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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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Equilibrium GC-content (GC*) around human recombination hotspots in different branches of the phylogeny.GC* is computed on each branch of the phylogeny (Figure 1): (A) Chimpanzee branch; (B) Hominini branch; (C) Denisovan branch; (D) Modern human branch. Profiles show the mean GC* computed on 32,987 human historical hotspots, over a 20 kb region centered on the middle of hotspots. Each dot is the average GC* over a 10 bp window. The line shows average GC* over 500 bp window.
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pgen-1004790-g006: Equilibrium GC-content (GC*) around human recombination hotspots in different branches of the phylogeny.GC* is computed on each branch of the phylogeny (Figure 1): (A) Chimpanzee branch; (B) Hominini branch; (C) Denisovan branch; (D) Modern human branch. Profiles show the mean GC* computed on 32,987 human historical hotspots, over a 20 kb region centered on the middle of hotspots. Each dot is the average GC* over a 10 bp window. The line shows average GC* over 500 bp window.

Mentions: A first approach to detect past recombination activity consists in analyzing substitution patterns, so as to infer the equilibrium GC-content (denoted GC*) along different branches of the phylogeny (see methods). Many lines of evidence indicate that in primates, recombination is driving the evolution of GC-content via the process of GC-biased gene conversion (gBGC), which results from a bias in the repair of AT:GC mismatches in heteroduplex DNA during meiotic recombination [36], [37]. Notably, it has been shown that GC* strongly correlates with present or past recombination rates [38]–[40]. We therefore measured GC* separately for each branch of the phylogeny at loci corresponding to the 32,981 human historical recombination hotspots [2]. As expected, we observed a strong peak of GC* centered on the middle of historical recombination hotspots, in the modern human branch (Figure 6D). In agreement with previous results [19], this peak is absent in the chimpanzee branch (Figure 6A), consistent with the fact that human and chimpanzee recombination hotspots do not overlap. Interestingly, we observed only a very limited bump of GC* in the Hominini branch (Figure 6B). This indicates that, up to a recent time, shortly before the Denisovan/modern human split, loci corresponding to human historical recombination hotspots were not subject to gBGC.


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)

Equilibrium GC-content (GC*) around human recombination hotspots in different branches of the phylogeny.GC* is computed on each branch of the phylogeny (Figure 1): (A) Chimpanzee branch; (B) Hominini branch; (C) Denisovan branch; (D) Modern human branch. Profiles show the mean GC* computed on 32,987 human historical hotspots, over a 20 kb region centered on the middle of hotspots. Each dot is the average GC* over a 10 bp window. The line shows average GC* over 500 bp window.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004790-g006: Equilibrium GC-content (GC*) around human recombination hotspots in different branches of the phylogeny.GC* is computed on each branch of the phylogeny (Figure 1): (A) Chimpanzee branch; (B) Hominini branch; (C) Denisovan branch; (D) Modern human branch. Profiles show the mean GC* computed on 32,987 human historical hotspots, over a 20 kb region centered on the middle of hotspots. Each dot is the average GC* over a 10 bp window. The line shows average GC* over 500 bp window.
Mentions: A first approach to detect past recombination activity consists in analyzing substitution patterns, so as to infer the equilibrium GC-content (denoted GC*) along different branches of the phylogeny (see methods). Many lines of evidence indicate that in primates, recombination is driving the evolution of GC-content via the process of GC-biased gene conversion (gBGC), which results from a bias in the repair of AT:GC mismatches in heteroduplex DNA during meiotic recombination [36], [37]. Notably, it has been shown that GC* strongly correlates with present or past recombination rates [38]–[40]. We therefore measured GC* separately for each branch of the phylogeny at loci corresponding to the 32,981 human historical recombination hotspots [2]. As expected, we observed a strong peak of GC* centered on the middle of historical recombination hotspots, in the modern human branch (Figure 6D). In agreement with previous results [19], this peak is absent in the chimpanzee branch (Figure 6A), consistent with the fact that human and chimpanzee recombination hotspots do not overlap. Interestingly, we observed only a very limited bump of GC* in the Hominini branch (Figure 6B). This indicates that, up to a recent time, shortly before the Denisovan/modern human split, loci corresponding to human historical recombination hotspots were not subject to gBGC.

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