Limits...
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.

Show MeSH

Related in: MedlinePlus

Historical human recombination profiles around lost and conserved HM motifs.Human historical recombination rates (cM/Mb) around HM motifs found in the human-Chimpanzee reconstructed ancestral sequence (F2 subset) and conserved in the human genome (black) or lost in the Hominini (blue) or human (green) branch. The 95% confidence interval of the mean recombination rates is shown by areas colored accordingly. Recombination rates are averaged on 2 kb overlapping windows (overlap  = 1 kb).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4230742&req=5

pgen-1004790-g005: Historical human recombination profiles around lost and conserved HM motifs.Human historical recombination rates (cM/Mb) around HM motifs found in the human-Chimpanzee reconstructed ancestral sequence (F2 subset) and conserved in the human genome (black) or lost in the Hominini (blue) or human (green) branch. The 95% confidence interval of the mean recombination rates is shown by areas colored accordingly. Recombination rates are averaged on 2 kb overlapping windows (overlap  = 1 kb).

Mentions: The dBGC model predicts that the small subset of HM motifs located in a highly recombining context should accumulate substitutions extremely rapidly. In agreement with that prediction, we observed that, along the modern human branch, the loss rate is almost 3 times higher for HM motifs located within historical hotspots compared to other HM motifs (3.5% vs. 1.2%; p = 4.6×10−7). Overall, 55% of the HM motifs detected as being mutated along the modern human branch are located within historical recombination hotspots (compared to 28% for motifs that have remained intact) (Table 2). Thus, on average, the historical recombination rate at HM motifs mutated in the modern human branch is more than two times higher than that at intact HM motifs (11.2 cM/Mb vs. 4.9 cM/Mb; Figure 5). Notably, we observed the same pattern with present-day recombination rates, inferred from pedigree-based genetic maps [35] (Figure S3). Moreover this pattern is observed even for the subset of HM mutations that are fixed in human populations (Figure S4). These observations show that mutations of HM motifs that were fixed in modern humans are generally located in loci that still have a high recombination activity in present-day populations. Hence, although mutations of HM motifs diminish the local recombination rate, they generally do not directly convert a hotspot into a coldspot.


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)

Historical human recombination profiles around lost and conserved HM motifs.Human historical recombination rates (cM/Mb) around HM motifs found in the human-Chimpanzee reconstructed ancestral sequence (F2 subset) and conserved in the human genome (black) or lost in the Hominini (blue) or human (green) branch. The 95% confidence interval of the mean recombination rates is shown by areas colored accordingly. Recombination rates are averaged on 2 kb overlapping windows (overlap  = 1 kb).
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004790-g005: Historical human recombination profiles around lost and conserved HM motifs.Human historical recombination rates (cM/Mb) around HM motifs found in the human-Chimpanzee reconstructed ancestral sequence (F2 subset) and conserved in the human genome (black) or lost in the Hominini (blue) or human (green) branch. The 95% confidence interval of the mean recombination rates is shown by areas colored accordingly. Recombination rates are averaged on 2 kb overlapping windows (overlap  = 1 kb).
Mentions: The dBGC model predicts that the small subset of HM motifs located in a highly recombining context should accumulate substitutions extremely rapidly. In agreement with that prediction, we observed that, along the modern human branch, the loss rate is almost 3 times higher for HM motifs located within historical hotspots compared to other HM motifs (3.5% vs. 1.2%; p = 4.6×10−7). Overall, 55% of the HM motifs detected as being mutated along the modern human branch are located within historical recombination hotspots (compared to 28% for motifs that have remained intact) (Table 2). Thus, on average, the historical recombination rate at HM motifs mutated in the modern human branch is more than two times higher than that at intact HM motifs (11.2 cM/Mb vs. 4.9 cM/Mb; Figure 5). Notably, we observed the same pattern with present-day recombination rates, inferred from pedigree-based genetic maps [35] (Figure S3). Moreover this pattern is observed even for the subset of HM mutations that are fixed in human populations (Figure S4). These observations show that mutations of HM motifs that were fixed in modern humans are generally located in loci that still have a high recombination activity in present-day populations. Hence, although mutations of HM motifs diminish the local recombination rate, they generally do not directly convert a hotspot into a coldspot.

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