Mitosis and meiosis both involve chromosome replication prior to cell division. However, the products of mitosis have the same ploidy as the initiating cell, while meiosis halves the cell’s ploidy. Furthermore, while mitosis gives rise to genetically identical products, meiosis generates genetic diversity to ensure that offspring are genetically different to their parents.
When it comes to cell division, most attention is particularly focused on what happens to chromosomes and chromosomal DNA in mitosis and meiosis. That is understand able because almost all of a cell’s DNA and genes are located in the chromosomes of the nucleus, and because there are very tight controls on the duplication and segregation of chromosomal DNA. In addition, however, mtDNA also undergoes replication, after which the mtDNA molecules need to be partitioned (segregated) between the daughter cells. As detailed below, the control over both the copy number and segregation of mtDNA is much less stringent than for chromosomal DNA.
Mitosis is the normal form of cell division
As an embryo develops through fetus, infant, and child to adult, many cell cycles are needed to generate the required number of cells. As many cells have a limited life span, there is also a continuous requirement to generate new cells, even in an adult organ ism. All of these cell divisions occur by mitosis, which is the normal process of cell division throughout the human life cycle. Mitosis ensures that a single parent cell gives rise to two daughter cells that are both genetically identical to the parent cell, barring any errors that might have occurred during DNA replication. During a human lifetime, there may be something like 1017 mitotic divisions.
The M phase of the cell cycle includes various stages of nuclear division ( prophase, prometaphase, metaphase, anaphase, and telophase), and also cell division (cytokinesis), which overlaps the final stages of mitosis (Figure 1). In preparation for cell division, the previously highly-extended, duplicated chromosomes contract and con dense so that, by the metaphase stage of mitosis, they are readily visible when viewed under the microscope.
Fig1. Mitosis (nuclear division) and cytokinesis (cell division). After S phase (in late interphase) each chromosome consists of two immensely long sister chromatids (not shown here) that are held together along their lengths by cohesin protein complexes. Then, in preparation for mitosis, the chromosomes begin to shorten and thicken. Early in prophase, centrioles (short, cylindrical structures composed of microtubules and associated proteins) begin to separate and migrate to opposite poles of the cell to form the spindle poles (SP). In prometaphase, the nuclear envelope breaks down, and the now highly-condensed chromosomes become attached at their centromeres to the array of microtubules extending towards the mitotic spindle. At metaphase, the chromosomes lie along the middle of the mitotic spindle, the equatorial plane, still with the sister chromatids bound together; at this stage most of the cohesin complexes have been removed, but residual cohesins at the centromere hold the duplicated DNA helices together. Removal of the residual cohesins at the centromere allows the onset of anaphase: the sister chromatids separate for the first time to form independent chromosomes, each with their own centromere. Later in anaphase, the centromeres are pulled by the microtubules of the spindle in the direction of opposing poles (arrows). The nuclear envelope forms again around the daughter nuclei during telophase, and the chromosomes decondense, completing mitosis. Before the final stages of mitosis, and most obviously at telophase, cytokinesis begins with constriction of the cell that will increase progressively to produce two daughter cells.
The chromosomes of early S phase have one DNA double helix but following DNA replication, two identical DNA double helices are produced. The two DNA helices are held together along their lengths by cohesins, protein complexes resembling the condensin proteins that compact chromatin. Precisely how the sister chromatids are held together by cohesins is uncertain. Three of the cohesin subunits can interact to form a large protein ring, and some models envisage cohesin rings encircling the two double helices to entrap them; other models imagine that cohesin rings form round the individual double helices and then interact to ensure that the two double helices are held tightly together.
Later, when the chromosomes undergo compaction in preparation for cell division, the cohesins are removed from all parts of the chromosomes apart from the centromeres. As a result, by prometaphase, when the chromosomes can now be viewed under the light microscope, individual chromosomes can now be seen to comprise two sister chromatids that are attached together at the centromere by the residual cohesin complexes that continue to bind the two DNA helices at this position.
Later still, at the start of anaphase, the residual cohesin complexes holding the sister chromatids together at the centromere are removed. The two sister chromatids can now disengage to become independent chromosomes that will be pulled to opposite poles of the cell and then distributed equally to the daughter cells (see Figure 1). Interaction between the mitotic spindle and the centromere is key to this process.
Note that we portray cell division here as being symmetrical, but some types of cell divisions, including many types of cell division in early development, and some stem cell divisions are asymmetric.
Meiosis is a specialized reductive cell division that gives rise to sperm and egg cells
Diploid primordial germ cells migrate into the embryonic gonad and engage in repeated rounds of mitosis, to generate spermatogonia in males and oogonia in females. Further growth and differentiation produce primary spermatocytes in the testis and primary oocytes in the ovary. This process requires many more mitotic divisions in males than in females, and likely contributes to sex differences in the mutation rate. The diploid spermatocytes and oocytes can then undergo meiosis, the cell division process that is designed to produce genetically unique haploid gametes. That is, each sperm cell produced by a man and each egg cell produced by a woman is designed to have a genome sequence that is unlike that of any other sperm or egg cell that they, or anybody else, produces.
Meiosis is a reductive division because it involves two successive cell divisions (meiosis I and II) but only one round of DNA replication. As a result, it gives rise to four hap loid cells. In males, the two meiotic cell divisions are each symmetrical, producing four functionally equivalent spermatozoa. Female meiosis is different because, at each meiosis, asymmetric cell division results in unequal division of the cytoplasm. The products of female meiosis I (the first meiotic division) are a large secondary oocyte and a small cell (polar body), which is discarded. During meiosis II, the secondary oocyte then gives rise to the large mature egg cell and a second polar body, which again is discarded (Figure 2).
Fig2. Male and female germ-line development and gametogenesis. (A) Diploid primordial germ cells migrate to the embryonic gonad (the male testis or the female ovary) and enter rounds of mitosis that establish spermatogonia (in males) and oogonia (in females). (B) These undergo further mitotic divisions, growth, and differentiation to produce diploid primary spermatocytes and diploid primary oocytes, which can enter meiosis. (C) Meiosis I. After DNA duplication, the cells become tetraploid but then divide to produce two diploid cells. In male gametogenesis, the cell division is symmetrical, generating identical, diploid secondary spermatocytes. In female meiosis I, by contrast, the division is asymmetric; the secondary oocyte is much larger than the first polar body, which is discarded. (D) Meiosis II. The diploid secondary spermatocyte and secondary oocyte divide without prior DNA synthesis to give haploid cell products. In male gametogenesis, this division is again symmetrical, producing two haploid spermatids from each secondary spermatocyte. In female meiosis II, the egg produced is much larger than the second (also discarded) polar body. (E) Maturation produces four spermatozoa and a single egg.
In humans, primary oocytes enter meiosis I during fetal development but are then all arrested at prophase until after the onset of puberty. After puberty in females, one primary oocyte completes meiosis with each menstrual cycle. Because ovulation can continue up to the fifth and sometimes sixth decades, this means that meiosis can be arrested for many decades in primary oocytes that are used in ovulation in later life. While arrested in prophase, the primary oocytes continue to grow to become large in size, acquiring an outer jelly coat and cortical granules, as well as reserves of ribosomes, mRNA, yolk, and other cytoplasmic resources that would sustain an early embryo. In males, huge numbers of sperm are produced continuously from puberty onward.
The second division of meiosis is identical to mitosis, but the first division has important differences. Its purpose is to generate genetic diversity, creating genetic differences between the daughter cells. This is done by two mechanisms: independent assortment of paternal and maternal homologs, and recombination.
Independent assortment
Every diploid cell contains two chromosome sets, and so has two copies (homologs) of each chromosome (except in the special case of the X and Y chromosomes in males). One homolog is paternally inherited and the other is maternally inherited.
During meiosis I the maternal and paternal homologs of each pair of replicated chromosomes undergo synapsis by pairing together to form a bivalent. (Although the X and Y chromosomes have very different sequences, they too can form a bivalent in male meiosis; see below.) Following DNA replication, the homologous chromosomes each comprise two sister chromatids, so each bivalent is a four-stranded structure at the metaphase plate. Spindle fibers then pull one complete chromosome (two chromatids) to either pole. In humans, for each of the 23 homologous pairs, the choice of which daughter cell each homolog enters is independent. This allows 223, or about 8.4 × 106, different possible combinations of parental chromosomes in the gametes that might arise from a single meiotic division (Figure 3).
Fig3. Independent assortment of maternal and paternal homologs during meiosis. The figure shows a random selection of just 5 of the 8,388,608 (223) theoretically possible combinations of homologs that might occur in haploid human spermatozoa after meiosis in a diploid primary spermatocyte. Maternally derived homologs are represented by pink boxes, and paternally derived homologs by blue boxes. For simplicity, the diagram ignores recombination.
Recombination The five stages of prophase of meiosis I (Figure 4) begin during fetal life and, in human females, can last for decades. During this extended process, the homologs within each bivalent normally exchange segments of DNA at randomly positioned but matching locations. At the zygotene stage (Figure 4B), a proteinaceous synaptonemal complex, consisting of proteins, forms between closely apposed homologous chromosomes. Completion of the synaptonemal complex marks the start of the pachytene stage (Figure 4C), during which recombination (crossover) occurs. Crossover involves physical breakage of the DNA in one paternal and one maternal chromatid, and the sub sequent joining of maternal and paternal fragments.
Fig4. The five stages of prophase in meiosis I. (A) In leptotene, the duplicated chromosomes, each with a pair of sister chromatids, begin to condense but remain unpaired (shown here are representative maternal and paternal chromosome 1 homologs, and maternal and paternal chromosome 7 homologs). (B) In zygotene, duplicated maternal and paternal homologs pair, to form bivalents comprising four chromatids. Pairing of homologous chromosomes leads to fusion of the maternal and paternal homologs (synapsis). (C) In pachytene, recombination (crossing over) occurs via the physical breakage and subsequent rejoining of maternal and paternal chromosome fragments. There are two crossovers in the bivalent on the left and one in the bivalent on the right. For simplicity, both crossovers on the left involve the same two chromatids. In reality, more crossovers may occur, involving three or even all four chromatids in a bivalent. (D) During diplotene, the homologous chromosomes may separate slightly, except at the chiasmata. (E) Diakinesis is marked by contraction of the bivalents and is the transition to metaphase I.
The mechanism allowing alignment of the homologs (Figure 4A and B) is not known, although such close apposition is required for recombination. Located at intervals on the synaptonemal complex are very large multiprotein assemblies, called recombination nodules, that may mediate recombination events. Recombined homologs appear to be physically connected at specific points. Each such connection marks the point of a crossover and is known as a chiasma (plural chiasmata). There are an average of 55 chiasmata per cell in human male meiosis, and around 90 or so chiasmata per cell in female meiosis, and most of these occur at recombination hotspots.
In addition to their role in recombination, chiasmata are thought to be essential for correct chromosome segregation during meiosis I. By holding maternal and paternal homologs of each chromosome pair together on the spindle until anaphase I, they have a role analogous to that of the centromeres in mitosis and in meiosis II. Children with incorrect numbers of chromosomes have been shown genetically to be often the product of gametes where a bivalent lacked chiasmata.
Meiosis II resembles mitosis, except that there are only 23 chromosomes instead of 46. Each chromosome already consists of two chromatids that become separated at ana phase II. However, while the sister chromatids of a mitotic chromosome are genetically identical, the two chromatids of a chromosome entering meiosis II (Figure 5) are usually genetically different from each other, as a result of recombination events that took place during meiosis I.
Fig5. Metaphase I to production of gametes. (A) At metaphase I, the bivalents align on the metaphase plate, at the center of the spindle apparatus. Contraction of spindle fibers draws the chromosomes in the direction of the spindle poles (arrows). (B) The transition to anaphase I occurs at the consequent rupture of the chiasmata. (C) Cytokinesis segregates the two chromosome sets, each to a different primary spermatocyte in males. Note that following recombination during prophase I (Figure4C), the chromatids share a single centromere but are no longer identical. (D) Meiosis II in each primary spermatocyte, which does not include DNA replication, generates unique genetic combinations in the haploid secondary spermatocytes. Only 2 of the possible 23 different human chromosomes are depicted, for clarity, so only 22 (= 4) of the possible 223 (8,388,608) possible combinations are illustrated. Although oogenesis can produce only one functional haploid gamete per meiotic division (see Figure 2), the processes by which genetic diversity arises are the same as in spermatogenesis.
In Figure 3, we illustrated how independent assortment of homologs (during ana phase I) would have an effect on genetic variation by itself alone. But if we include the additional effects of recombination between homologs (during prophase I), and consider just chromosome 1, the combined effects could produce the additional variation seen in Figure 6. The combined effects of independent assortment of homologs and recombination ensure that each gamete is genetically unique. Each man can produce vast numbers of genetically distinct gametes, but only a limited number of eggs are produced by a woman.
Fig6. Recombination superimposes additional genetic variation at meiosis I. Figure 3 illustrates the contribution to genetic variation at meiosis I made by independent assortment of homologs, but for simplicity it ignores the contribution made by recombination. In reality, each transmitted chromosome is a mosaic of paternal and maternal DNA sequences, as shown here.
X–Y pairing
maternal paternal sperm 1 sperm 2 sperm 3 sperm 4 sperm 5 During meiosis I in a human primary oocyte, each chromosome has a fully homologous partner, and the two X chromosomes synapse and engage in crossover just like any other pair of homologs. In male meiosis there is a problem. The human X and Y sex chromosomes are very different from one another. Not only is the X very much larger than the Y, but it has a rather different DNA content and very many more genes than the Y. Nevertheless, the X and Y do pair during prophase I, thus ensuring that at anaphase I each daughter cell receives one sex chromosome, either an X or a Y.
Human X and Y chromosomes pair end-to-end rather than along the whole length, thanks to short regions of homology between the X and Y chromosomes at the very ends of the two chromosomes. Pairing is sustained by an obligatory crossover in a 2.6 Mb homology region at the tips of the short arms, but crossover also sometimes occurs in a second homology region, 0.32 Mb long, at the tips of the long arms. Genes in the terminal X–Y homology regions have some interesting properties:
• They are present as homologous copies on the X and Y chromosomes
• They are mostly not subject to the transcriptional inactivation that affects most X-linked genes as a result of the normal decondensation of one of the two X chromosomes in female mammalian somatic cells (X-inactivation)
• They display inheritance patterns like those of genes on autosomal chromosomes, rather than X-linked or Y-linked genes
As a result of their autosomal-like inheritance, the terminal X–Y homology regions are known as pseudoautosomal regions. We will describe them in more detail in Chapter 13 when we consider how sex chromosomes evolved in mammals.
Mitosis and meiosis: the key similarities and differences
Mitosis involves a single turn of the cell cycle. After the DNA is replicated during S phase, the two sister chromatids of each chromosome are divided equally between the daughter cells during M phase. Meiotic cell division also involves one round of DNA synthesis, but this is followed by two cell divisions without an intervening second round of DNA synthesis, allowing diploid cells to generate haploid products. While the second cell division of meiosis is identical to that of mitosis, the first meiotic division has distinct features that enable genetic diversity to arise. This relies on two mechanisms: independent assortment of paternal and maternal homologs, as well as recombination (Table1).
Table1. COMPARING MITOSIS AND MEIOSIS
Mitochondrial DNA replication and segregation
In advance of cell division, mitochondria increase in mass, and mtDNA molecules replicate before being segregated into daughter mitochondria that then need to segregate into daughter cells. Whereas the replication of nuclear DNA molecules is tightly controlled, the replication of mtDNA molecules is not directly linked to the cell cycle.
Replication of mtDNA molecules simply involves increasing the number of DNA copies in the cell, without requiring equal replication of individual mtDNAs. That can mean that some individual mtDNAs might not be replicated and other mtDNA molecules might be replicated several times (Figure 7).
Fig7. Unequal replication of individual mitochondrial DNAs. Unlike in the nucleus, where replication of each chromosomal DNA molecule normally produces two copies, replication of mitochondrial DNA (mtDNA) is not so tightly regulated. When a mitochondrion increases in mass in preparation for cell division, the overall amount of mitochondrial DNA increases in proportion, but individual mtDNAs replicate unequally. In this example, the mtDNA with the green tag fails to replicate and the one with the red tag replicates to give three copies. Variants of mtDNA can arise through mutation so that a person can inherit a mixed population of mtDNAs (heteroplasmy). Unequal replication of pathogenic and nonpathogenic mtDNA variants can have important consequences.
Whereas the segregation of nuclear DNA molecules into daughter cells needs to be equal and is tightly controlled, segregation of mtDNA molecules into daughter cells can be unequal. Even if the segregation of mtDNA molecules into daughter mitochondria is equal (as shown in Figure 7), the segregation of the mitochondria into daughter cells is thought to be stochastic.
