Meiosis

• 1. Introduction

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  Meiosis is the cell division that makes sex possible. It begins with one diploid cell that carries two copies of every chromosome, and it ends with four cells that each carry only one. To get there, the genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code along each strand. The result is a sperm or an egg that is genetically unlike either parent. When errors creep in, the cost is steep. Aneuploidy, an abnormal number of chromosomes, is the leading known cause of miscarriage and the most frequent genetic cause of developmental disabilities. So how does a single cell halve its chromosomes without losing the instructions a new life will need? Why does this process run on two divisions instead of one? And why did nature build something so error-prone into the foundation of every plant, animal, and fungus that reproduces sexually? The answers reach from a German biologist peering at sea urchin eggs to a protein the Japanese named after a guardian spirit.

• 2. Two Divisions, Four Cells

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  DNA replication comes first, during the S phase that can be called premeiotic or meiotic S-phase. Each chromosome is copied so it consists of two identical sister chromatids, held together by sister chromatid cohesion. What follows is not one division but two, meiosis I and meiosis II, with no second round of replication between them. Meiosis I is the reductional division. It separates homologous chromosomes, joined as tetrads, into two haploid cells that still carry chromatid pairs. Because the ploidy drops from diploid to haploid here, this is where the chromosome count is actually halved. Meiosis II is the equational division, mechanically similar to mitosis. The cohesion between sister chromatids is released and they segregate from one another, producing four haploid cells from the two made in meiosis I. Diploid human cells contain 23 pairs of chromosomes, 46 in total, including one pair of sex chromosomes, half maternal and half paternal. Meiosis produces gametes that each contain one set of 23 chromosomes. When an egg and a sperm fuse, the resulting zygote is diploid again, with mother and father each contributing 23. This same pattern, though not the same number, runs in every organism that uses meiosis.

• 3. The Long Prophase

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  Prophase I is by far the longest phase of meiosis, lasting 13 out of 14 days in mice. It unfolds in named substages, each describing how the chromosomes look. The first is leptotene, from Greek words meaning thin threads, where individual chromosomes become visible strands within the nucleus. Recombination is initiated here by the enzyme SPO11, which creates programmed double strand breaks, around 300 per meiosis in mice. Single stranded DNA filaments coated by RAD51 and DMC1 then invade the homologous chromosomes. Zygotene, meaning paired threads, brings the homologs much more closely and stably together in a process called synapsis, sometimes called the bouquet stage because the telomeres cluster at one end of the nucleus. Pachytene, meaning thick threads, is the stage at which all autosomal chromosomes have synapsed and crossing over is completed. Most breaks are repaired without forming crossovers, resulting in gene conversion, but at least one per chromosome forms a crossover that exchanges genetic information. During diplotene, meaning two threads, the synaptonemal complex disassembles and the homologs pull apart slightly, but stay bound at the chiasmata where crossing-over occurred. In human fetal oogenesis, all developing oocytes reach this stage and arrest before birth, a suspended state called the dictyotene or dictyate stage. It can last until puberty or even later. Diakinesis, meaning moving through, condenses the chromosomes further, the first point where all four parts of the tetrads are actually visible.

• 4. Sorting And Splitting

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  Homologous pairs line up along the metaphase plate during metaphase I, aligned by counterbalancing forces from microtubules emanating from the two kinetochores. The random orientation of each bivalent, independent of the others, is the physical basis of the independent assortment of chromosomes. In anaphase I, kinetochore microtubules shorten and pull the homologous chromosomes to opposite poles. Here meiosis breaks from mitosis. Only the cohesin from the chromosome arms is degraded. The cohesin around the centromere stays protected by a protein named Shugoshin, Japanese for guardian spirit, which keeps the sister chromatids from separating while the homologs are pulled apart. Telophase I ends the first division when chromosomes reach the poles, each daughter cell now holding half the chromosomes, each still a pair of chromatids. Cytokinesis does not fully complete, leaving cytoplasmic bridges that let the cytoplasm be shared until the end of meiosis II. In metaphase II, the new equatorial plate is rotated 90 degrees from meiosis I, perpendicular to the previous plate. Anaphase II cleaves the remaining centromeric cohesin, no longer shielded by Shugoshin, so the sister chromatids finally segregate. Telophase II decondenses the chromosomes and reforms the nuclear envelopes, producing four daughter cells. Human and mouse oocytes manage this without centrosomes. In mice, roughly 80 microtubule organizing centers form a sphere in the ooplasm and merge into a barrel shaped spindle.

• 5. The Engine Of Variation

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  New combinations of DNA created during meiosis are a major source of genetic variation, alongside mutation. The process generates diversity in two ways. The first is the Law of Independent Assortment, the random and independent distribution of chromosomes to each daughter cell. The second is crossing over, the physical exchange of homologous chromosomal regions during prophase I. Because of recombination, a single chromatid can carry a new mix of maternal and paternal information, and a single gamete can hold an assortment of maternal, paternal, and recombinant chromatids. This is the raw variation upon which natural selection can act. Recombination among the 23 pairs of human chromosomes redistributes not just whole chromosomes but pieces of each. There is an estimated 1.6-fold more recombination in females than in males. Maternal DNA recombines approximately 42 times on average, paternal DNA approximately 27 times. On average, 1 million base pairs correspond to 1 centiMorgan. Yet this exchange is not universal. In the oocytes of the silkworm Bombyx mori, meiosis is completely achiasmate, lacking crossovers, even though synaptonemal complexes are present during pachytene.

• 6. An Adaptation For Repair

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  Genetic recombination can be viewed as fundamentally a DNA repair process. When it happens during meiosis, the argument runs, it is an adaptation for repairing the genomic DNA passed on to progeny. The experimental hints are striking. Hydrogen peroxide causes oxidative stress and oxidative DNA damage. When the yeast Schizosaccharomyces pombe is treated with it, the frequency of mating and the formation of meiotic spores rises by 4 to 18-fold. Volvox carteri, a haploid green algae that is only facultatively sexual, can be induced by heat shock to reproduce by meiotic sex, and antioxidants inhibit that induction. The prophase I arrest in females may serve the same end. In humans, oocytes form between three and four months of gestation within the fetus and are present at birth. During the arrested dictyate stage, which may last for decades, four copies of the genome are present in the oocyte. That fourfold redundancy was proposed to provide the information needed to repair damage in the DNA of the germline. Prophase I arrested oocytes have a high capability for efficient repair, particularly of double-strand breaks. DNA repair capability appears to be a key quality control mechanism in the female germ line and a critical determinant of fertility.

• 7. Discovery And A Disputed Name

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  Sea urchin eggs gave up the secret first. In 1876 the German biologist Oscar Hertwig discovered and described meiosis. It was described again in 1883, at the level of chromosomes, by the Belgian zoologist Edouard Van Beneden, working with Ascaris roundworm eggs. Its meaning for reproduction and inheritance came later, in 1890, when German biologist August Weismann noted that two cell divisions were needed to turn one diploid cell into four haploid cells if the chromosome number was to be maintained. In 1911 the American geneticist Thomas Hunt Morgan detected crossovers in meiosis in the fruit fly Drosophila melanogaster, helping establish that genetic traits are carried on chromosomes. The word itself comes from the Greek meiosis, meaning lessening. J.B. Farmer and J.E.S. Moore introduced it to biology in 1905, but with the idiosyncratic spelling maiosis, proposing to apply the terms Maiosis or Maiotic phase to cover the two divisions that Flemming had called Heterotype and Homotype. The spelling was changed to meiosis by Koernicke in 1905 and by Pantel and De Sinety in 1906, to follow the usual conventions for transliterating Greek.

• 8. Across Life And Its Failures

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  Every sexually reproducing eukaryote uses meiosis, including animals, plants, and fungi, and it is essential for oogenesis and spermatogenesis. Archaea and bacteria do not, reproducing asexually by binary fission, though horizontal gene transfer moves DNA between them in a process sometimes called sexual. The shape of the life cycle varies. In the diplontic cycle, as in humans, diploid germ-line stem cells undergo meiosis to make haploid gametes. In the haplontic cycle of many fungi and protozoa, the zygote undergoes meiosis immediately. In the haplodiplontic cycle, the alternation of generations, meiosis produces spores rather than gametes. There are even oddities. A very rare one-divisional meiosis occurs in some flagellates, the parabasalids and oxymonads, from the gut of the wood-feeding cockroach Cryptocercus. The errors carry names. Nondisjunction, the failure of normal separation, leaves gametes with too many or too few of a chromosome, a common mechanism for trisomy or monosomy. Most monosomic and trisomic human embryos are not viable, but some aneuploidies are tolerated, such as trisomy of chromosome 21, the smallest chromosome. That condition is Down syndrome. Trisomy of chromosome 13 is Patau syndrome, and trisomy of chromosome 18 is Edwards syndrome. The probability of nondisjunction in human oocytes increases with maternal age, presumably due to the loss of cohesin over time, the same molecular glue that Shugoshin once stood guard over.