Meiosis ( ) represents a specialized form of cell division occurring in the germ cells of sexually reproducing organisms, leading to the production of gametes, such as sperm or egg cells. This intricate process involves two successive rounds of division, ultimately yielding four daughter cells, each possessing a haploid set of chromosomes (a single copy of each). Crucially, before these divisions, genetic material from the paternal and maternal homologous chromosomes undergoes crossing over, which generates novel genetic combinations on each chromosome. Subsequently, during fertilization, the haploid cells generated via meiosis from a male and a female organism fuse to form a zygote, a diploid cell characterized by two copies of each chromosome.
Meiosis ( ) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a zygote, a cell with two copies of each chromosome.
Aberrations occurring during meiosis, which result in aneuploidy (an abnormal number of chromosomes), are identified as the predominant known cause of miscarriage and represent the most frequent genetic etiology of developmental disabilities.
In meiosis, DNA replication is succeeded by two rounds of cell division, culminating in the production of four daughter cells, each possessing half the chromosomal complement of the original parent cell. These two sequential meiotic divisions are designated as Meiosis I and Meiosis II. Before the onset of meiosis, during the S phase of the cell cycle, the DNA of each chromosome is replicated, resulting in two identical sister chromatids that remain associated through sister chromatid cohesion. This specific S-phase is often referred to as "premeiotic S-phase" or "meiotic S-phase". Immediately following DNA replication, meiotic cells enter a prolonged G2-like stage known as meiotic prophase. During this critical period, homologous chromosomes pair and undergo genetic recombination, a precisely programmed process involving DNA cleavage and repair that enables the exchange of genetic information. A subset of these recombination events leads to crossovers, which form physical linkages, known as chiasmata (singular: chiasma, derived from the Greek letter Chi, Χ), between homologous chromosomes. In most organisms, these chiasmata facilitate the accurate segregation of each pair of homologous chromosomes during Meiosis I, yielding two haploid cells that contain half the number of chromosomes present in the parent cell.
During Meiosis II, the cohesion between sister chromatids is released, leading to their segregation from one another, a process analogous to that observed in mitosis. In certain instances, all four meiotic products develop into gametes, such as sperm, spores, or pollen. However, in female animals, three of the four meiotic products are typically eliminated through extrusion into polar bodies, with only one cell maturing to produce an ovum. The halving of the chromosome number during meiosis enables gametes to fuse during fertilization, forming a diploid zygote that contains two copies of each chromosome, one inherited from each parent. Therefore, the alternating cycles of meiosis and fertilization are fundamental to sexual reproduction, ensuring the consistent maintenance of chromosome number across successive generations. For example, diploid human cells contain 23 pairs of chromosomes, including one pair of sex chromosomes (totaling 46 chromosomes), with half originating from the mother and half from the father. Meiosis generates haploid gametes (ova or sperm), each containing a single set of 23 chromosomes. When an egg and a sperm fuse, the resulting zygote becomes diploid once more, with both the mother and father contributing 23 chromosomes. This overarching pattern, though with variations in the precise number of chromosomes, is characteristic of all organisms that utilize meiosis.
Meiosis is a fundamental biological process observed in all sexually reproducing organisms, encompassing both single-celled and multicellular eukaryotes, including animals, plants, and fungi. It constitutes an essential mechanism for both oogenesis and spermatogenesis.
Overview
While the process of meiosis is fundamentally related to the more general cellular division process of mitosis, it is distinguished by two crucial differences:
Meiosis commences with a diploid cell, which inherently possesses two copies of each chromosome, referred to as homologs. Initially, the cell undergoes DNA replication, resulting in each homolog comprising two identical sister chromatids. Subsequently, each set of homologs pairs and engages in homologous recombination, facilitating the exchange of genetic information, which frequently leads to the formation of physical connections known as crossovers between the homologs. During the first meiotic division, the spindle apparatus segregates the homologs into separate daughter cells. The cells then proceed to a second division without an intervening round of DNA replication. In this subsequent division, the sister chromatids are segregated into distinct daughter cells, ultimately yielding a total of four haploid cells. Female animals exhibit a slight deviation from this pattern, producing one large ovum and three smaller polar bodies. Due to recombination, an individual chromatid can incorporate a novel combination of maternal and paternal genetic information, thereby generating offspring that are genetically distinct from either parent. Furthermore, a single gamete can contain an assortment of maternal, paternal, and recombinant chromatids. This genetic diversity, a product of sexual reproduction, significantly contributes to the variation in traits upon which natural selection operates.
Meiosis shares numerous mechanisms with mitosis, the form of cell division employed by eukaryotes to produce two genetically identical daughter cells from a single parent cell. In certain plants, fungi, and protists, meiosis culminates in the formation of spores, which are haploid cells capable of vegetative division without requiring fertilization. Conversely, some eukaryotes, such as bdelloid rotifers, lack the capacity for meiosis and have evolved the ability to reproduce through parthenogenesis.
Meiosis does not occur in archaea or bacteria, which typically reproduce asexually via binary fission. Nevertheless, a "sexual" process termed horizontal gene transfer involves the transmission of DNA from one bacterium or archaeon to another, followed by the recombination of these DNA molecules originating from different parental sources.
History
The initial discovery and description of meiosis occurred in sea urchin eggs in 1876, attributed to the German biologist Oscar Hertwig. Subsequently, in 1883, the Belgian zoologist Edouard Van Beneden provided a chromosomal-level description of the process in Ascaris roundworm eggs. However, the profound significance of meiosis for reproduction and inheritance was elucidated only in 1890 by the German biologist August Weismann, who posited that two cell divisions were essential to transform one diploid cell into four haploid cells while maintaining a constant chromosome number. In 1911, the American geneticist Thomas Hunt Morgan identified crossovers during meiosis in the fruit fly Drosophila melanogaster, a finding instrumental in establishing that genetic traits are transmitted on chromosomes.
The term "meiosis" originates from the Greek word μείωσις, signifying 'lessening'. It was introduced into biological terminology by J.B. Farmer and J.E.S. Moore in 1905, initially rendered with the idiosyncratic spelling "maiosis":
We propose to apply the terms Maiosis or Maiotic phase to cover the whole series of nuclear changes included in the two divisions that were designated as Heterotype and Homotype by Flemming.
The spelling was subsequently standardized to "meiosis" by Koernicke (1905) and by Pantel and De Sinety (1906) to conform to conventional Greek transliteration practices.
Phases
Meiosis is delineated into Meiosis I and Meiosis II, which are further subdivided into Karyokinesis I, Cytokinesis I, Karyokinesis II, and Cytokinesis II, respectively. The preparatory stages preceding meiosis are identical in structure and nomenclature to the interphase of the mitotic cell cycle. Interphase itself is segmented into three distinct phases:
- Growth 1 (G1) phase: During this highly active phase, the cell synthesizes a vast array of proteins, encompassing the enzymes and structural proteins requisite for its growth. In G§23§, each chromosome consists of a single linear DNA molecule.
- Synthesis (S) phase: The genetic material undergoes replication; each chromosome within the cell duplicates to form two identical sister chromatids, which remain attached at a centromere. This replication does not alter the cell's ploidy, as the number of centromeres remains constant. The identical sister chromatids have not yet condensed into the densely packaged chromosomes observable under a light microscope; this condensation will occur during prophase I of meiosis.
- The G2 phase, typically observed before mitosis, is absent in meiosis. Instead, meiotic prophase exhibits the closest resemblance to the G§45§ phase of the mitotic cell cycle.
Following interphase, the meiotic process unfolds in two successive divisions: meiosis I and meiosis II. Meiosis I involves the segregation of replicated homologous chromosomes, each comprising two sister chromatids, into two distinct daughter cells, thereby halving the chromosome count. Subsequently, during meiosis II, sister chromatids dissociate, leading to the segregation of the resulting daughter chromosomes into four daughter cells. In diploid organisms, the cells produced through meiosis are haploid, possessing a single copy of each chromosome. Certain species exhibit an intervening quiescent period, termed interkinesis, between meiosis I and meiosis II.
Both Meiosis I and Meiosis II are subdivided into prophase, metaphase, anaphase, and telophase stages, which serve functions analogous to their counterparts in the mitotic cell cycle. Consequently, meiosis encompasses the stages of Meiosis I (prophase I, metaphase I, anaphase I, telophase I) and Meiosis II (prophase II, metaphase II, anaphase II, telophase II).
During meiosis, a heightened transcription of particular genes is observed. Beyond robust meiotic stage-specific mRNA expression, extensive translational controls, such as the selective utilization of pre-existing mRNA, also govern the ultimate meiotic stage-specific protein expression of genes. Therefore, both transcriptional and translational regulatory mechanisms are crucial for orchestrating the extensive cellular reorganization required for meiosis.
Meiosis I
Meiosis I involves the segregation of homologous chromosomes, which are initially associated as tetrads (2n, 4c), resulting in two haploid cells (n chromosomes, 23 in humans). Each of these cells subsequently contains chromatid pairs (1n, 2c). Given that the ploidy level decreases from diploid to haploid, Meiosis I is designated as a reductional division. In contrast, Meiosis II functions as an equational division, mirroring mitosis, where sister chromatids separate, ultimately yielding four haploid daughter cells (1n, 1c).
Prophase I
Prophase I constitutes the most protracted stage of meiosis, extending for 13 out of 14 days in mice. During this phase, homologous maternal and paternal chromosomes undergo pairing, synapsis, and genetic information exchange via homologous recombination, leading to the formation of at least one crossover per chromosome. These crossovers manifest as visible chiasmata (plural; singular chiasma). This intricate process ensures stable association between homologous chromosomes, thereby facilitating their precise segregation during the initial meiotic division. The paired and replicated chromosomes are referred to as bivalents (comprising two chromosomes) or tetrads (comprising four chromatids), with each chromosome originating from a different parent. Prophase I is further delineated into several substages, categorized based on the morphological characteristics of the chromosomes.
Leptotene
The initial substage of Prophase I is the leptotene stage, also termed leptonema, derived from Greek roots signifying "thin threads." During this phase of Prophase I, individual chromosomes, each composed of two replicated sister chromatids, become distinct and visible as filamentous structures within the nucleus. Each chromosome organizes into a linear arrangement of loops, a process mediated by cohesin. Concurrently, the lateral elements of the synaptonemal complex assemble to form an "axial element," from which these loops extend. Recombination commences during leptotene, catalyzed by the enzyme SPO11, which induces programmed double-strand breaks (approximately 300 per meiosis in mice). This enzymatic activity leads to the formation of single-stranded DNA filaments, which are subsequently coated by RAD51 and DMC1. These coated filaments then invade homologous chromosomes, establishing inter-axis bridges and facilitating the pairing or co-alignment of homologues (achieving a proximity of approximately 400 nm in mice).
Zygotene
Following leptotene, the zygotene stage, also referred to as zygonema, commences. This term originates from Greek words meaning "paired threads." In certain organisms, this stage is also known as the bouquet stage due to the characteristic clustering of telomeres at one pole of the nucleus. During zygotene, homologous chromosomes achieve a significantly closer (approximately 100 nm) and more stable association, a process termed synapsis. This close pairing is facilitated by the assembly of the transverse and central elements of the synaptonemal complex. Synapsis is hypothesized to proceed in a zipper-like manner, initiating from a recombination nodule. The resulting paired chromosomes are designated as bivalent or tetrad chromosomes.
Pachytene
The pachytene stage, also identified as pachynema and derived from Greek terms signifying "thick threads," marks the point where all autosomal chromosomes have undergone synapsis. During this phase, homologous recombination, encompassing chromosomal crossover, is finalized through the repair of double-strand breaks that originated in leptotene. The majority of these breaks are repaired without generating crossovers, leading to gene conversion. Nevertheless, a specific subset of breaks (at least one per chromosome) does form crossovers between non-sister (homologous) chromosomes, facilitating the exchange of genetic material. This exchange between homologous chromatids results in genetic recombination, ensuring that each chromosome retains its complete informational content without any resulting gaps. Due to the indistinguishable nature of chromosomes within the synaptonemal complex, the actual event of crossing over is not discernible via standard light microscopy; chiasmata only become visible in the subsequent stage.
Diplotene
During the diplotene stage, also referred to as diplonema, a term derived from Greek words meaning "two threads," the synaptonemal complex undergoes disassembly, and homologous chromosomes begin to slightly separate. Despite this separation, the homologous chromosomes within each bivalent maintain tight connections at the chiasmata, which are the sites where crossing-over previously took place. These chiasmata persist on the chromosomes until they are cleaved during the transition to anaphase I, enabling the homologous chromosomes to migrate to opposing cellular poles.
In human fetal oogenesis, all developing oocytes progress to this stage and subsequently undergo arrest in prophase I prior to birth. This prolonged quiescent state is designated as the dictyotene stage or dictyate. It endures until meiosis recommences to prepare the oocyte for ovulation, an event that occurs at puberty or potentially later.
Diakinesis
Chromosomes undergo further condensation during the diakinesis stage, a term originating from Greek words meaning "moving through." This phase represents the initial point in meiosis where the four components of the tetrads become distinctly visible. The sites of crossing over become intertwined, creating an overlapping effect that renders the chiasmata clearly discernible. Apart from this specific observation, the remainder of this stage closely parallels the prometaphase of mitosis: nucleoli vanish, the nuclear membrane fragments into vesicles, and the meiotic spindle commences its formation.
Meiotic Spindle Formation
In contrast to mitotic cells, human and mouse oocytes lack centrosomes for the generation of the meiotic spindle. In murine oocytes, approximately 80 MicroTubule Organizing Centers (MTOCs) coalesce into a spherical structure within the ooplasm, initiating the nucleation of microtubules that extend towards and attach to chromosomes at their kinetochores. Progressively, these MTOCs merge, culminating in the formation of two distinct poles and a barrel-shaped spindle. Within human oocytes, spindle microtubule nucleation commences directly on the chromosomes, forming an aster that subsequently expands to envelop them. Chromosomes then migrate along the microtubules towards the spindle's equator, where their kinetochores establish end-on attachments to the microtubules.
Metaphase I
Homologous pairs migrate and align along the metaphase plate. Kinetochore microtubules originating from both spindle poles attach to their corresponding kinetochores, causing the paired homologous chromosomes to arrange themselves along an equatorial plane that bisects the spindle. This alignment is maintained by continuous counterbalancing forces exerted on the bivalents by microtubules emanating from the two kinetochores of homologous chromosomes, a configuration termed bipolar attachment. The fundamental physical mechanism underlying the independent assortment of chromosomes is the random orientation of each bivalent along the metaphase plate, relative to the orientation of other bivalents along the same equatorial axis. The cohesin protein complex maintains the linkage between sister chromatids from their replication until anaphase I. In mitotic division, the opposing forces exerted by kinetochore microtubules generate tension, which the cell detects, preventing progression into anaphase until all chromosomes are correctly bi-oriented. In meiosis, the establishment of this tension typically necessitates at least one crossover per chromosome pair, in addition to the cohesin between sister chromatids.
Anaphase I
Kinetochore microtubules undergo shortening, thereby drawing homologous chromosomes, each comprising a pair of sister chromatids, toward opposing cellular poles. Concurrently, non-kinetochore microtubules extend, facilitating the separation of centrosomes. The cell subsequently elongates, preparing for central division. Distinct from mitosis, cohesin located on the chromosome arms is degraded, whereas cohesin encircling the centromere is preserved by Shugoshin, a protein (derived from the Japanese for "guardian spirit"). This protective mechanism ensures that sister chromatids remain associated while homologous chromosomes are segregated.
Telophase I
The initial meiotic division concludes upon the arrival of chromosomes at the cellular poles. Each nascent daughter cell subsequently possesses a haploid chromosome complement, with each chromosome still composed of a pair of chromatids. The spindle network's microtubules dissipate, and a novel nuclear membrane encapsulates each haploid set. Cytokinesis, characterized by the invagination of the cell membrane in animal cells or the development of a cell wall in plant cells, then proceeds, culminating in the formation of two daughter cells. Nevertheless, cytokinesis often remains incomplete, forming "cytoplasmic bridges" that permit cytoplasmic exchange between daughter cells until the termination of meiosis II. Sister chromatids maintain their attachment throughout Telophase I.
Following Telophase I, cells may transition into a quiescent phase termed interkinesis or interphase II. During this interval, DNA replication does not transpire.
Meiosis II
Meiosis II represents the second meiotic division, typically involving equational segregation, which entails the separation of sister chromatids. Mechanistically, this process bears resemblance to mitosis; however, its genetic outcomes are profoundly distinct. It culminates in the generation of four haploid cells (n chromosomes; 23 in humans) from the two haploid cells (each containing n chromosomes, themselves composed of two sister chromatids) generated during Meiosis I. The four principal stages of Meiosis II are Prophase II, Metaphase II, Anaphase II, and Telophase II.
During Prophase II, the nucleoli and nuclear envelope once again dissipate, while chromatids undergo shortening and thickening. Centrosomes migrate toward the polar regions, organizing the spindle fibers essential for the second meiotic division.
During Metaphase II, each centromere possesses two kinetochores, which establish connections with spindle fibers originating from centrosomes positioned at opposing poles. The newly formed equatorial metaphase plate is oriented 90 degrees relative to its position in Meiosis I, thus lying perpendicular to the preceding plate.
Subsequently, Anaphase II commences, during which the residual centromeric cohesin, no longer safeguarded by Shugoshin, is cleaved. This cleavage facilitates the segregation of sister chromatids. Conventionally, these separating sister chromatids are re-designated as sister chromosomes as they migrate toward opposite poles.
The process culminates in Telophase II, a stage analogous to Telophase I, characterized by the decondensation and elongation of chromosomes, alongside the disassembly of the spindle apparatus. Nuclear envelopes subsequently re-form, and either cleavage furrow formation or cell plate development ultimately yields a total of four daughter cells, each containing a haploid complement of chromosomes.
Upon completion of these stages, meiosis concludes, resulting in the formation of four novel daughter cells.
Origin and Function
Origin of Meiosis
Meiosis is considered a fundamental characteristic of eukaryotic organisms, likely emerging early in their evolutionary history. Eukaryotes previously believed to lack meiotic reproduction have recently been demonstrated to possess, or to have once possessed, this capacity. For instance, Giardia intestinalis, a prevalent intestinal parasite, was formerly thought to originate from a lineage preceding the evolution of meiosis and sexual reproduction. Nevertheless, G. intestinalis has now been identified as containing a core complement of meiotic genes, specifically including five genes unique to meiosis. Furthermore, evidence of meiotic recombination, signifying sexual reproduction, has been detected in G. intestinalis. Parasitic protozoa belonging to the genus Leishmania, responsible for human diseases, represent another group formerly considered asexual. However, these organisms have been demonstrated to exhibit a sexual cycle compatible with a meiotic mechanism. While amoebae were historically considered asexual, evidence now suggests that most lineages are anciently sexual, with the majority of asexual groups likely emerging recently and independently. Based on phylogenetic analysis, Dacks and Rogers posited that facultative sexual reproduction was probably present in the last common ancestor of eukaryotes.
Genetic Variation
Meiosis generates novel DNA combinations, serving as a crucial source of genetic variation in conjunction with mutation, thereby producing new allele combinations that can confer advantages. Gamete genetic diversity arises from meiosis through two primary mechanisms: (1) Independent Assortment: The autonomous alignment of homologous chromosome pairs at the metaphase plate during metaphase I, followed by the orientation of sister chromatids in metaphase II and their subsequent segregation during anaphase I and II, ensures a random and independent distribution of chromosomes to each daughter cell and, ultimately, to gametes. (2) Crossing Over: The reciprocal exchange of homologous chromosomal segments via homologous recombination during prophase I leads to novel arrangements of genetic material within chromosomes. Nevertheless, this physical exchange is not universally observed during meiosis. For instance, in the oocytes of the silkworm Bombyx mori, meiosis is entirely achiasmate, meaning it lacks crossovers. Despite the presence of synaptonemal complexes during the pachytene stage of meiosis in B. mori, homologous recombination involving crossing-over does not occur between the paired chromosomes.
Prophase I Arrest
Female mammals and avian species are born with their complete complement of oocytes required for subsequent ovulations, with these oocytes arrested in the prophase I stage of meiosis. In humans, for instance, oocytes develop within the fetus between three and four months of gestation, thus being present at birth. Throughout this prophase I arrest stage, known as dictyate, which can persist for several decades, oocytes contain four copies of the genome. This arrest of oocytes at the four-genome-copy stage has been hypothesized to furnish the informational redundancy necessary for repairing germline DNA damage. The repair mechanism employed seems to be homologous recombinational repair. Oocytes arrested in prophase I exhibit a robust capacity for efficient DNA damage repair, especially concerning exogenously induced double-strand breaks. Consequently, DNA repair capability emerges as a pivotal quality control mechanism within the female germline and a crucial factor influencing fertility.
Meiosis as an Adaptation for Germline DNA Repair
Genetic recombination can be fundamentally understood as a DNA repair process, and its occurrence during meiosis represents an adaptation for rectifying genomic DNA transmitted to offspring. Empirical evidence suggests that a significant advantage of meiosis lies in the recombinational repair of germline DNA damage, exemplified by the following instances. Hydrogen peroxide is an agent known to induce oxidative stress, which results in oxidative DNA damage. Exposure of the yeast Schizosaccharomyces pombe to hydrogen peroxide led to a 4- to 18-fold increase in mating frequency and meiotic spore formation. Volvox carteri, a haploid, multicellular, facultatively sexual green alga, can be prompted by heat shock to undergo meiotic sexual reproduction. The induction of this process is suppressible by antioxidants, suggesting that heat shock-induced meiotic sex is probably mediated by oxidative stress, which subsequently causes elevated DNA damage.
Occurrence
Life Cycles
Meiosis is an integral component of eukaryotic life cycles characterized by sexual reproduction. These cycles encompass a recurring sequence of growth and development, facilitated by mitotic cell division, followed by gamete generation through meiosis, and subsequent fertilization. Germ cells are responsible for gamete production during specific phases of the life cycle. Conversely, somatic cells constitute the organism's physical structure and do not participate in gamete formation.
The cyclical interplay of meiosis and fertilization establishes an alternation between haploid and diploid cellular states. The predominant organismal phase within a life cycle can manifest in three forms: a diploid state (termed the diplontic life cycle), a haploid state (referred to as the haplontic life cycle), or a combination of both (haplodiplontic life cycle). The haplodiplontic cycle is distinguished by the presence of two discrete organismal phases, one composed of haploid cells and the other of diploid cells.
Within the diplontic life cycle, which involves pre-gametic meiosis and is exemplified by humans, the organism exists as a multicellular diploid entity. This organism develops through mitotic divisions originating from a diploid zygote. Diploid germ-line stem cells within the organism subsequently undergo meiosis, generating haploid gametes (spermatozoa in males and ova in females). These gametes then fuse during fertilization to reconstitute the diploid zygote. The resulting diploid zygote then undergoes successive mitotic cellular divisions to develop into the mature organism.
In the haplontic life cycle, characterized by post-zygotic meiosis, the organism exists predominantly in a haploid state. This haploid organism develops through the proliferation and differentiation of a single haploid cell, referred to as a gamete. Haploid gametes from two sexually distinct organisms unite to form a diploid zygote. Immediately following its formation, this zygote undergoes meiosis, producing four haploid cells. These haploid cells subsequently undergo mitosis to develop into the mature haploid organism. Numerous fungi and protozoa exhibit the haplontic life cycle.
The haplodiplontic life cycle, which involves sporic or intermediate meiosis, is defined by an alternation between haploid and diploid organismal states. This phenomenon is also recognized as the alternation of generations. Germ-line cells of the diploid organism undergo meiosis, resulting in the production of spores. These spores then proliferate via mitosis, developing into a haploid organism. Subsequently, a gamete from this haploid organism fuses with a gamete from another haploid organism, forming a zygote. The zygote then undergoes successive mitotic divisions and differentiation to generate a new diploid organism. Conceptually, the haplodiplontic life cycle can be viewed as an integration of both diplontic and haplontic life cycle characteristics.
In Plants and Animals
Meiosis is a ubiquitous process across all animal and plant kingdoms. While the fundamental outcome—the generation of gametes possessing half the parental chromosome number—remains consistent, the specific mechanisms vary. In animals, meiosis directly yields gametes. Conversely, land plants and certain algae exhibit an alternation of generations, wherein meiosis within the diploid sporophyte generation produces haploid spores rather than gametes. Upon germination, these spores undergo iterative mitotic cell divisions, culminating in the development of a multicellular haploid gametophyte generation. This gametophyte then directly produces gametes, obviating the need for further meiotic events.
Across both animal and plant phyla, the ultimate stage involves the fusion of gametes to form a zygote, thereby restoring the species-specific diploid chromosome complement.
In Mammals
In female mammals, meiosis takes place within specialized cells termed oocytes (singular: oocyte). Each primary oocyte undergoes two meiotic divisions, both characterized by unequal cytokinesis. The first meiotic division yields a larger daughter cell and a significantly smaller polar body, which may or may not proceed to a second division. During meiosis II, the division of the larger daughter cell produces a second polar body and a single haploid cell, which subsequently matures into an ovum. Consequently, in females, the meiotic progression of a single primary oocyte culminates in the formation of one mature ovum and either two or three polar bodies.
Meiosis in females is characterized by distinct arrest points. Developing oocytes undergo arrest during prophase I of meiosis I, remaining quiescent within a protective follicular structure composed of somatic cells. During this arrested phase, the oocyte nucleus is referred to as the germinal vesicle. The initiation of each menstrual cycle involves the anterior pituitary's secretion of Follicle-Stimulating Hormone (FSH), which promotes the maturation of a subset of follicles through a process termed folliculogenesis. Throughout folliculogenesis, the maturing oocytes re-enter meiosis, progressing until metaphase II of meiosis II, at which point they experience a second arrest immediately preceding ovulation. Key indicators of meiotic resumption include the disintegration of the germinal vesicle, chromosomal condensation, and the formation of the bipolar metaphase I spindle. Successful fertilization by sperm triggers the resumption and completion of meiosis in these oocytes. In human folliculogenesis, typically one follicle achieves dominance, while the remaining follicles undergo atresia. Female meiosis, occurring during oogenesis, deviates from typical meiotic processes by incorporating a prolonged period of meiotic arrest, known as the dictyate stage, and by operating without the involvement of centrosomes.
In males, meiosis is integral to spermatogenesis, taking place within the seminiferous tubules of the testes. This meiotic process within spermatogenesis is confined to spermatocytes, which subsequently differentiate into spermatozoa. The meiosis of primordial germ cells commences at puberty, a significantly later developmental stage compared to females. Testicular tissues in males inhibit meiosis through the degradation of retinoic acid, a compound hypothesized to stimulate meiosis. This inhibition is circumvented at puberty when Sertoli cells, located within the seminiferous tubules, initiate endogenous retinoic acid synthesis. The responsiveness to retinoic acid is additionally modulated by proteins such as nanos and DAZL. Genetic investigations involving loss-of-function mutations in retinoic acid-synthesizing enzymes have demonstrated a postnatal requirement for retinoic acid in stimulating spermatogonia differentiation, which subsequently leads to spermatocytes entering meiosis several days later; however, retinoic acid is not essential for the initial onset of meiosis.
In female mammals, meiosis commences immediately following the migration of primordial germ cells to the embryonic ovary. Certain research indicates that retinoic acid originating from the mesonephros (primitive kidney) promotes meiosis in embryonic ovarian oogonia, while embryonic male testicular tissues inhibit meiosis by degrading retinoic acid. Nevertheless, genetic loss-of-function analyses of retinoic acid-producing enzymes have revealed that retinoic acid is not indispensable for the initiation of either female meiosis, which occurs during embryogenesis, or male meiosis, which begins postnatally.
Flagellates
Although most eukaryotes exhibit a two-divisional meiosis, occasionally achiasmatic, a highly uncommon variant known as one-divisional meiosis has been observed in certain flagellates (parabasalids and oxymonads) inhabiting the gut of the wood-feeding cockroach Cryptocercus.
Role in human genetics and disease
Recombination events occurring across the 23 pairs of human chromosomes facilitate the redistribution of both entire chromosomes and segments thereof. Furthermore, females exhibit an estimated 1.6-fold higher rate of recombination compared to males. Additionally, average female recombination rates are elevated at centromeres, whereas male recombination rates are higher at telomeres. Typically, one million base pairs (1 Mb) correlate with one centimorgan (cM), which represents a 1% recombination frequency. The precise frequency of crossover events remains undetermined. Estimates suggest that in yeast, mice, and humans, each meiotic cell generates at least 200 double-strand breaks (DSBs). Nevertheless, only a fraction of these DSBs (approximately 5–30%, varying by organism) ultimately lead to crossovers, resulting in merely 1-2 crossovers per human chromosome.
In humans, recombination rates differ between maternal and paternal DNA:
- Maternal DNA undergoes recombination approximately 42 times on average.
- Paternal DNA undergoes recombination approximately 27 times on average.
Nondisjunction
Meiotic errors, specifically nondisjunction, can produce gametes containing an aberrant number of chromosomes, thereby potentially causing chromosomal disorders.
Normal chromosomal segregation during meiosis I or sister chromatid separation in meiosis II is designated as disjunction. Conversely, abnormal segregation is termed nondisjunction. This anomaly leads to the formation of gametes possessing an aberrant number of chromosomes, either in excess or deficiency, constituting a frequent etiology for conditions such as trisomy or monosomy. Nondisjunction may manifest during meiosis I, meiosis II, or mitotic cellular division.
While the majority of human embryos exhibiting monosomy or trisomy are non-viable, certain aneuploidies are compatible with life, notably trisomy of chromosome 21, the smallest human chromosome. The phenotypic spectrum of these aneuploidies varies considerably, encompassing severe developmental impairments and asymptomatic presentations. Associated medical conditions comprise:
- Down syndrome: Characterized by trisomy of chromosome 21.
- Patau syndrome: Associated with trisomy of chromosome 13.
- Edwards syndrome: Defined by trisomy of chromosome 18.
- Klinefelter syndrome: Involves the presence of supernumerary X chromosomes in males, exemplified by karyotypes such as XXY, XXXY, or XXXXY.
- Turner syndrome: Characterized by the absence of one X chromosome in females, typically denoted as X0.
- Triple X syndrome: Defined by the presence of an additional X chromosome in females.
- Jacobs syndrome: Characterized by the presence of an additional Y chromosome in males.
The incidence of nondisjunction in human oocytes exhibits a positive correlation with advancing maternal age, hypothesized to result from the progressive degradation of cohesin complexes.
Comparative Analysis with Mitosis
To facilitate comprehension of meiosis, a comparative analysis with mitosis is beneficial. The subsequent table delineates the distinctions between these two cellular division processes.
Molecular Regulatory Mechanisms
Experimental investigations utilizing Xenopus laevis oocytes suggest a significant role for Maturation Promoting Factor (MPF) in meiosis. MPF derived from mammalian oocytes has been shown to induce germinal vesicle breakdown (GVB) in both starfish and Xenopus laevis oocytes. MPF activity is elevated preceding GVB but subsequently diminishes towards the conclusion of meiosis I. The concentrations of CDK1 and cyclin B correlate with oocyte GVB competence, indicating probable regulation at the translational rather than transcriptional level. During meiosis II, MPF activity re-emerges prior to metaphase II and persists at high levels until fertilization.
In mammals, meiotic arrest is initiated by natriuretic peptide type C (NPPC), secreted by mural granulosa cells, which, in conjunction with natriuretic peptide receptor 2 (NPR2) on cumulus cells, stimulates the production of cyclic guanosine 3′,5′-monophosphate (cGMP). Subsequently, cGMP permeates oocytes, arresting meiosis through the inhibition of phosphodiesterase 3A (PDE3A) and the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP). Within the oocyte, the G-protein-coupled receptor GPR3/12 activates adenylyl cyclase, leading to cAMP generation. cAMP then stimulates protein kinase A (PKA), which phosphorylates and activates the nuclear kinase WEE2. PKA additionally contributes to the phosphorylation of the CDK1 phosphatase CDC25B, retaining it within the cytoplasm; conversely, unphosphorylated CDC25B translocates to the nucleus. Protein kinase C (PKC) might also contribute to the inhibition of meiotic progression toward metaphase II. Collectively, CDK1 activity is suppressed, thereby preventing the resumption of meiosis. Oocytes further enhance the expression of NPR2 and inosine monophosphate dehydrogenase in cumulus cells, consequently increasing cGMP production. Similarly, follicle-stimulating hormone and estradiol stimulate the expression of both NPPC and NPR2. Hypoxanthine, a purine believed to originate within the follicle, also demonstrates inhibitory effects on in vitro oocyte meiosis. A surge in luteinizing hormone (LH) triggers oocyte maturation, facilitating the release of oocytes from meiotic arrest and their progression from prophase I through metaphase II. LH-induced epidermal growth factor-like factors, such as amphiregulin and epiregulin, synthesized in mural granulosa cells, decrease oocyte cGMP levels by impeding cGMP transport via cumulus cell-oocyte gap junctions and by diminishing NPPC levels and NPR2 activity. Indeed, these LH-induced epidermal growth factor-like factors may lead to the complete destabilization and breakdown of gap junctions. Furthermore, LH-induced epidermal growth factor-like factors can stimulate the production of other oocyte maturation factors in cumulus cells, including steroids and follicular fluid-derived meiosis-activating sterol (FF-MAS). FF-MAS facilitates progression from metaphase I to metaphase II and may contribute to the stabilization of metaphase II arrest. The resumption of meiosis is further supported by the nuclear export of WEE2, a consequence of CDK1 activation. Phosphodiesterases (PDEs) metabolize cAMP and can be transiently activated through PKA-mediated phosphorylation. Sustained regulation of phosphodiesterases, however, may necessitate the modulation of protein expression. For instance, hypoxanthine acts as a PDE inhibitor, potentially impeding cAMP metabolism. Various kinases, including protein kinase B, Aurora kinase A, and polo-like kinase 1, are implicated in the resumption of meiosis. Mechanistic parallels exist between meiotic prophase I arrest and resumption and the mitotic G2 DNA damage checkpoint, specifically involving CDC14B-based activation of APC-CDH1 for arrest and CDC25B-based resumption. Meiotic arrest necessitates the inhibitory phosphorylation of CDK1 at amino acid residues Thr-14 and Tyr-15 by MYT1 and WEE1, alongside the regulation of cyclin B levels mediated by the anaphase-promoting complex (APC). Cyclin B, whose synthesis culminates at the conclusion of meiosis I, regulates CDK1. During anaphase I, cyclin B undergoes degradation via an ubiquitin-dependent pathway. The synthesis of cyclin B and the activation of CDK1 induce oocytes to enter metaphase, whereas entry into anaphase occurs subsequent to ubiquitin-mediated cyclin B degradation, which reduces CDK1 activity. Proteolysis of adhesion proteins between homologous chromosomes is integral to anaphase I, while the proteolysis of adhesion proteins between sister chromatids characterizes anaphase II. Meiosis II arrest is mediated by cytostatic factor (CSF), which comprises the MOS protein, mitogen-activated protein kinase kinase (MAPKK/MEK1), and MAPK. The protein kinase p90 (RSK) represents a crucial target of MAPK and may impede entry into S-phase between meiosis I and II by reactivating CDK1. Evidence suggests that RSK facilitates entry into meiosis I by inhibiting MYT1, thereby activating CDK1. CSF-mediated arrest may occur via the regulation of the APC, functioning as a component of the spindle assembly checkpoint.
In the budding yeast S. cerevisiae, Clb1 functions as the primary meiotic regulatory cyclin, although Clb3 and Clb4 are also expressed during meiosis and activate a p34cdc28-associated kinase immediately preceding the first meiotic division. The IME1 transcription factor initiates entry into meiotic S-phase, with its regulation influenced by nutritional inputs. The a1/α2 complex represses a repressor of IME1, thereby initiating meiosis. Numerous meiotic regulatory genes have been identified in S. cerevisiae, including several key examples. IME1 facilitates sporulation in non-a/α diploids. IME2/SME1 promotes sporulation in the presence of nitrogen, supports recombination in a/α cells that express RME1 (a meiotic inhibitor), and encodes a protein kinase homolog. Similarly, MCK1 (meiosis and centromere regulatory kinase) also supports recombination in a/α cells expressing RME1 and encodes a protein kinase homolog. SME2 enables sporulation when ammonia or glucose are available. Furthermore, UME1-5 facilitate the expression of specific early meiotic genes in vegetative, non-a/α cells.
In the fission yeast S. pombe, the Cdc2 kinase and Cig2 cyclin collectively initiate the premeiotic S phase, whereas cyclin Cdc13 and the CDK activator Cdc25 are essential for both meiotic divisions. However, the Pat1-Mei2 system constitutes a central component of S. pombe meiotic regulation. Mei2 serves as the primary meiotic regulator, translocating between the nucleus and cytoplasm and collaborating with meiRNA to promote meiosis I. Additionally, Mei2 is implicated in mitotic exit and the induction of premeiotic S phase. Mei2 may inactivate the DSR-Mmi1 system by sequestering Mmi1, thereby stabilizing the expression of meiosis-specific transcripts. Mei2 can also induce growth arrest and G1 phase arrest. Pat1, a Ser/Thr protein kinase, phosphorylates Mei2, an RNA-binding protein, at residues Ser438 and Thr527. This phosphorylation event may reduce Mei2's half-life by increasing its susceptibility to degradation by a proteasome involving E2 Ubc2 and E3 Ubr1. The Mei4 transcription factor is indispensable for the transcriptional activation of cdc25 during meiosis, and a mei4 mutant exhibits cell cycle arrest. Mes1 inhibits the APC/C activator Slp1, which allows Cdc2-Cdc13 MPF activity to drive the second meiotic division.
The CEP1 gene product in yeast, which binds to the centromeric region CDE1, is hypothesized to contribute to chromosome pairing during meiosis I.
Meiotic recombination is facilitated by double-stranded breaks, which are catalyzed by the Spo11 protein. Mre11, Sae2, and Exo1 also contribute to DNA breakage and subsequent recombination. Following these breaks, homologous recombination typically occurs. This recombination can proceed via either a double Holliday junction (dHJ) pathway or synthesis-dependent strand annealing (SDSA). The latter pathway exclusively yields noncrossover products.
Meiotic cell division also appears to be subject to checkpoint control. In S. pombe, a checkpoint mechanism is believed to involve Rad proteins, S. pombe Mek1 (possessing an FHA kinase domain), Cdc25, Cdc2, and an unidentified factor.
In vertebrate oogenesis, the cytostatic factor (CSF) plays a crucial role in the transition into meiosis II.
References
References
Footnotes
Citations
Cited Texts
- Freeman S (2005). Biological Science (3rd ed.). Upper Saddle River, NJ: Pearson Prentice Hall. ISBN 978-0-13-140941-5.
- Meiosis Flash Animation Archived 2010-08-23 at the Wayback Machine
- Meiosis at Kimball's Biology Pages
- CCO The Cell-Cycle Ontology
- Stages of Meiosis animation
- "Abby Dernburg Seminar: Chromosome Dynamics During Meiosis"