Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates

Baker, Zachary; Schumer, Molly; Haba, Yuki; Bashkirova, Lisa; Holland, C. D.; Rosenthal, Gil G.; Przeworski, Molly

doi:10.7554/elife.24133

Cited by 136 publications

(266 citation statements)

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“…Because of incomplete available DNA and protein sequences, we are almost certain to miss some species where ZCWPW1 is present, and similarly it is challenging to identify PRDM9 orthologues (Baker et al, 2017). Despite this, we see extremely high overlap between PRDM9 and ZCWPW1 occurrence.…”

Section: Zcwpw1 Co-evolves With Prdm9mentioning

confidence: 94%

“…Based on publicly available databases, we identified likely ZCWPW1 orthologues in 167 species in total, aligned each to the human reference ZCWPW1 protein, and compared against a previous analysis of PRDM9 (Baker et al, 2017). The alignment reveals the regions containing the CW and PWWP domains to be the most conserved among species (Figure 1), while other parts of the protein appear to have been lost in some species.…”

Section: Zcwpw1 Co-evolves With Prdm9mentioning

confidence: 99%

“…In humans, mice, and likely many other vertebrates (Baker et al, 2017), the locations at which recombination occurs is determined by the binding locations of PRDM9, which recognises a specific sequence motif encoded by its zinc finger array (Baudat et al, 2010;Myers et al, 2010;Parvanov et al, 2010). At these sites, Spo11 catalyzes recombination-initiating double strand breaks (DSBs), a subset of which are repaired by recombination with the homologous chromosome.…”

Section: Introductionmentioning

confidence: 99%

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ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

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During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility. Graphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

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Section: Zcwpw1 Co-evolves With Prdm9mentioning

confidence: 94%

Section: Zcwpw1 Co-evolves With Prdm9mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

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“…CGIs, suggesting that the ancestor of these species and other mammalian species has acquired the PRDM9-dependent regulation of recombination while maintaining the ancestral mechanism of localizing recombination nearby genes and CGIs (Auton et al, 2012). However, a recent study implicated a possible involvement of PRDM9 in recombination in more basal vertebrate lineages (Baker et al, 2017), which warrants further in-depth analysis of the evolutionary origin of the PRDM9-dependent recombination.…”

Section: Cgi As a Molecular Hallmark Of Recombination Hotspotsmentioning

confidence: 99%

Whole‐genome patterns of linkage disequilibrium across flycatcher populations clarify the causes and consequences of fine‐scale recombination rate variation in birds

et al. 2017

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Recombination rate is heterogeneous across the genome of various species and so are genetic diversity and differentiation as a consequence of linked selection. However, we still lack a clear picture of the underlying mechanisms for regulating recombination.Here we estimated fine-scale population recombination rate based on the patterns of linkage disequilibrium across the genomes of multiple populations of two closely related flycatcher species (Ficedula albicollis and F. hypoleuca). This revealed an overall conservation of the recombination landscape between these species at the scale of 200 kb, but we also identified differences in the local rate of recombination despite their recent divergence (<1 million years). Genetic diversity and differentiation were associated with recombination rate in a lineage-specific manner, indicating differences in the extent of linked selection between species. We detected 400-3,085 recombination hotspots per population. Location of hotspots was conserved between species, but the intensity of hotspot activity varied between species. Recombination hotspots were primarily associated with CpG islands (CGIs), regardless of whether CGIs were at promoter regions or away from genes. Recombination hotspots were also associated with specific transposable elements (TEs), but this association appears indirect due to shared preferences of the transposition machinery and the recombination machinery for accessible open chromatin regions. Our results suggest that CGIs are a major determinant of the localization of recombination hotspots, and we propose that both the distribution of TEs and fine-scale variation in recombination rate may be associated with the evolution of the epigenetic landscape.

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“…Now, in eLife, Molly Przeworski of Columbia University and colleagues – including Zachary Baker and Molly Schumer as joint first authors – report the results of a series of experiments that shed light on some of these questions (Baker et al, 2017). …”

mentioning

confidence: 99%

Birth and death of a protein

Clément

Massy

2017

eLife

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Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates

Cited by 136 publications

References 112 publications

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Whole‐genome patterns of linkage disequilibrium across flycatcher populations clarify the causes and consequences of fine‐scale recombination rate variation in birds

Birth and death of a protein

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