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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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Related in: MedlinePlus

Recombination rates and strength of dBGC on HM motifs in the human genome.(A) Distribution of human historical recombination rates (cM/Mb), measured over a 2 kb window centered on HM motifs from human autosomes (hg19 assembly; no filter). Red: motifs located within historical recombination hotspots. Blue: motifs located outside hotspots. (B) Distribution of estimated population-scaled dBGC coefficient (G) on HM motifs located in recombination hotspots in the human genome. Median  = 57.5.
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pgen-1004790-g004: Recombination rates and strength of dBGC on HM motifs in the human genome.(A) Distribution of human historical recombination rates (cM/Mb), measured over a 2 kb window centered on HM motifs from human autosomes (hg19 assembly; no filter). Red: motifs located within historical recombination hotspots. Blue: motifs located outside hotspots. (B) Distribution of estimated population-scaled dBGC coefficient (G) on HM motifs located in recombination hotspots in the human genome. Median  = 57.5.

Mentions: The strength of dBGC at a given locus is proportional to the absolute difference in recombination rate between the original (hot) allele and the mutant (colder) allele [25]. This difference can be large only if the recombination rate at this locus is high. Hence HM motifs that are located at lowly recombining loci are not expected to undergo dBGC. It is important to note that the recombination rate at HM motifs is highly variable across the genome: 8% of HM motifs concentrate 60% of all crossover events located in the vicinity of HM motifs (±2 kb) (Figure 4A). It is therefore expected that the intensity of dBGC should be stronger for HM motifs located in a genomic context prone to recombination. To test that prediction, we re-estimated G from DAF spectra, in three subsets of equal sample size, binned according to the local historical recombination rate (measured on a 2 kb window centered on motif position). As expected, G increases with increasing historical recombination rates, from G = 0.96 in the first tercile to G = 14.64 in the third tercile (Table S4).


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)

Recombination rates and strength of dBGC on HM motifs in the human genome.(A) Distribution of human historical recombination rates (cM/Mb), measured over a 2 kb window centered on HM motifs from human autosomes (hg19 assembly; no filter). Red: motifs located within historical recombination hotspots. Blue: motifs located outside hotspots. (B) Distribution of estimated population-scaled dBGC coefficient (G) on HM motifs located in recombination hotspots in the human genome. Median  = 57.5.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004790-g004: Recombination rates and strength of dBGC on HM motifs in the human genome.(A) Distribution of human historical recombination rates (cM/Mb), measured over a 2 kb window centered on HM motifs from human autosomes (hg19 assembly; no filter). Red: motifs located within historical recombination hotspots. Blue: motifs located outside hotspots. (B) Distribution of estimated population-scaled dBGC coefficient (G) on HM motifs located in recombination hotspots in the human genome. Median  = 57.5.
Mentions: The strength of dBGC at a given locus is proportional to the absolute difference in recombination rate between the original (hot) allele and the mutant (colder) allele [25]. This difference can be large only if the recombination rate at this locus is high. Hence HM motifs that are located at lowly recombining loci are not expected to undergo dBGC. It is important to note that the recombination rate at HM motifs is highly variable across the genome: 8% of HM motifs concentrate 60% of all crossover events located in the vicinity of HM motifs (±2 kb) (Figure 4A). It is therefore expected that the intensity of dBGC should be stronger for HM motifs located in a genomic context prone to recombination. To test that prediction, we re-estimated G from DAF spectra, in three subsets of equal sample size, binned according to the local historical recombination rate (measured on a 2 kb window centered on motif position). As expected, G increases with increasing historical recombination rates, from G = 0.96 in the first tercile to G = 14.64 in the third tercile (Table S4).

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