominadae genes, which I find very interesting. This reviewer also suggests an hypothesis to explain observations of the RSD analysis, which I think could be worth exploring.
(3) Personally, I am wondering how the contribution of ancestral and lineage-specific polymorphisms could bias the estimation of substitution rates in closely related species (see e.g. doi: 10.1093/molbev/msz203)?
Besides, the author might find this reference on DSB evolution in mice useful in relation to their own observations in mice (doi: 10.1093/molbev/mst154).
I look forward to receiving a revised version of the manuscript.
Carina Farah Mugal