Key Points
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Meiosis is a defining event of mammalian gametogenesis, and errors of meiosis lead to infertility or aneuploidy.
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Recombination, chromosome pairing and segregation are key events of meiosis that are coupled to each other.
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Recombination is initiated by induction of genetically programmed double-strand breaks. These breaks are concentrated at 'hot spots' that are are genetically and epigenetically determined, and influence haplotype structure.
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Meiotic recombination occurs between chromatids on homologous chromosomes and results in crossovers (at least one per chromosome) and non-crossover exchanges. Recombination between sister chromatids is suppressed.
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The synaptonemal complex and sister-chromatid cohesion are essential for maintaining chromosome pairing and promoting recombination.
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Rigorous assessment of meiotic events is crucial for the successful application of assisted reproductive technologies and efforts directed to in vitro derivation of gametes.
Abstract
Meiosis is an essential stage in gamete formation in all sexually reproducing organisms. Studies of mutations in model organisms and of human haplotype patterns are leading to a clearer understanding of how meiosis has adapted from yeast to humans, the genes that control the dynamics of chromosomes during meiosis, and how meiosis is tied to gametic success. Genetic disruptions and meiotic errors have important roles in infertility and the aetiology of developmental defects, especially aneuploidy. An understanding of the regulation of meiosis, coupled with advances in genomics, may ultimately allow us to diagnose the causes of meiosis-based infertilities, more wisely apply assisted reproductive technologies, and derive functional germ cells.
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Acknowledgements
The authors thank P. Cohen, J. Eppig, K. Paigen and L. Reinholdt for comments on the manuscript. We apologize to authors whose papers could not be cited owing to space limitations.
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DATABASES
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FURTHER INFORMATION
Glossary
- Disjunction
-
The separation of chromosomes or chromatids during anaphase of mitosis or meiosis. The failure of chromosomes to separate at anaphase is called non-disjunction.
- Aneuploidy
-
The presence of an abnormal number of chromosomes, either more or less than the diploid number. It is associated with cell and organismal inviability, birth defects and cancer.
- Chromatid
-
An identical copy of a chromosome that is created through DNA replication. The two sister chromatids of a chromosome each become a chromosome when their centromeres are separated in mitosis or in the second meiotic division.
- Synapsis
-
The intimate apposition that occurs after pairing of homologous chromosomes along their length during prophase I of meiosis; synapsis is mediated by a proteinaceous structure, the synaptonemal complex.
- Double-strand break
-
A serious form of DNA damage that is created enzymatically during meiosis and that stimulates repair by crossover or non-crossover recombination.
- Induced pluripotent stem cells
-
These are derived from somatic cells by 'reprogramming' or de-differentiation triggered by the transfection of pluripotency genes, which alters the somatic cells to a state that is similar to that of embryonic stem cells.
- Cohesins
-
Multi-protein complexes that maintain tight association (cohesion) of sister chromatids.
- Resection
-
In the context of recombination, strand-biased enzymatic removal of nucleotides at the site of a double-strand break. In most recombination models, resection occurs in the 5′ to 3′ direction.
- Gene conversion
-
Originally coined to describe non-Mendelian segregation of alleles obtained from a single meiosis, this typically (but not always) refers to a non-reciprocal form of non-crossover recombination that results in the alteration of the sequence of a gene (or DNA sequence) to that of its homologue. In ectopic gene conversion, the donor and recipient DNA strands are not allelic copies of the same locus.
- Checkpoint
-
A mechanism that monitors the fidelity of cellular events and triggers cell cycle arrest and possibly apoptosis when errors are not corrected. In meiosis, unrepaired DNA damage and synapsis failure trigger checkpoints that can halt meiotic progression.
- Piwi-interacting RNAs
-
Small germ-cell RNAs that interact with PIWI proteins. They are thought to be involved in the repression of retrotransposon expression during gametogenesis.
- Interference
-
A phenomenon in which the occurrence of a crossover recombination at one position on a chromosome suppresses the frequency of additional, nearby crossovers; inhibition decreases with physical distance.
- Bivalent
-
Two paired or synapsed homologous chromosomes, each formed of two sister chromatids.
- Dictyate
-
A 'resting' stage at the end of the first meiotic prophase. It is at the end of diplonema but before the resumption of meiosis and the onset of progress to metaphase of the first meiotic division.
- Anastral spindle
-
A spindle formed without centrosomes (microtubule- organizing centres) or the astral microtubules that usually surround the centrioles at spindle poles.
- Univalent
-
An unpaired chromosome at metaphase I: usually one that has failed to synapse or recombine with its homologue.
- Acrocentric chromosome
-
A chromosome with a centromere near to one end so that one arm is very short.
- Isodicentric chromosome
-
A cytogenetically anomalous chromosome characterized by the presence of two centromeres, with additional, identical copies of DNA segments joined end to end.
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Handel, M., Schimenti, J. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11, 124–136 (2010). https://doi.org/10.1038/nrg2723
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DOI: https://doi.org/10.1038/nrg2723
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BMC Genomics (2024)
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A loss-of-function variant in ZCWPW1 causes human male infertility with sperm head defect and high DNA fragmentation
Reproductive Health (2024)
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The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis
Nature Communications (2023)
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The proper interplay between the expression of Spo11 splice isoforms and the structure of the pseudoautosomal region promotes XY chromosomes recombination
Cellular and Molecular Life Sciences (2023)
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A Novel Frameshift Microdeletion of the TEX12 Gene Caused Infertility in Two Brothers with Nonobstructive Azoospermia
Reproductive Sciences (2023)