For example, local nucleosome occupancy can be altered with chromatin remodelers. Although the potential to target recombination toward genes in crops is significant as it can reduce the cost and time to produce novel plant varieties, several challenges exist and the application of these techniques to plant meiosis remains to be demonstrated.
Arabidopsis thaliana is found in many different natural habitats showing extensive intraspecific variation in measurable traits that differ quantitatively between accessions Weigel, ; The Genomes Consortium, The genomes of a total of 1, natural inbred A. Intraspecific variation in meiotic recombination frequency was found in various plants Lawrence et al.
For instance, F1 Arabidopsis hybrids from 32 diverse accessions revealed extensive variation in CO rate Ziolkowski et al. Several confounding factors could account for these CO changes. For example, each ecotype has distinct genetic information and the degree of polymorphism represses CO rate Lawrence et al. F1 hybrid plants arising from parents with potentially distinct epigenomes could also influence recombination locally Cortijo et al.
In addition, trans-acting factors exerted by polymorphic loci can modulate recombination. The first plant quantitative trait loci for recombination was recently identified as HEI10 and over-expression of HEI10 in Arabidopsis causes a greater than twofold increase in CO formation genome-wide Ziolkowski et al. Additional trans-acting factors probably exist.
For example, MSH2 presents gene copy number variations among Arabidopsis accessions and represses recombination between divergent genomes Emmanuel et al.
Genetic and genotypic A—B interactions seem to impact chiasma number and distribution Ortiz et al. B chromosomes in rye are transcriptionally active containing several B-enriched transcriptionally active tandem repeats Martis et al. More than B-encoded anther transcripts show similarity to proteins with functional annotation. By standard crossing schemes they could be easily introduced and removed without recombining with As.
Although HR is conserved across species Mercier et al. In Arabidopsis figl1 shows an increase in meiotic recombination without affecting fertility Girard et al. Meiotic studies in non-model plant species also revealed differences e. This long male diplotene stage is characterized by microsporocyte growth, synthesis and accumulation of mRNAs and proteins, and changes in chromatin conformation, i.
Further studies in the European larch or other gymnosperms may reveal additional insights into chromatin dynamics and transcription during meiosis and differences in induction and progression of male vs. In numerous plant species, primarily during male prophase I, cytomixis occurs, i. How cytomixis is regulated or interconnected to meiotic progression is unclear. In translocation heterozygote plants CO formation is restricted to distinct chromosome regions commonly leading to long chromosome chains Stack and Soulliere, ; Rauwolf et al.
In Oenothera meiosis, for instance, a spatiotemporal genome compartmentation occurs, i. How this tightly restricted CO localization is achieved or how balanced chromosome segregation occurs is unclear. Moreover, in closely related species such as Allium differences in recombination patterns are found, i. Thus, although general mechanisms of meiosis and HR are conserved, studies in different species, including non-model species, may widen our knowledge of plant meiosis revealing differences and similarities and possibly enabling a deeper understanding of underlying mechanisms.
In recent years studies, mainly in Arabidopsis but also in selected crops and non-model species, have increased our understanding of plant meiotic progression and recombination and many genes and factors involved in these processes were identified. However, much remains to be learned, even though our current knowledge may provide a basic foundation to explore whether meiotic recombination in crops can be manipulated to improve and accelerate plant breeding programs.
Differences in plant genome organization particularly repetitive DNA content and ploidy level accompanied by differences in chromatin and epigenetic features likely account for differences in meiotic progression and recombination patterns. Thus, available and new approaches are needed to investigate the underlying mechanisms and factors responsible for differences and similarities in meiotic progression and recombination between model, crop and non-model plants to ultimately translate our knowledge into crop breeding programs.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AH declared a shared affiliation, though no other collaboration, with one of the authors SH to the handling Editor.
Ahuja, J. Control of meiotic pairing and recombination by chromosomally tethered 26S proteasome. Science , — Albini, S. A karyotype of the Arabidopsis thaliana genome derived from synaptonemal complex analysis at prophase I of meiosis. Plant J. Synaptonemal complex spreading in Allium cepa and A. Chromosoma 95, — Anderson, L. Combined fluorescent and electron microscopic imaging unveils the specific properties of two classes of meiotic crossovers.
Armstrong, S. Asy1, a protein required for meiotic chromosome synapsis, localizes to axis-associated chromatin in Arabidopsis and Brassica. Cell Sci. Banaei-Moghaddam, A. Formation and expression of pseudogenes on the b chromosome of rye.
Plant Cell 25, — Barakate, A. The synaptonemal complex protein ZYP1 is required for imposition of meiotic crossovers in barley. Plant Cell 26, — Bennypaul, H. Virus-induced gene silencing VIGS of genes expressed in root, leaf, and meiotic tissues of wheat. Genomics 12, — Berchowitz, L. Fluorescent Arabidopsis tetrads: a visual assay for quickly developing large crossover and crossover interference data sets. PLoS Genet. Bhullar, R. Silencing of a metaphase I-specific gene results in a phenotype similar to that of the Pairing homeologous 1 Ph1 gene mutations.
Bishop, D. DMC1: a meiosis-specific yeast homolog of E. Cell 69, — Brar, G. Rec8 phosphorylation and recombination promote the step-wise loss of cohesins in meiosis. Nature , — Braynen, J. Transcriptome analysis of floral buds deciphered an irregular course of meiosis in polyploid Brassica rapa. Plant Sci. Cabral, G. Chiasmatic and achiasmatic inverted meiosis of plants with holocentric chromosomes. Nat Commun Cai, X. The Arabidopsis SYN1 cohesin protein is required for sister chromatid arm cohesion and homologous chromosome pairing.
Cao, J. Whole-genome sequencing of multiple Arabidopsis thaliana populations. Carballo, J. Cell , — Carchilan, M.
Transcriptionally active heterochromatin in rye B chromosomes. Plant Cell 19, — Cavallari, N. Chaturvedi, P. Cell-specific analysis of the tomato pollen proteome from pollen mother cell to mature pollen provides evidence for developmental priming.
Proteome Res. Chelysheva, L. Chen, C. BMC Plant Biol. Cho, W. Choi, K. Meiotic recombination hotspots — a comparative view. Recombination rate heterogeneity within Arabidopsis disease resistance genes. Arabidopsis meiotic crossover hot spots overlap with H2A.
Z nucleosomes at gene promoters. Genome Res. Choulet, F. Structural and functional partitioning of bread wheat chromosome 3B. Science Colas, I. Collado-Romero, M. Unravelling the proteomic profile of rice meiocytes during early meiosis. Cortijo, S. Mapping the epigenetic basis of complex traits. Cuacos, M.
Atypical centromeres in plants—what they can tell us. De Muyt, A. E3 ligase Hei a multifaceted structure-based signaling molecule with roles within and beyond meiosis. Genes Dev. Deal, R. Demirci, S. Distribution, position and genomic characteristics of crossovers in tomato recombinant inbred lines derived from an interspecific cross between Solanum lycopersicum and Solanum pimpinellifolium.
Dreissig, S. Measuring meiotic crossovers via multi-locus genotyping of single pollen grains in barley. PLoS One e Sequencing of single pollen nuclei reveals meiotic recombination events at megabase resolution and circumvents segregation distortion caused by postmeiotic processes.
Dubin, M. DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation. Dukowic-Schulze, S. The meiotic transcriptome architecture of plants. The transcriptome landscape of early maize meiosis. Duncan, S. A method for detecting single mRNA molecules in Arabidopsis thaliana.
Plant Methods Emmanuel, E. EMBO Rep. Fauser, F. In planta gene targeting. Ferdous, M. In this section, we focus on our emerging understanding of the role of chromosomes in the dance, and how their structure and dynamic behavior contribute to the successful completion of meiosis.
Gratifyingly, since this review celebrates 50 years of the SSR, SSR members have played and continue to play pivotal roles in the unfolding of knowledge about meiotic chromosomes and their fate. Although its initial discovery predates by a decade the founding of the SSR, arguably the discovery of the SC between homologous chromosomes in spermatocytes by Monte Moses [ 24 , 25 ] launched our current understanding of meiotic mechanisms.
As we know now, the SC is an intricate proteinaceous structure that facilitates both recombination and intimate pairing or synapsis between homologous chromosomes. The original elegant descriptions of the SC by Moses which were quite amazing given the primitive state of electron microscopy in the mids! The rest, as they say, is history, because this method, originally for meiotic karyotyping using silver-stained preparations, gave way to preparations for immunofluorescence Figure 3 that have greatly expanded our knowledge of molecular mechanisms of meiosis Figure 2 , and reviewed in detail below and allowed us to measure recombination rates at a cytological level [ 27 ].
While electron microscopy provided initial insight into the structure of the SC Figure 3 , the real breakthroughs came with the arrival of three enabling technologies: antibodies, high-resolution light microscopy, and targeted mutagenesis. The growing toolbox of meiotic markers and mouse mutants has provided many insights into the mechanisms of chromosome synapsis and its link to recombination [ 2 , 3 , 28—31 ]. We came to recognize that the SC—initially observed as thick lines by silver staining—is composed of many proteins, intricately connected and with spatial and temporal patterns reflecting their functional specializations Figure 2.
After discovery of the first mammalian SC proteins SYCP1—3 , many other components of the meiotic machinery were identified by reverse genetics, forward genetic screens, yeast-two-hybrid screens, proteomics, and gene expression analyses [ 2 ]. Antibodies against various components of the SC combined with electron and fluorescence microscopy Figure 3 played a major role in elucidating the 3D structure of the SC [ 32—34 ]. During early meiotic prophase I, AEs form simultaneously with the cohesin cores, together establishing the axis required to support meiotic recombination [ 36—38 ].
The cohesin complexes are presumed to help associate the sister chromatids of each homolog and may also play a role in association of nonsister chromatids in homology pairing. During assembly of the AEs, the chromosome shortens, implicating another set of SMC protein complexes, the condensins, whose role in meiosis is not yet clear [ 39—41 ]. Following assembly of the AEs, an interdependent network of protein interactions leads to formation of the CE that brings about synapsis, the completion of which defines the onset of pachynema Figure 2.
Visible as a dense structure by electron microscopy Figure 3 , the CE is comprised of at least five proteins, as well as overlapping transverse elements, all identified during the last decade [ 29 , 42 ]. The ability of liquid crystals to self-assemble, undergo rapid phase transitions, and transduce signals could explain both structure and function of the SC. We eagerly await future studies exploring and testing this exciting idea. This exploration of the role of the SC highlights one of the central questions in meiosis, namely how homologous chromosome interactions are coordinated with molecular events of recombination.
Mouse mutants have revealed that DSBs are not intrinsically required for assembly of SCs; however, they are essential for ensuring that SCs form between homologous chromosomes [ 50 , 51 ].
In turn, pairing and synapsis between homologous chromosomes are required for DSB repair. Although it is tempting to imagine DNA tentacles scanning the genome for homology, this would be grossly inefficient.
Instead DSBs must be aided by specific features of meiotic chromosomes that bring homologs together and enhance local DNA interactions. Initially, a significant DSB-independent pairing of homologs is established during the pre-meiotic interphase and maintained early in meiotic prophase [ 52 ].
Together these features bring homologous DNA sequences to close proximity starting at telomeric ends, thus in theory reducing the perimeter of physical distance necessary to scan for homology. Therefore, it is not surprising that recombination is often high near telomeres and SC assembly is first observed at telomeric ends of chromosomes, although there are notable exceptions to this generality, including the human female [ 56 ].
Interstitial synapsis initiation sites driven by DSBs are thought to stabilize homolog pairing during the rapid chromosome movements driven by telomeres.
These dynamic chromosome movements in meiotic cells were first described just over 40 years ago, and since then they have been observed in many model organisms, including mammals [ 57—59 ].
Such movements have been shown to be mediated by SUN-KASH proteins connecting telomeres to the nuclear envelope and to microtubules in the cytoplasm [ 54 , 59—61 ]. Additional features of meiotic chromosomes may play a role in homolog pairing and recombination. Three different flavors of cohesin complexes are involved in chromatin organization in mammalian meiotic cells [ 66 , 67 ].
A barcode-like localization pattern has been observed for RAD21L- and REC8-containing complexes on chromosome axis, leading to the idea that axis patterning may facilitate chromosome pairing and subsequent synapsis [ 68 ].
As in a zipper, a common model for the SC, the corresponding cohesin blocks on homologous chromosomes would come together and promote early pairing of homologs, which would then be proofread by DNA homology-dependent mechanism. It has been also proposed that RAD21L-containing cohesin rings form around nonsister chromatids matched by DNA homology providing a platform for recruitment of central region protein SYCP1 and initiation of synapsis between homologs [ 69 ].
Although both ideas are attractive, they require further experimental evidence. The structure and function of the SC is conserved in sexually reproducing organisms [ 70 , 71 ], and influences the most critical outcome of meiotic prophase I—the exchange of DNA between maternal and paternal chromosomes or CO. Because COs occur only in the context of assembled CEs, the SC is thought to be a major factor in CO regulation, although how this regulation is exerted is only partially understood.
Crossovers are tightly controlled: most organisms have at least one obligatory CO per homolog pair CO assurance ; COs are nonrandomly positioned, so that adjacent COs are further apart than expected if they were randomly distributed CO interference ; and total CO numbers are maintained at a relatively constant level CO homeostasis.
Interestingly, class II COs are not constrained by interference and it remains unclear whether they are regulated by homeostatic mechanisms [ 16 , 72 ]. Mechanisms underlying CO assurance have been difficult to study, and involve processes of both SC assembly and recombination. Crossover interference was first described a century ago even before the discovery of the SC , observed as reduced probability of a CO in a region adjacent to an existing CO [ 76 , 77 ].
However, the mechanism underlying CO interference remains elusive and the role of the SC in CO interference has been disputed [ 74 , 78 , 79 ]. Multiple models have been proposed to explain CO interference reviewed in [ 72 , 80—83 ].
Because of the spatial distribution of COs along the physical length of meiotic chromosome axis it is thought that the CO patterning signal molecular, biochemical, or physical is propagated along the chromosomes. However, the best candidate for such a polymer, the SC, seems to be dispensable for CO interference at least in mice and yeast [ 85 , 86 ].
Alternatively, polymerization could reflect spreading of a biochemical signal such as phosphorylation, ubiquitination or sumoylation of histone, cohesin, or other axis-bound protein [ 87 , 88 ]. Additional models suggest that mechanical signals such as stress [ 74 , 78 , 89 ] or chromosome oscillatory movements transmit the interference signal [ 90 ]. The stress relief or beam-film model proposes that mechanical stress, linked to physical state of the chromosome, drives propagation of the CO-inhibitory signal which decreases with distance [ 89 , 91 ].
The chromosomal dance itself, observed as chromosome movements driven by telomeres [ 54 ], has been implicated in CO interference. This model proposes that chromosome oscillatory movements create waves along the length of chromosome pairs and COs form preferentially at the nodal regions of such waves where homologs are at the highest proximity [ 90 ].
In contrast, the counting model postulates that a fixed number of NCOs occurs between two CO sites [ 92—94 ]. Despite providing a good model for observed CO numbers and distribution, it seems unresolved exactly which structures or factors are being counted. Chromosome axes and recombination intermediates can be immunolabeled and observed as thick lines decorated by numerous foci like beads on a string [ 95 ].
To assess interference between COs and their precursors, distribution of measurements of axis length and foci numbers are analyzed using the Coefficient of Coincidence CoC or gamma distribution method [ 73 , 76 , 86 , 96 ]. Interestingly, interference between recombination intermediates is maintained in the absence of the CE, or even of the SC altogether, further confirming that recombination interference is established independent of the SC [ 73 , 75 , 97 ].
Moreover, it has been suggested that CO interference and assurance are both the products of the same mechanism, one that is independent of SC assembly, at least in the mouse [ 73 , 86 ].
Parallels have been observed between the mechanisms of interference and homeostasis in various model organisms, and these lead to the idea that both are the result of the same patterning process [ 14 , 78 ].
Although the exact role of SC in regulating COs may not yet be resolved, components of the SC have also been implicated in other aspects of recombination-based partner exchange. To ensure proper chromosome segregation, homologs must be connected by at least one chiasma, which can be formed only if CO occurs between nonsister chromatids. During mitosis, recombination for instance, to repair DNA damage takes place between sister chromatids, which are held together by cohesin rings following replication.
This unique feature of meiotic recombination, described variously as the barrier to sister chromatid repair BSCR , or interhomolog bias, provides an additional complexity to CO regulation [ 98 ]. How BSCR is implemented in mammals is still poorly understood. Although it is widely accepted that meiotic DSBs cannot be repaired without a mature SC, the molecular basis of this interdependency remains poorly understood. The sex chromosomes pose special challenges in meiosis.
In female germ cells, the two homologous X chromosomes experience no impediment to their pairing or recombination, and in fact, behave much like autosomal chromosomes. In contrast, in male germ cells the X and Y chromosomes are quite different in length genomic content Figure 2 , top panel , and this profoundly affects their structural modifications and behavior, which are not like those of the autosomal chromosomes. This sexual dimorphism in behavior of sex chromosomes gets at the heart of the role of the Y chromosome in spermatogenesis and fertility, which is still not fully resolved.
Interestingly, the evolving study of the XY body has paralleled the history of the SSR, with both endeavors originating at roughly the same time. The XY body is a domain of repressive chromatin associated with a unique and still incompletely understood array of proteins involved in chromatin modifications, DNA damage repair, and other functions, including, surprisingly, protein translation [ ]. The single most obvious feature of the XY body is that it is a domain of unpaired chromatin that is in marked contrast to the completely synapsed chromosomes in the autosomal domain of the spermatocyte nucleus.
In the past 50 years, and most notably in the past decade, reproductive scientists and geneticists have both contributed to the exploding literature surrounding this fascinating process.
We know far more about how it happens than we do about why it happens [ ]. A general signal transduction model is emerging, whereby unsynapsed chromosome axes activate signal proteins, including axis elements themselves, e.
Thus, although precise temporal order of steps and fine details remain to be worked out, we have a reasonably good grasp on the key players in MSCI, and, indeed, meiotic silencing MSUC in general [ ].
However, in contrast to this mechanistic view, we are still relatively in the dark about why MSCI and MSUC, in general, are necessary for successful meiosis and fertility. One might suppose that repressive chromatin might prevent the formation of DSBs that cannot be repaired in the absence of a homolog [ ], but temporal order of events mitigates this argument, as DSBs occur before synapsis [ ] and before MSCI, in the unpaired nonhomologous regions of the sex chromosomes [ 48 , ].
One often neglected consideration in attempts to decipher the biological rationale behind MSCI is its timing: MSCI is initiated after autosomal synapsis the completion of which marks the beginning of the pachytene stage and is readily apparent by the middle of the pachytene stage, correlating with the timing of both the presumed synapsis checkpoint [ , ] and the onset of competency for the meiotic division phase [ ].
This is also the time when the transcriptome of the spermatocyte changes dramatically [ ] with the production of a diverse array of transcripts that support postmeiotic spermiogenesis. But it turns out that there is great validity to this seemingly paradoxical idea.
Ectopic autosomal expression of transgenes representing two genes on the Y chromosome, Zfy1 and Zfy2 , inhibits progress of meiotic prophase and causes apoptosis of spermatocytes; however, when the transgenes are on the X chromosome and silenced by MSCI, they do not inhibit meiotic progress [ ]. Moreover, Zfy1 and Zfy2 are required for normal postmeiotic sperm differentiation and fertilization function [ ].
Together, these observations present a conundrum: How can the same genes be both toxic for and required for normal spermatogenesis? Is it related to their role as transcriptional activators? Or is it a sexually antagonistic interaction with their X-encoded counterpart, Zfx? Clearly, there is much left to learn about MSCI, and the function of meiotic silencing of unpaired chromatin in general! These proteins are first removed at the end of meiotic prophase from the chromosome arms allowing homologs to separate , but remain at sister centromeres until removed in preparation for the second, equational, meiotic division.
Like much of meiosis, onset of the division phase is sexually dimorphic in mammals; coordinated with follicle growth and hormonal input in females and occurring without arrest and maybe even cell autonomous in males.
These divisions involve coordination between chromosomal elements disassembly of the SC, redistribution of proteins such as cohesins, and centromeric specializations and the cytoplasmic elements that contribute to the formation of the meiotic spindle apparatus.
The principles of Mendelian genetics suggest that chromosome segregation during the two meiotic divisions is equal, resulting in equal representation of any particular allele or chromosome in offspring; at least this is what we thought 50 years ago. In this noncanonical and infrequent segregation pattern, sister chromatids, rather than homologous chromosomes, are segregated during first meiotic division. There is evidence for biased segregation of so-called selfish elements in the genome [ , ].
Given that one of the key conditions predisposing to nonrandom segregation is asymmetry of the meiotic division [ ], it is not surprising that most cases of TRD studied in mammals involve female meiosis, where the cytoplasmic divisions of meiosis I and II are markedly unequal thus while four chromatids segregate to four gametic products in males, there is only one gametic product in females; Figure 1.
Studies of segregation of the mouse Om ovum mutant locus provided evidence for biased segregation at the second meiotic division [ ], and although there has been high-resolution genetic mapping of the trait [ ], the mechanism remains unknown.
In the mouse Collaborative Cross, a complex multiparent cross constructed to incorporate genetic diversity [ ], there is biased transmission of Chr 2, attributable to a large copy-number variant designated R2d2 responder to drive 2 on Chr 2 [ , ].
A new type of biased segregation has been recently observed in human oocytes in second meiotic division, namely preferential segregation of recombinant chromatid to the oocyte and nonrecombinant to polar body [ ].
The molecular mechanism of this recombinant-favoring drive remains elusive but it has been suggested that selection against nonrecombined haplotypes could suppress selfish elements [ ]. Generally, we have very little idea of molecular mechanisms in the female meiotic divisions by which unbalanced segregation might occur, although evidence has suggested that both asymmetry of the spindle apparatus and functional heterozygosity or unequal strength of paired homologous centromeres [ , ] may play roles.
Recent exciting findings relate these at a molecular level. Lampson and colleagues [ ] provide evidence that spindle asymmetry in the mouse oocyte is driven by asymmetric microtubule tyrosination directed by CDC42 signaling from the oocyte cortex.
Intriguingly, CDC42 in the cortex depends on signaling from chromosomes near the cortex, driving their own transmission [ ]. Many questions remain to be resolved, but from this elegant study we get a hint of the complexity of the involvement of chromosomes in directing their own fate, and it is becoming clear that they are not passive passengers, but are equal partners with the cytoplasmic elements controlling the division phases. Not only is meiosis the chromosomal foundation of successful reproduction, but also infertility has been a window through which to observe meiosis and consequences of error.
Not surprisingly, if there is no dance of the chromosomes, there are no gametes. Thus, meiosis is not just a defining event of gametogenesis, it is essential. Moreover, the intricate meiotic chromosome dance reviewed above poses many steps where things can go wrong, impacting formation of chromosomally normal euploid gametes and offspring. And, although gametic aneuploidy is documented more thoroughly in humans than in mice, mice err too, and several studies provide evidence for aging-related increases in oocyte aneuploidy and fertility impairment in mice [ — ].
What have studies on fertility impairment and anueploidy in humans and mice taught us about the meiotic dance of chromosomes? One of the most interesting if not surprising findings emerging from study of meiotic error in humans and mouse mutants is that there is considerable sexual dimorphism in chromatin organization, recombination, and toleration of meiotic defects by male versus female germ cells Figure 1.
For many such traits, we have learned more from the human than from other common research models. Possibly this is because of higher frequency, across diverse human populations, of gene variants impacting on meiotic segregation although the burgeoning efforts to exploit new mouse diversity populations may uncover genes or gene interactions influencing meiotic segregation outcomes [ ]. In humans, female gametic aneuploidy is greater than male, and females have a greater proportion of chromosomes lacking a CO [ ].
Somewhat counterintuitively, human females also have a higher rate of recombination than males [ ], and this paradox may reflect inefficient CO maturation in female germ cells [ ]. Male—female differences in recombination rate are established early in meiosis with sexual dimorphism in numbers of foci of proteins e. Exactly how numbers and placement of COs in females are related to increased gametic aneuploidy is not well understood, but overall, there are considerable sex differences in organization of the chromosomal axes and DNA loops; in comparison to males, females have longer SCs and shorter DNA loops for the same genomic DNA [ ].
These marked differences may be a reflection of sexually dimorphic assembly of axis components. The requirement for some proteins mediating chromosome dynamics, for instance, those of the CEs of the SC e. However, the story is different when considering the meiosis-specific cohesins and some proteins of LEs along chromatids. SYCP3, SYCP2, exhibit abnormalities of meiotic chromosome dynamics, only the males are infertile, exhibiting arrest of meiosis and absence of postmeiotic germ cells [ — ].
In contrast, females produce offspring, albeit in decreased numbers and with increased aneuploidy [ ]. Female germ cells are more sensitive to cohesin gene dosage heterozygosity [ ].
One possible explanation is that oocytes have meiotic checkpoint mechanisms with reduced stringency [ ]. The features of mammalian female reproduction limited number of germ cells, narrow temporal window for meiosis, cyclicity, and physiologically demanding prenatal and postnatal maternal care of offspring may have led to evolution of mechanistic variability and less stringent quality control.
Indeed, it has been postulated that female gametic aneuploidy may be evolutionarily advantageous, imposing spacing of costly offspring [ , ].
Another intriguing sexually dimorphic facet of meiotic infertility is the effect of aging, perhaps especially in humans. As already reviewed Figure 1 , meiotic divisions in males occur in cells that are undergoing meiosis without interruption, while in females meiotic prophase is initiated long before the meiotic divisions.
The fact that gametic aneuploidy seems more common in humans than in mice, the other major model mammalian organism, may have to do with the relative paucity of gene variants causing error in strains of laboratory mice selected for productivity, but probably is much more a reflection of germ-cell age in the face of chronological age in years.
However, more careful recent analyses determined that there is a paternal effect; surprisingly, it turns out to be a negative one where younger fathers are more likely to have a child with Down syndrome [ , ]. Interestingly, increased trends of Down syndrome have been also reported in extremely young mothers [ ]. Previous studies failed to detect these effects as they often excluded young parents due to their limited representation.
Gametic aneuploidy in most cases can be traced back to meiotic CO errors. Recent advances in technology and understanding of CO regulation from model organisms offer an attractive explanation for aneuploidies in young males and potentially females and aging females. It has been observed that spermatocytes from young males have lower numbers of MLH1 foci than those from adult males [ ], as well as fewer than expected from the numbers of recombination intermediates [ ].
This decrease has been attributed to inefficient CO maturation in young males [ ]. This inherent vulnerability of bivalent chromosomes could be exacerbated by age-dependent loss of sister-chromatid cohesion [ , ].
Indeed, age-dependent cohesin deterioration has been long considered as one of the major causes of aneuploidy in human eggs [ ]. It has been postulated that cohesin complexes, once loaded onto meiotic chromosomes, are not replenished, thus weakening those connections between sister chromatids which normally must persist until fertilization and the onset of meiosis II [ 22 , — ].
Although it would seem beneficial to refresh sister-chromatid cohesion as chromosomes wait for meiotic resumption, apparently there is no such mechanism and cohesin proteins rely on their inherent stability.
Both sexual dimorphism in meiosis and the diversification of gametogenesis programs that arose during evolution pose problems for human reproduction. Females appear to have chosen to guard genome quality by limiting the number of cell divisions, thus decreasing the risk of potential de novo germline mutations. The downside is that they produce fewer eggs, and these have to be stored for a long time before they can be fertilized.
This strategy may not be a problem when females produce offspring at a young age, but this is not always the case in the modern human population. The strategy in males appears to be to continuously produce large quantities of gametes from continually rejuvenating precursors; however, this potentially sacrifices gametic genomic quality due to mitotic mutation rate and consequent age-related accumulation of de novo germline mutations [ , ].
Likewise, this can be an issue among human males extending fatherhood to an advanced age. Genetic mutants, high-resolution imaging, and protein identification technologies have been and will continue to be pivotal in expanding our understanding. What do we need to get there? And will our technologies impact human reproductive health care and fertility interventions? We posit that the most exciting, enabling, and clinically transforming advancement will be a robust system for meiosis in vitro.
The reason probably lies in the not-yet fully appreciated extent of signals from the surrounding gonadal soma that instruct and propel meiosis. The roles of retinoic acid in initiation of meiosis are well known [ , ], and some steps and transitions of meiotic prophase may be noncell autonomous, subject to exogenous influence, e. Much of the effort toward meiosis in vitro has been in the context of deriving functional germ cells in vitro, e. However, the output is generally measured in terms of a few gametes, requiring intervention with assisted reproductive technologies ARTs for offspring production.
We would want to use such a system for analysis of chromosome behavior, e. Most importantly, we will have to gain a better understanding of the regulatory signals, both cell autonomous and exogenous, that regulate the sequential steps of mammalian meiosis.
This will probably entail much more extensive in vivo genetic analyses; advances like genome editing using site-specific nucleases [ ], synchronization of seminiferous tubule stages [ ], and reconstitution of ovarian follicles [ ] are important steps in this direction. We will also have to identify a source of large numbers of meiosis-competent cells. Meiotic cells of course do not self-renew, so the ideal system would be a robustly proliferating stem cell that could be induced to enter meiosis in vitro; recent reports of germ cell derivation from iPS cells are encouraging [ , , ].
Assuming that sometime in the next half decade we will have cultures of large numbers of cells executing the dance of the chromosomes faithfully and accurately, there are a number of exciting possibilities.
Foremost among them would be the opportunity to observe homology pairing by real-time superresolution imaging.
Bar-coded, chromosome-specific fluorescent signals [ — ] would allow us to finally resolve the important players in homology recognition, both the DNA sequences and the specific proteins. The ability to manipulate the intracellular and nuclear environment would help test theories about the liquid crystal organization of chromatin. Parsing out the final steps of resolution of CO formation would have implications not only for understanding origins of aneuploidy, but for DNA repair processes in general.
The implications of meiosis in vitro are great not only for these fundamental and basic problems, but also for reproductive toxicology, oncofertility, and therapeutics around infertility. Bioengineering is an emerging and rapidly expanding field which will add additional capabilities to study the intricate cellular processes such as chromosome dynamics and recombination.
Although stem cells can be coaxed to undergo meiosis in a dish and produce haploid gametes, the meiotic chromosome dance is not well choreographed. This can compromise efficiency and may lead to chromosomal abnormalities in in vitro-derived gametes.
That's what meiosis is all about. It's taking that complete set and breaking it down to a so-called haploid set and also providing the opportunity for recombination to occur to sort of scramble the copies and produce new kinds of outcomes, which is critical for the diversity of a species. Meiosis is one of those things that's hard to really get your mind around.
There's meiosis 1, there's meiosis So this one's getting pulled onto this side. It has a little bit from the original, so a little bit of that right over there.
And then you have this one getting pulled on this side. So draw it the best I can, the colors, alright, so it looks like that, although it's nice to have, it's kinda easy to keep track of cause these switch colors like that. This one getting pulled on this side. And finally finally this one getting pulled onto that side. And let me draw the centrosomes. So that's my, oops, centrosome, and once again, it's pulling, or I guess you could say the chromosomes are being moved and these things are pushing each other apart.
The two centrosomes might be pushing apart to get to the opposite ends of the actual cell, but they're bringing, there's all sorts of interesting mechanisms that are bringing along these microtubules, bringing the chromosomes, once again splitting the homologous pairs.
And how they split is random. You know, this pink one could have been on the right side, this orange one could have been on the left side, or vice versa, and once again, this adds more variation amongst the gametes, so even all of the resulting gametes that get produced, they all will have different genetic information.
So this is anaphase I. You're pulling these apart, and then you could imagine what happens in telophase I. So telophase I, telophase, telophase I. Telophase I, and this is fairly analogous to what happens in mitosis in telophase.
So now you have your cytokinesis is beginning, and actually, it might even begin earlier, in mitosis it happens as early as anaphase, at least the cytokinesis is starting, but you're starting to see that. The homologous pairs are fully split apart, and they're at opposite ends, and actually they can begin to unravel into their chromatin state, so this one began to unravel into its chromatin state. It has a little bit of the magenta. Oops, it has a little bit of the magenta right over here.
This is unravelling as well. This is unravelling like that, once it gets into its chromatin state. The cellular, and let me do the other ones as well. So this is this one right over here. It's beginning to unravel. This one over here, beginning to unravel. It's got a bit of orange on it.
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