High prevalence of Prdm9-independent recombination hotspots in placental mammals

Joseph, J.; Prentout, D.; Laverré, A.; Tricou, T.; Duret, L.

doi:10.1101/2023.11.17.567540

Cited by 6 publications

(1 citation statement)

References 87 publications

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“…They observe that most mammals have a high GC-content equilibrium state with the exception of humans, mice, some felids and cetaceans. This suggests that most mammals experience some boost in GC-content due to a certain degree of recombination at TSSs despite the fact these organisms contain functional versions of PRDM9 (Joseph et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

The GC-content at the 5’ends of human protein-coding genes is undergoing mutational decay

Qiu,

Kang,

Korfmann

et al. 2024

Preprint

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In vertebrates, most protein-coding genes have a peak of GC-content near their 5' transcriptional start site (TSS). This feature promotes both the efficient nuclear export and translation of mRNAs. Despite the importance of GC-content for RNA metabolism, its general features, origin, and maintenance remain mysterious. We investigated the evolutionary forces shaping GC-content at the transcriptional start site (TSS) of genes through both comparative genomic analysis of nucleotide substitution rates between different species and by examining human de novo mutations. Our data suggests that GC-peaks at TSSs were present in the last vertebrate common ancestor and are largely dictated by recombination patterns. We observe that in primates and rodents, where recombination is directed away from TSSs by PRDM9, GC-content at protein-coding gene TSSs is currently undergoing mutational decay. In canids, which lack PRDM9 and perform recombination at TSSs, GC-content at protein-coding gene TSSs is increasing. These patterns extend into the open reading frame affecting protein-coding regions, and we show that changes in GC-content due to recombination affect synonymous codon position choices at the start of the open reading frame. Our results indicate that although high GC-content in protein-coding genes may be shaped by selective pressures to enhance expression, the dynamics of GC-content in mammals are largely shaped by patterns of recombination.

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Section: Discussionmentioning

confidence: 99%

The GC-content at the 5’ends of human protein-coding genes is undergoing mutational decay

Qiu,

Kang,

Korfmann

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

High prevalence of PRDM9-independent recombination hotspots in placental mammals

Joseph,

Prentout,

Laverré

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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In many mammals, recombination events are concentrated in hotspots directed by a sequence-specific DNA-binding protein named PRDM9. Intriguingly, PRDM9 has been lost several times in vertebrates, and notably among mammals, it has been pseudogenized in the ancestor of canids. In the absence of PRDM9, recombination hotspots tend to occur in promoter-like features such as CpG islands. It has thus been proposed that one role of PRDM9 could be to direct recombination away from PRDM9-independent hotspots. However, the ability of PRDM9 to direct recombination hotspots has been assessed in only a handful of species, and a clear picture of how much recombination occurs outside of PRDM9-directed hotspots in mammals is still lacking. In this study, we derived an estimator of past recombination activity based on signatures of GC-biased gene conversion in substitution patterns. We quantified recombination activity in PRDM9-independent hotspots in 52 species of boreoeutherian mammals. We observe a wide range of recombination rates at these loci: several species (such as mice, humans, some felids, or cetaceans) show a deficit of recombination, while a majority of mammals display a clear peak of recombination. Our results demonstrate that PRDM9-directed and PRDM9-independent hotspots can coexist in mammals and that their coexistence appears to be the rule rather than the exception. Additionally, we show that the location of PRDM9-independent hotspots is relatively more stable than that of PRDM9-directed hotspots, but that PRDM9-independent hotspots nevertheless evolve slowly in concert with DNA hypomethylation.

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Increased positive selection in highly recombining genes does not necessarily reflect an evolutionary advantage of recombination

Joseph

2024

Preprint

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It is commonly thought that the long-term advantage of meiotic recombination is to dissipate genetic linkage, allowing natural selection to act independently on different loci. It is thus theoretically expected that genes with higher recombination rates evolve under more effective selection, and can adapt more easily to environmental change. On the other hand, recombination is often associated with GC-biased gene conversion (gBGC), which theoretically interferes with selection by promoting the fixation of deleterious GC alleles. To test these predictions, several empirical studies assessed whether selection was more effective in highly recombining genes (due to dissipation of genetic linkage) or less effective (due to gBGC), implicitly assuming a fixed distribution of fitness effects (DFE) for all genes. In this study, I directly derive the expected shape of the DFE from the evolutionary history of a gene (shaped by mutation, selection, drift and gBGC) under empirical fitness landscapes. I show that genes that have known high levels of gBGC are less fit and thus have more opportunities for beneficial mutations. Only a slight decrease in the genome-wide intensity of gBGC leads to the fixation of these beneficial mutations, particularly in highly recombining genes. This shows that increased positive selection in highly recombining genes is not by itself an evidence for more effective selection due to the dissipation of genetic linkage. Additionally, I show that the death of a long-lived recombination hotspot can lead to a higherdN/dSthan its birth, but with substitutions patterns biased towards AT, and only at selected position. This shows that controlling for a substitution bias towards GC is therefore not sufficient to rule out the contribution of gBGC to signatures of accelerated evolution.

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High prevalence of Prdm9-independent recombination hotspots in placental mammals

Cited by 6 publications

References 87 publications

The GC-content at the 5’ends of human protein-coding genes is undergoing mutational decay

The GC-content at the 5’ends of human protein-coding genes is undergoing mutational decay

High prevalence of PRDM9-independent recombination hotspots in placental mammals

Increased positive selection in highly recombining genes does not necessarily reflect an evolutionary advantage of recombination

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