Meiosis

Meiosis is the specialised form of nuclear division that produces haploid gametes from diploid germ cell precursors. It is the single mechanistic process that makes sexual reproduction genetically possible.

It consists of two sequential divisions, meiosis I and meiosis II, preceded by a single round of DNA replication. Its mechanics are best understood at the level of individual substages, since specific errors at specific substages produce specific, clinically recognisable outcomes.

Before meiosis begins, the diploid germ cell undergoes a single round of DNA replication during the S phase of the cell cycle. This duplicates each of its 46 chromosomes into two identical sister chromatids joined at a centromere.

The cell now contains 46 chromosomes, each composed of two chromatids. The total DNA content is 4N, twice the normal diploid DNA content, even though the chromosome number remains 46.

This single replication event is not repeated between meiosis I and meiosis II. This is the critical mechanical difference that allows the two sequential divisions of meiosis to reduce chromosome number, rather than simply duplicating the diploid state as mitosis does.

Meiosis I is termed the reductional division because it is the step at which chromosome number is actually halved. It separates homologous chromosome pairs (maternally and paternally derived versions of each chromosome) from one another, rather than separating sister chromatids.

Prophase I is by far the longest and most complex phase of meiosis. It is subdivided into five recognised substages.

• Leptotene: chromosomes begin to condense and become visible as thin threads.
• Zygotene: homologous chromosomes begin to pair along their length, a process called synapsis. A specialised proteinaceous structure, the synaptonemal complex, forms and physically holds the paired homologues in precise alignment.
• Pachytene: synapsis is complete. Each paired set of homologous chromosomes is now visible as a bivalent, or tetrad, since it comprises four chromatids in total. Crossing over occurs: the physical exchange of chromosomal segments between non-sister chromatids of the two homologous chromosomes, mediated by specific recombination enzyme complexes. This is the specific substage at which genetic recombination occurs.
• Diplotene: the synaptonemal complex breaks down and the homologous chromosomes begin to separate slightly. They remain attached only at the specific points, chiasmata, where crossing over occurred. In oocytes specifically, diplotene is the stage at which meiosis arrests for a prolonged period, in humans from before birth until shortly before ovulation, potentially decades later.
• Diakinesis: chromosomes reach maximum condensation and the nuclear envelope breaks down in preparation for metaphase.

Metaphase I follows. The paired homologous chromosome bivalents align at the metaphase plate. Each bivalent is oriented independently of every other bivalent, a property termed independent assortment.

Anaphase I separates the two homologous chromosomes of each pair from one another. Each homologue, still composed of two sister chromatids, moves to opposite poles of the cell. This is mechanistically distinct from mitotic anaphase, in which sister chromatids, not homologous chromosomes, separate.

Telophase I and cytokinesis complete the division. They produce two daughter cells, each now haploid in chromosome number (23 chromosomes). Each chromosome is still composed of two sister chromatids, giving a DNA content of 2N.

Meiosis II is termed the equational division because it is mechanically analogous to a standard mitotic division, separating sister chromatids from one another rather than homologous chromosomes, and it proceeds without any further round of DNA replication beforehand.

Prophase II, metaphase II, anaphase II, and telophase II follow the same general sequence as mitosis: chromosomes condense, align individually at the metaphase plate, sister chromatids separate and move to opposite poles, and the nuclear envelope reforms. The result is four haploid daughter cells in total from the original single diploid precursor, each containing 23 chromosomes, now single chromatids rather than paired sister chromatids, giving a final DNA content of 1N, true haploid content.

The overall numerical consequence of the two sequential divisions is that a single diploid germ cell, containing 46 chromosomes, gives rise to four haploid cells. Each contains 23 chromosomes, a single representative of each of the 23 homologous chromosome pairs present in the original diploid cell.

This halving is achieved specifically at meiosis I, through separation of homologous pairs. It is preserved, not further altered, through meiosis II, which simply distributes the already-halved chromosome complement between four final daughter cells.

Crossing over is the physical exchange of chromosomal material between non-sister chromatids of homologous chromosomes. It occurs during pachytene of prophase I. It is the specific mechanism that generates new combinations of alleles along a single chromosome, combinations that did not exist together on either parental chromosome before recombination.

The physical sites at which crossing over has occurred remain visible as chiasmata during diplotene and diakinesis. Typically at least one chiasma forms per chromosome pair.

Crossing over also serves an essential mechanical function beyond generating genetic variation. The physical connection provided by a chiasma is required to hold homologous chromosomes correctly aligned and paired until anaphase I.

A chromosome pair that fails to form any chiasma at all is at substantially increased risk of failing to segregate correctly. This contributes directly to nondisjunction.

Independent assortment is the random, independent orientation of each homologous chromosome pair at the metaphase I plate. The specific combination of maternal and paternal chromosomes distributed to a given daughter cell at the end of meiosis I is determined independently for each of the 23 chromosome pairs. All maternal or all paternal chromosomes are not kept together as a single block.

With 23 independently assorting chromosome pairs, independent assortment alone allows 2 to the power of 23 theoretically possible distinct chromosomal combinations. That is over 8 million distinct possible combinations from a single individual's gametes. This does not account for the additional variation introduced by crossing over.

Crossing over adds essentially limitless variation at the level of individual gene combinations within each chromosome. Which specific gamete participates in fertilisation adds further randomness.

Meiosis collectively ensures that genetically identical gametes are, for practical purposes, never produced. The same applies to genetically identical siblings, other than monozygotic twins.

Three distinct mechanisms operating during meiosis, taken together, are responsible for the genetic uniqueness of every gamete produced.

• Crossing over during pachytene of prophase I generates new allele combinations within individual chromosomes.
• Independent assortment during metaphase I generates new combinations of entire maternal and paternal chromosomes between different daughter cells.
• Random fertilisation is the essentially random pairing of one specific paternal gamete with one specific maternal gamete, out of the vast number of genetically distinct gametes each parent can produce. It provides a final additional layer of genetic variation at the point the two gametic contributions are actually combined.