Fertility Costs of Meiotic Drivers

Zanders, Sarah E; Unckless, Robert L.

doi:10.1016/j.cub.2019.03.046

Cited by 86 publications

(62 citation statements)

References 125 publications

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“…Further, SPG6 includes type spermatogonial cells transitioning to preleptotene spermatocytes based on the expression of conserved meiotic genes, such as PRDM9, ZCWPW1, and REC8. In addition to the known, classic meiotic genes, our dataset uncovers many primate-specific genes (i.e., lacking mouse orthologs) that are active in human and macaque SPG6, including the simianspecific Variably Charged (VC) gene family (VCX, VCX2, VCX3A, VCX3B) 94 , which is an X chromosome multi-copy gene family theorized to play a role in meiotic drive 94,95 . Recent studies have shown that VCX may be regulated by PRDM9 96 , further underscoring its potential role in meiosis.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis

Shami

Zheng

Munyoki

et al. 2020

Preprint

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Spermatogenesis is a highly regulated process that produces sperm to transmit genetic information to the next generation. Although extensively studied in mice, our current understanding of primate spermatogenesis is limited to populations defined by state-specific markers defined from rodent data. As between-species differences have been reported in the process duration and cellular differentiation hierarchy, it remains unclear how molecular markers and cell states are conserved or have diverged from mice to man. To address this challenge, we employ single-cell RNA-sequencing to identify transcriptional signatures of major germ and somatic cell-types of the testes in human, macaque and mice. This approach reveals differences in expression throughout spermatogenesis, including the stem/progenitor pool of spermatogonia, classical markers of differentiation, potential regulators of meiosis, the kinetics of RNA turnover during spermatid differentiation, and germ cell-soma communication. These datasets provide a rich foundation for future targeted mechanistic studies of primate germ cell development and in vitro gametogenesis. potential communications with the germline. Overall, this study provides the first single-cell comparative analysis of the spermatogenesis program between primates and rodents. Such a new resource is expected to improve our knowledge base for future studies of germ cell development in primates, and ultimately improve our understanding of the intrinsic and extrinsic evolutionary changes of the gametogenesis program. Knowledge gained from these data will inform fertility restoration efforts, including SSC culture and in vitro gametogenesis. ResultsSingle-cell sequencing identifies major germ and somatic cell types of adult human and macaque testes. Using the Drop-seq platform, we generated single cell transcriptome data from ~14K and ~22K adult human and rhesus macaque testes, respectively. Using these datasets, our overall strategy was to first identify major cell types and states in the adult human and rhesus macaque testes separately, then combine them, along with our previous reported mouse data 12 , to define evolutionarily conserved or diverged programs within germ cells and the somatic cells of the testis (Figure 1A). The doublet rates for the human and macaque datasets is estimated to be <2%, therefore, allowing reliable analysis of individual cells (Figure S1A). After QC filtering (see Methods), 13,837 and 21,574 cells were retained from human and macaque, respectively, with an average of 3,210 unique molecular identifiers (UMIs) per cell, and 1,304 genes detected per cell. This sequencing depth and the number of detected genes was sufficient to define major cell types 13,14 . Systematic comparisons of technical batches (such as Human 1.1-1.5, Figure S1B-C) and biological replicates (4 humans and 5 macaques, Figure S1D-E) confirmed high batch-to-batch or individual-to-individual concordance, despite the variable proportions of cell types in different samples, likely due to differences i...

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis

Shami

Zheng

Munyoki

et al. 2020

Preprint

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“…However, many eukaryotic genomes contain 'selfish' elements that bias their own transmission such that they are overrepresented in the viable gametes [2][3][4]. These loci are known as meiotic drivers and they can both directly and indirectly reduce fitness through a number of mechanisms (reviewed in [5,6]).…”

Section: Introductionmentioning

confidence: 99%

Dramatically diverse Schizosaccharomyces pombe wtf meiotic drivers all display high gamete-killing efficiency

et al. 2020

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Meiotic drivers are selfish alleles that can force their transmission into more than 50% of the viable gametes made by heterozygotes. Meiotic drivers are known to cause infertility in a diverse range of eukaryotes and are predicted to affect the evolution of genome structure and meiosis. The wtf gene family of Schizosaccharomyces pombe includes both meiotic drivers and drive suppressors and thus offers a tractable model organism to study drive systems. Currently, only a handful of wtf genes have been functionally characterized and those genes only partially reflect the diversity of the wtf gene family. In this work, we functionally test 22 additional wtf genes for meiotic drive phenotypes. We identify eight new drivers that share between 30-90% amino acid identity with previously characterized drivers. Despite the vast divergence between these genes, they generally drive into >85% of gametes when heterozygous. We also identify three wtf genes that suppress other wtf drivers, including two that also act as autonomous drivers. Additionally, we find that wtf genes do not underlie a weak (64% allele transmission) meiotic driver on chromosome 1. Finally, we find that some Wtf proteins have expression or localization patterns that are distinct from the poison and antidote proteins encoded by drivers and suppressors, suggesting some wtf genes may have non-meiotic drive functions. Overall, this work expands our understanding of the wtf gene family and the burden selfish driver genes impose on S. pombe.

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“…However, many eukaryotic genomes contain ‘selfish’ elements that bias their own transmission into the viable gametes generated by a heterozygote (2–4). These loci are known as meiotic drivers and they can directly and indirectly reduce fitness through a number of mechanisms (reviewed in (5, 6)).…”

Section: Introductionmentioning

confidence: 99%

Dramatically diverseS. pombe wtfmeiotic drivers all display high gamete-killing efficiency

Núñez

Sabbarini

Eickbush

et al. 2019

Preprint

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Meiotic drivers are selfish genetic loci that force their transmission into more than 50% of the viable gametes made by heterozygotes. Meiotic drivers are known to cause infertility in a diverse range of eukaryotes and are predicted to affect the evolution of genome structure and meiosis. The wtf gene family of Schizosaccharomyces pombe includes both meiotic drivers and drive suppressors and thus offers a tractable model organism to study drive systems. Currently, only a handful of wtf genes have been functionally characterized and those genes only partially reflect the diversity of the wtf gene family. In this work, we functionally test 22 additional wtf genes. We identify eight new drivers that share between 30-90% amino acid identity with previously characterized drivers. Despite the vast divergence between these genes, they generally drive into >85% gametes when heterozygous. We also find three new wtf genes that suppress drive, including two that also act as autonomous drivers. Additionally, we find that wtf genes do not underlie a weak (64%) transmission bias caused by a locus or loci on chromosome 1. Finally, we find that some Wtf proteins have expression or localization patterns that are distinct from the poison and antidote proteins encoded by drivers and suppressors, suggesting some wtf genes may have non-meiotic drive functions. Overall, this work expands our understanding of the wtf gene family and the burden selfish driver genes impose on S. pombe.Article SummaryDuring gametogenesis, the two gene copies at a given locus, known as alleles, are each transmitted to 50% of the gametes (e.g. sperm). However, some alleles cheat so that they are found in more than the expected 50% of gametes, often at the expense of fertility. This selfish behavior is known as meiotic drive. Some members of the wtf gene family in the fission yeast, Schizosaccharomyces pombe, kill the gametes (spores) that do not inherit them, resulting in meiotic drive favoring the wtf allele. Other wtf genes act as suppressors of drive. However, the wtf gene family is diverse and only a small subset of the genes has been characterized. Here we analyze the functions of other members of this gene family and found eight new drivers as well as three new suppressors of drive. Surprisingly, we find that drive is relatively insensitive to changes in wtf gene sequence as highly diverged wtf genes execute gamete killing with similar efficiency. Finally, we also find that the expression and localization of some Wtf proteins are distinct from those of known drivers and suppressors, suggesting that these proteins may have non-meiotic drive functions.

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Fertility Costs of Meiotic Drivers

Cited by 86 publications

References 125 publications

Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis

Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis

Dramatically diverse Schizosaccharomyces pombe wtf meiotic drivers all display high gamete-killing efficiency

Dramatically diverseS. pombe wtfmeiotic drivers all display high gamete-killing efficiency

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