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The red queen model of recombination hotspots evolution in the light of archaic and modern human genomes.

Lesecque Y, Glémin S, Lartillot N, Mouchiroud D, Duret L - PLoS Genet. (2014)

Bottom Line: Recombination is an essential process in eukaryotes, which increases diversity by disrupting genetic linkage between loci and ensures the proper segregation of chromosomes during meiosis.However, the reasons for these changes and the rate at which they occur are not known.Surprisingly, however, our analyses indicate that Denisovan recombination hotspots did not overlap with modern human ones, despite sharing similar PRDM9 target motifs.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France.

ABSTRACT
Recombination is an essential process in eukaryotes, which increases diversity by disrupting genetic linkage between loci and ensures the proper segregation of chromosomes during meiosis. In the human genome, recombination events are clustered in hotspots, whose location is determined by the PRDM9 protein. There is evidence that the location of hotspots evolves rapidly, as a consequence of changes in PRDM9 DNA-binding domain. However, the reasons for these changes and the rate at which they occur are not known. In this study, we investigated the evolution of human hotspot loci and of PRDM9 target motifs, both in modern and archaic human lineages (Denisovan) to quantify the dynamic of hotspot turnover during the recent period of human evolution. We show that present-day human hotspots are young: they have been active only during the last 10% of the time since the divergence from chimpanzee, starting to be operating shortly before the split between Denisovans and modern humans. Surprisingly, however, our analyses indicate that Denisovan recombination hotspots did not overlap with modern human ones, despite sharing similar PRDM9 target motifs. We further show that high-affinity PRDM9 target motifs are subject to a strong self-destructive drive, known as biased gene conversion (BGC), which should lead to the loss of the majority of them in the next 3 MYR. This depletion of PRDM9 genomic targets is expected to decrease fitness, and thereby to favor new PRDM9 alleles binding different motifs. Our refined estimates of the age and life expectancy of human hotspots provide empirical evidence in support of the Red Queen hypothesis of recombination hotspots evolution.

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Differential loss of HM motifs across recent human history.The number of intact HM and CM motifs found in the reconstructed sequence (F2 subset) of human and chimpanzee last common ancestor (HC) and in the last human-Denisovan common ancestor (HD) is indicated with a simple arrow. Loss rates of HM and CM motifs are indicated for each branch. HM and CM loss rates were compared with a proportion test (p-value: p). Sequences of both motifs are shown below the tree. Double arrows represent populations divergence times [28], [29].
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pgen-1004790-g001: Differential loss of HM motifs across recent human history.The number of intact HM and CM motifs found in the reconstructed sequence (F2 subset) of human and chimpanzee last common ancestor (HC) and in the last human-Denisovan common ancestor (HD) is indicated with a simple arrow. Loss rates of HM and CM motifs are indicated for each branch. HM and CM loss rates were compared with a proportion test (p-value: p). Sequences of both motifs are shown below the tree. Double arrows represent populations divergence times [28], [29].

Mentions: The major human allele of PRDM9 (allele A, present at a frequency of 84% in European populations and 50% in African populations [11]) recognizes a specific sequence motif, whose core consensus is CCTCCCTNNCCAC[9], [10]. This motif promotes recombination specifically in humans, not in chimpanzee, and is particularly active in the context of THE1 transposable elements [10], [19]. As predicted by the self-destructive dBGC drive model, it was previously shown that this motif has accumulated an excess of substitutions specifically in the human lineage, after its divergence from chimpanzee, and that the HM loss rate was particularly strong within THE1 elements [10]. Based on the dBGC model [25], the authors proposed that HM had been active for a period of time corresponding to the last 20% to 40% of the time since the human-chimpanzee split [10]. This estimate was however based on poorly known parameters, and was therefore provided as a conservative upper bound [10]. To obtain a more direct dating of the onset of the HM motif activity, we used the Denisovan genome so as to determine when the HM motifs started to be subject to dBGC during the evolution of modern and archaic humans (Figure 1). We analyzed the evolution of HM motifs both within and outside human recombination hotspots. For this, we used recombination maps inferred by HapMap from patterns of linkage disequilibrium in human populations [2]. These maps reflect the average crossover rates across human populations over many generations. We will hereafter refer to these data as human "historical" recombination rates. Given that the list of human historical hotspots is currently available only for autosomes, we excluded sex chromosomes from our analyses.


The red queen model of recombination hotspots evolution in the light of archaic and modern human genomes.

Lesecque Y, Glémin S, Lartillot N, Mouchiroud D, Duret L - PLoS Genet. (2014)

Differential loss of HM motifs across recent human history.The number of intact HM and CM motifs found in the reconstructed sequence (F2 subset) of human and chimpanzee last common ancestor (HC) and in the last human-Denisovan common ancestor (HD) is indicated with a simple arrow. Loss rates of HM and CM motifs are indicated for each branch. HM and CM loss rates were compared with a proportion test (p-value: p). Sequences of both motifs are shown below the tree. Double arrows represent populations divergence times [28], [29].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230742&req=5

pgen-1004790-g001: Differential loss of HM motifs across recent human history.The number of intact HM and CM motifs found in the reconstructed sequence (F2 subset) of human and chimpanzee last common ancestor (HC) and in the last human-Denisovan common ancestor (HD) is indicated with a simple arrow. Loss rates of HM and CM motifs are indicated for each branch. HM and CM loss rates were compared with a proportion test (p-value: p). Sequences of both motifs are shown below the tree. Double arrows represent populations divergence times [28], [29].
Mentions: The major human allele of PRDM9 (allele A, present at a frequency of 84% in European populations and 50% in African populations [11]) recognizes a specific sequence motif, whose core consensus is CCTCCCTNNCCAC[9], [10]. This motif promotes recombination specifically in humans, not in chimpanzee, and is particularly active in the context of THE1 transposable elements [10], [19]. As predicted by the self-destructive dBGC drive model, it was previously shown that this motif has accumulated an excess of substitutions specifically in the human lineage, after its divergence from chimpanzee, and that the HM loss rate was particularly strong within THE1 elements [10]. Based on the dBGC model [25], the authors proposed that HM had been active for a period of time corresponding to the last 20% to 40% of the time since the human-chimpanzee split [10]. This estimate was however based on poorly known parameters, and was therefore provided as a conservative upper bound [10]. To obtain a more direct dating of the onset of the HM motif activity, we used the Denisovan genome so as to determine when the HM motifs started to be subject to dBGC during the evolution of modern and archaic humans (Figure 1). We analyzed the evolution of HM motifs both within and outside human recombination hotspots. For this, we used recombination maps inferred by HapMap from patterns of linkage disequilibrium in human populations [2]. These maps reflect the average crossover rates across human populations over many generations. We will hereafter refer to these data as human "historical" recombination rates. Given that the list of human historical hotspots is currently available only for autosomes, we excluded sex chromosomes from our analyses.

Bottom Line: Recombination is an essential process in eukaryotes, which increases diversity by disrupting genetic linkage between loci and ensures the proper segregation of chromosomes during meiosis.However, the reasons for these changes and the rate at which they occur are not known.Surprisingly, however, our analyses indicate that Denisovan recombination hotspots did not overlap with modern human ones, despite sharing similar PRDM9 target motifs.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France.

ABSTRACT
Recombination is an essential process in eukaryotes, which increases diversity by disrupting genetic linkage between loci and ensures the proper segregation of chromosomes during meiosis. In the human genome, recombination events are clustered in hotspots, whose location is determined by the PRDM9 protein. There is evidence that the location of hotspots evolves rapidly, as a consequence of changes in PRDM9 DNA-binding domain. However, the reasons for these changes and the rate at which they occur are not known. In this study, we investigated the evolution of human hotspot loci and of PRDM9 target motifs, both in modern and archaic human lineages (Denisovan) to quantify the dynamic of hotspot turnover during the recent period of human evolution. We show that present-day human hotspots are young: they have been active only during the last 10% of the time since the divergence from chimpanzee, starting to be operating shortly before the split between Denisovans and modern humans. Surprisingly, however, our analyses indicate that Denisovan recombination hotspots did not overlap with modern human ones, despite sharing similar PRDM9 target motifs. We further show that high-affinity PRDM9 target motifs are subject to a strong self-destructive drive, known as biased gene conversion (BGC), which should lead to the loss of the majority of them in the next 3 MYR. This depletion of PRDM9 genomic targets is expected to decrease fitness, and thereby to favor new PRDM9 alleles binding different motifs. Our refined estimates of the age and life expectancy of human hotspots provide empirical evidence in support of the Red Queen hypothesis of recombination hotspots evolution.

Show MeSH
Related in: MedlinePlus