Meiosis and the sources of genetic variation

Reduction division and the homologous pair

Meiosis produces haploid cells from a diploid cell through one round of DNA replication followed by two divisions. In meiosis I, homologous chromosomes pair and then separate. In meiosis II, sister chromatids separate. Crossing over and independent assortment generate different combinations of alleles in the products.

A human body cell carries 46 chromosomes as 23 homologous pairs: two copies of chromosome 1, two of chromosome 2, and so on, one member of each pair inherited from each parent. The two members of a pair are the same length and carry the same genes at the same loci, though they can differ in which alleles sit at those loci and in non-coding and structural sequence between them. Mitosis does not pair them; meiosis does, and the pairing is what makes the first division a reduction division.

The halving is necessary. If a sperm carrying 46 chromosomes fertilised an egg carrying 46, the zygote would have 92 and the next generation 184. Gametes are therefore haploid: one chromosome from each pair, 23 in total. The chromosomes are not discarded at random. A gamete missing chromosome 7 and carrying two copies of chromosome 12 lacks the genes of one chromosome and has an extra dose of another, and such gametes usually give inviable zygotes. Pairing the homologues and separating them gives each product exactly one representative of each pair.

Describe the drawing

Meiosis animated through six stages. Prophase one: two homologous pairs lie inside a cell, each chromosome already two chromatids, and one pair is crossed over at a chiasma marked in coral, and from then on one chromatid of each long chromosome carries a tip in the other colour. Metaphase one: both bivalents lie on the equator with spindle fibres running to poles on either side, and the maternal chromosome of one pair faces the opposite way to the maternal chromosome of the other. Anaphase one: whole chromosomes, still two chromatids each, are dragged to opposite poles. Metaphase two: two smaller cells, each with its chromosomes lined up singly on its own equator. Anaphase two: the centromeres divide and the chromatids separate. Finally four haploid cells, each carrying one long and one short chromosome in a different combination, two of the long ones with a swapped tip from the crossover.

DNA replication happens once, in the interphase before meiosis begins, and not again between the two divisions. So a cell entering meiosis has 46 chromosomes and 92 chromatids; the cells leaving meiosis I have 23 chromosomes and 46 chromatids each; the four cells leaving meiosis II have 23 chromosomes and 23 chromatids each. The chromosome number halves at the first division and the DNA content halves at both.

Homologous pair

Two chromosomes of the same length carrying the same genes at the same loci, one from each parent, though not necessarily the same alleles.

Diploid

Having chromosomes in homologous pairs, written 2n.

Haploid

Having one chromosome from each homologous pair, written n.

Bivalent

The structure formed when a homologous pair comes together in prophase I: two chromosomes, four chromatids.

Reduction division

A division that halves the chromosome number. Meiosis I is one; meiosis II is not.

Prophase I: pairing, and the exchange that follows

Prophase I is the longest and the most eventful stage in the whole process. The chromosomes condense as they do in mitosis, and each chromosome then aligns with its homologue along their whole length. That pairing is called synapsis, and the paired structure is a bivalent. Because both chromosomes were replicated in interphase, a bivalent contains four chromatids, which is why some books call it a tetrad.

While the homologues are aligned, chromatids break and rejoin. A chromatid of the maternal chromosome and a chromatid of the paternal chromosome, which are non-sister chromatids, break at the same point and each joins to the other's cut end. The point where they cross is a chiasma, plural chiasmata, and it is visible down a good microscope. When the bivalent later comes apart, the two chromatids that took part leave carrying a stretch of DNA from the other parent's chromosome.

Describe the drawing

Three panels reading left to right. On the left a bivalent: one cyan maternal chromosome and one amber paternal chromosome lying side by side, each drawn as two chromatids joined at a centromere, four chromatids in all. In the middle the two inner chromatids cross at a coral dot and continue up the other side, so each runs cyan below the crossing and amber above it or the reverse. On the right the four separated chromatids: one wholly cyan, one wholly amber, and two carrying a tip of the other colour.

After crossing over, sister chromatids are no longer genetically identical. A chromatid can carry the maternal allele of one gene and the paternal allele of a gene further along the same chromosome, a combination that existed on neither chromosome the cell started with. Crossing over is the only mechanism in meiosis that makes new combinations of alleles within a chromosome; without it, alleles of genes on the same chromosome would be inherited together.

Crossing over

The exchange of equivalent sections of DNA between non-sister chromatids of a homologous pair during prophase I.

Chiasma

The visible point at which two non-sister chromatids cross during a bivalent's crossover.

Recombinant

A chromatid, or an offspring, carrying a combination of alleles that neither parental chromosome carried.

Metaphase I and independent assortment

At metaphase I the bivalents move to the equator, and the second source of variation arises there. Each bivalent settles with one member facing one pole and the other facing the opposite pole, and the orientation of each bivalent is independent of the orientation of every other. That is independent assortment. Maternal and paternal chromosomes are therefore not kept together: a gamete can receive any mixture of the two.

Describe the drawing

Two metaphase plates side by side, each with a dashed equator and two homologous pairs lying across it. In the left plate the maternal cyan chromosomes of the two pairs face opposite ways; in the right plate the shorter pair has flipped, so both cyan chromosomes lie on the same side. Arrows lead from each plate down to the poles, and below sit four gametes, each holding one long and one short chromosome in a different colour combination.

number of chromosome combinations in a gamete = 2ⁿn is the haploid number: the number of homologous pairs. Crossing over is not included in this count, and makes the true figure much larger.

With n = 23, that is 2²³ = 8 388 608 different chromosome combinations a single human gamete could carry. Fertilisation is random, so any one of those sperm could meet any one of those eggs: 2²³ × 2²³ = 2⁴⁶, or about 7 × 10¹³ different zygotes from one couple, before crossing over is taken into account.

The number of metaphase I arrangements is not the same quantity as the number of gametes. An arrangement and its mirror image, with every bivalent flipped, produce the same pair of daughter cells, so the number of genuinely distinct metaphase I arrangements is 2ⁿ⁻¹. Each arrangement sends a different combination to each of the two poles, so 2ⁿ⁻¹ arrangements still give 2ⁿ kinds of gamete. Answer whichever the question asked for, and say which you have counted.

The second division, and the chromosome and chromatid counts

Meiosis II starts with two haploid cells whose chromosomes are still two chromatids each, and it does to them what mitosis would: chromosomes line up singly on a new equator, centromeres divide, chromatids are pulled apart. The outcome is four haploid cells. Because crossing over happened back in prophase I, the two cells produced from each meiosis I product need not be identical to each other either. Where the two chromatids of a chromosome differ, which one goes to which pole depends on how that chromosome orients at metaphase II, and each chromosome orients independently of the others: this is the random orientation of sister chromatids.

The counts are set out below for a cell with a diploid number of 8.

The chromosome number halves once, at the first division. The chromatid number halves twice, once at each division, because the cell divides in two each time; what the centromeres do at anaphase II is not to reduce that count but to turn each chromatid into a chromosome in its own right. A cell at the end of meiosis I is already haploid, even though it contains as much DNA as an unreplicated diploid cell. On a graph of DNA mass per cell against time, the mass doubles during interphase, falls back to the unreplicated diploid level when the cell divides at the end of meiosis I, and halves again when each cell divides at the end of meiosis II.

The differences between mitosis and meiosis are set out below.

In an unfamiliar life cycle, find meiosis by the chromosome number: it sits wherever a diploid stage gives rise to a haploid one, just as fertilisation sits wherever two haploid cells fuse. In many fungi and algae the zygote is the only diploid cell and undergoes meiosis at once, so the organism itself is haploid. In a fern or a moss, meiosis in the diploid generation makes haploid spores, which grow into a haploid generation that later makes gametes by mitosis.

The eight stages, and the structures involved in each

Meiosis is divided into eight named stages, four in each division. Three structures change alongside the chromosomes: the spindle, the nuclear envelope and the cell surface membrane. Interphase, when the DNA is replicated and the organelles are doubled, precedes meiosis and is not one of the eight stages.

Prophase I is the long one, and most of the machinery moves during it. The chromosomes condense and become visible, each already two chromatids joined at a centromere. Homologues pair as bivalents and cross over at chiasmata. The nucleolus disappears, the nuclear envelope breaks up into small vesicles, and a spindle of microtubules is built between two poles of the cell. In an animal cell a pair of centrioles moves to each pole and the spindle grows out from them; most plant cells have no centrioles at all, and the spindle is organised from a region at each pole without them.

Metaphase I: the bivalents move to the equator and settle there, each held by spindle fibres attached to its centromeres, with one member of every pair facing each pole. The nuclear envelope is gone. The orientation of each bivalent is independent of the others, which is independent assortment.

Anaphase I: the spindle fibres shorten and pull whole chromosomes, still two chromatids each, to opposite poles. The centromeres do not divide, and the chiasmata slip apart at the ends of the chromatids as the homologues separate.

Telophase I: the chromosomes arrive at the poles. In many species a nuclear envelope re-forms around each group and the chromosomes partly uncoil; in others neither happens and the cell goes straight on into the second division. The spindle breaks down either way. Cytokinesis usually follows, and it is the stage at which the cell surface membrane changes: in an animal cell a ring of protein filaments just inside the membrane contracts and draws it inwards as a cleavage furrow, deepening until the cell is pinched in two. A plant cell cannot be pinched, because its wall is rigid, so vesicles from the Golgi apparatus line up along the old equator and fuse into a cell plate that becomes the new cell surface membranes and, between them, the new wall.

A short gap called interkinesis may follow. No DNA replication occurs in it, and some species have no gap at all.

Prophase II: the chromosomes condense again; any nuclear envelope that re-formed breaks down once more; and a new spindle is built in each of the two cells, usually with its axis at right angles to the axis of the first one.

Metaphase II: the chromosomes line up singly on the equator of each cell, not in pairs, with spindle fibres from both poles attached to each centromere.

Anaphase II: now the centromeres divide. The spindle fibres shorten, the sister chromatids are pulled to opposite poles, and each one, once separated, is a chromosome in its own right.

Telophase II: the chromosomes reach the poles and uncoil, nuclear envelopes form around four haploid nuclei, the nucleoli reappear and the spindles break down. Cytokinesis, by furrow or by cell plate, completes four haploid cells. In a flowering plant those four are the products of a pollen mother cell in the anther, and they often stay together as a group of four for a while before separating.

Spindle

A framework of microtubules running between the poles of a dividing cell, which attaches to centromeres and moves the chromosomes.

Cytokinesis

The division of the cytoplasm that follows nuclear division: by a cleavage furrow in an animal cell and by a cell plate in a plant cell.

Cell plate

The line of vesicles that fuse across the equator of a dividing plant cell, forming the new cell surface membranes and the new cell wall between the daughter cells.

A stage can be identified from a photomicrograph in three steps. First, count the cells: two cells lying side by side, each with its own set of chromosomes, indicate the second division. Second, locate the chromosomes. Thick and tangled with the envelope breaking up indicates prophase; in a line across the middle, metaphase; strung out between the middle and the poles, anaphase; gathered in clumps at the poles, telophase. Third, for metaphase and anaphase only, separate the first division from the second. At metaphase I the chromosomes lie on the equator in homologous pairs, so the line is two chromosomes deep, while at metaphase II they lie in a single line. At anaphase I each moving object is a whole chromosome of two chromatids, often a V or a rod with a visible split along it; at anaphase II each is a single chromatid, and there are twice as many of them per cell as there are chromosomes in a gamete.

Three sources of variation, and non-disjunction

Sexual reproduction generates genetic variation at three points. Where a question asks how meiosis produces variation, name the first two; include the third where the question refers to sexual reproduction rather than to meiosis alone.

Crossing over in prophase I makes new combinations of alleles along a single chromosome. Independent assortment at metaphase I makes new combinations of whole chromosomes. Random fertilisation then combines any one gamete with any other. Mutation supplies the alleles that these three processes recombine; it is a separate process and is not a product of meiosis.

Separation sometimes fails. If a homologous pair does not separate at anaphase I, or a pair of sister chromatids does not separate at anaphase II, the result is non-disjunction: gametes with one chromosome too many and gametes with one too few. What those gametes give at fertilisation is the subject of the next section. The same failure at anaphase II affects only two of the four products rather than all four, which is a distinction some specifications ask you to draw.

Polysomy, monosomy and Turner's syndrome

A gamete produced by non-disjunction has n + 1 or n − 1 chromosomes. When it fuses with a normal gamete, the zygote has 2n + 1 or 2n − 1, and every cell that divides from it by mitosis carries the same count.

Polysomy is the presence of one or more extra copies of a chromosome; three copies is a trisomy. Monosomy is the presence of a single copy of a chromosome where there should be a pair. Both are changes in chromosome number by less than a whole set, called aneuploidy, and both are chromosome mutations rather than changes to a base sequence.

A karyotype is written as the total chromosome count followed by the sex chromosomes, with any other change after them. A typical female is 46,XX and a typical male 46,XY. A boy with Down's syndrome is 47,XY,+21, meaning 47 chromosomes with an extra chromosome 21, and a girl with Turner's syndrome is 45,X, meaning 45 chromosomes with a single X and no second sex chromosome.

Down's syndrome is the standard example of polysomy. In most cases the person has three copies of chromosome 21 in every cell, and in most of those the extra copy came from the egg. The risk rises with the mother's age, which is consistent with a non-disjunction that happens in the egg rather than the sperm.

The third copy of the genes on chromosome 21 raises the amount of many of their products, and that imbalance gives the features of the syndrome, which include learning difficulties that vary widely between people and a higher risk of heart defects present from birth.

Monosomy is far less often seen at birth, because losing one copy of a chromosome halves the dose of every gene on it. An embryo with a single copy of any autosome almost never survives to be born. The one complete monosomy regularly found in live births is a single X: Turner's syndrome, 45,X. Even so, most 45,X embryos are lost during pregnancy, and about one girl in every 2500 born has the condition.

Describe the drawing

A father with the chromosomes 46,XY at the top. Arrows lead to two kinds of sperm produced when his X and Y fail to separate at anaphase I: one carrying both X and Y, and one, marked O, carrying no sex chromosome. Each is fertilised by a normal egg carrying an X. The first gives a zygote 47,XXY, a male with Klinefelter's syndrome, an example of polysomy. The second gives 45,X, a female with Turner's syndrome, an example of monosomy, shown in coral. A line at the bottom notes that the same failure in a mother gives eggs with two X chromosomes and eggs with none.

A 45,X zygote forms when a gamete with no sex chromosome at all fuses with a normal gamete carrying an X. The gamete with no sex chromosome can be a sperm, when the father's X and Y failed to separate, or an egg, when the mother's two X chromosomes failed to separate. Either division of meiosis can be the one at fault.

The partner gamete from the same non-disjunction has the extra sex chromosome, and if it is fertilised it gives a polysomy instead, such as 47,XXY, which is Klinefelter's syndrome in a male.

A single X is survivable where a single autosome is not because a female cell already works with one active X. In each cell of a 46,XX female one of the two X chromosomes is largely switched off early in development, so a 45,X cell has close to the usual dose of most X-linked gene products.

A small number of genes on the X escape the switching off and are normally active in two copies; having one copy of these is thought to produce the features of the syndrome. SHOX, a gene that affects the growth of the long bones, is the one linked to short stature.

The usual features of Turner's syndrome are short stature and ovaries that do not develop normally, so that most girls with it do not go through puberty without hormone treatment and most are infertile. Some have a narrowing of the aorta or differences in the kidneys. Intelligence is usually within the normal range.

Non-disjunction

The failure of a homologous pair to separate at anaphase I, or of sister chromatids to separate at anaphase II, giving gametes with one chromosome too many or too few.

Polysomy

The presence of one or more extra copies of a chromosome in a cell, as in trisomy 21.

Monosomy

The presence of only one copy of a chromosome where a diploid cell should have a pair, as in 45,X.

Aneuploidy

A chromosome number that differs from the normal by less than a whole set.

Turner's syndrome

The condition of a female with a single X chromosome and no second sex chromosome, 45,X: a monosomy.

Down's syndrome

The condition of a person with three copies of chromosome 21: a trisomy, and so a polysomy.