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Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots

Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9...

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Autores principales: Baker, Christopher L., Petkova, Pavlina, Walker, Michael, Flachs, Petr, Mihola, Ondrej, Trachtulec, Zdenek, Petkov, Petko M., Paigen, Kenneth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569383/
https://www.ncbi.nlm.nih.gov/pubmed/26368021
http://dx.doi.org/10.1371/journal.pgen.1005512
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author Baker, Christopher L.
Petkova, Pavlina
Walker, Michael
Flachs, Petr
Mihola, Ondrej
Trachtulec, Zdenek
Petkov, Petko M.
Paigen, Kenneth
author_facet Baker, Christopher L.
Petkova, Pavlina
Walker, Michael
Flachs, Petr
Mihola, Ondrej
Trachtulec, Zdenek
Petkov, Petko M.
Paigen, Kenneth
author_sort Baker, Christopher L.
collection PubMed
description Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9 (+/-) heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape.
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spelling pubmed-45693832015-09-18 Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots Baker, Christopher L. Petkova, Pavlina Walker, Michael Flachs, Petr Mihola, Ondrej Trachtulec, Zdenek Petkov, Petko M. Paigen, Kenneth PLoS Genet Research Article Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9 (+/-) heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape. Public Library of Science 2015-09-14 /pmc/articles/PMC4569383/ /pubmed/26368021 http://dx.doi.org/10.1371/journal.pgen.1005512 Text en © 2015 Baker et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Baker, Christopher L.
Petkova, Pavlina
Walker, Michael
Flachs, Petr
Mihola, Ondrej
Trachtulec, Zdenek
Petkov, Petko M.
Paigen, Kenneth
Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots
title Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots
title_full Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots
title_fullStr Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots
title_full_unstemmed Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots
title_short Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots
title_sort multimer formation explains allelic suppression of prdm9 recombination hotspots
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569383/
https://www.ncbi.nlm.nih.gov/pubmed/26368021
http://dx.doi.org/10.1371/journal.pgen.1005512
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