Cell Division and Chromosomes

02. Cell Division and Chromosomes

Eukaryotic bodies grow and maintain their tissues by cell division, a tightly choreographed process that copies the genome and partitions it into new cells. This chapter follows a cell through the phases of its division cycle, the surveillance systems that guard each step, and the two kinds of nuclear division that produce somatic cells and gametes. It then covers how DNA is packaged, how chromosomes are organized and displayed, and what happens when chromosome segregation fails.

Cell Cycle Phases

The cell cycle is the ordered series of events by which a cell duplicates its contents and divides. It has two broad parts: interphase, the long period of growth and preparation, and the M phase, when the nucleus and cell actually divide. During G1 phase (first gap) the cell grows and works normally; during S phase (synthesis) DNA is replicated, so each chromosome becomes two identical sister chromatids joined at a shared centromere; during G2 phase (second gap) the cell grows further and verifies that replication finished cleanly. Cells that stop dividing leave the cycle into G0 phase, a resting state that may be permanent or reversible.

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Think of the cell cycle like preparing a birthday party. The cell spends most of its time getting things ready, growing, and making copies of everything it owns, and then a short burst of activity divides it into two. Copying the instruction book, the DNA, happens only once, and it must be finished before the cell can split. After the split, each daughter cell starts the same routine again.

Checkpoints and Regulation by Cyclins CDKs and p53

The cycle is driven by engines and slowed by brakes. The engines are cyclin dependent kinases (CDKs), enzymes that attach phosphate groups to target proteins, and their activating partners, cyclins, whose concentrations rise and fall through the cycle. CDK2 (gene CDK2, chromosome 12q13.2) drives entry into S phase, and CDK1 (gene CDK1, chromosome 10q21.2) drives entry into mitosis. The brakes are checkpoints, surveillance gates that halt the cycle when conditions are wrong: the G1/S checkpoint verifies that DNA is intact, the G2/M checkpoint verifies that replication is complete and undamaged, and the spindle assembly checkpoint delays anaphase until every chromosome is attached to the spindle.

Damage signals travel through a cascade. The ATM kinase (gene ATM, chromosome 11q22.3) signals DNA double strand breaks and activates CHEK2 (gene CHEK2, chromosome 22q12.1), which stabilizes the p53 protein (gene TP53, chromosome 17p13.1). p53 is a tumor suppressor whose functions are DNA damage response, cell cycle arrest, and apoptosis, the programmed death of damaged cells. The retinoblastoma protein (RB) (gene RB1, chromosome 13q14.2) blocks passage into S phase while unphosphorylated. Losing these brakes promotes cancer: loss of function of TP53 causes Li Fraumeni syndrome, an autosomal dominant condition with multiple cancers at young ages.

Common Mistake: A common error is to call cyclins enzymes. Cyclins are regulatory subunits whose levels rise and fall through the cycle; the catalytic kinase activity belongs to the CDK. A CDK without its cyclin partner is largely inactive.

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Checkpoints are like tollbooths on a highway. A car cannot pass a tollbooth until it has paid the fee, and a cell cannot move to the next phase until the tollbooth verifies that everything is in order, such as DNA that is fully copied and undamaged. If a problem is found, the gate stays down and the cell stops until the problem is fixed, or it destroys itself if the damage cannot be repaired. That is why cells with broken checkpoints can divide with damaged DNA, which is a step toward cancer.

Mitosis Stage by Stage

Mitosis is the nuclear division that produces two daughter nuclei genetically identical to the parent. In prophase, the duplicated chromosomes condense into visible rods and the spindle begins to form. In prometaphase, the nuclear envelope breaks down and spindle microtubules attach to each chromosome at its kinetochore, a protein structure on the centromere. During metaphase, chromosomes line up at the metaphase plate with sister chromatids facing opposite poles. Anaphase begins when the sister chromatids separate and are pulled to opposite poles; each separated chromatid now counts as one chromosome. In telophase, the chromosome sets arrive at the poles, the nuclear envelope reforms, and cytokinesis divides the cytoplasm, yielding two cells. A human cell with 2n = 46 chromosomes produces two daughters, each with 46 chromosomes.

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Mitosis is like photocopying a document and giving one copy to each of two coworkers. The pages are first neatly lined up down the middle of the table, and then each page is split so that one copy slides to the left and one to the right. Each side ends up with a complete set, so the two piles are identical. The cell then splits down the middle, and each half has a full set of instructions.

Meiosis I and II with Prophase I Substages

Meiosis is the specialized division that produces gametes with half the chromosome number of the parent. One round of DNA replication is followed by two consecutive divisions. Meiosis I separates homologous chromosomes, the two copies of each chromosome, one from each parent, and is called the reductional division because it halves the chromosome number. Meiosis II separates sister chromatids and is called the equational division. In humans, meiosis produces four sperm in males and one ovum plus polar bodies in females, each with n = 23 chromosomes.

Prophase I is divided into five substages. In leptotene, chromosomes condense and begin to find their partners. In zygotene, homologous chromosomes pair up gene by gene in a process called synapsis, forming a tetrad, a bundle of four chromatids. In pachytene, crossing over exchanges segments between nonsister chromatids. In diplotene, homologs begin to separate but stay attached at chiasmata, the visible sites of crossing over. In diakinesis, chromosomes condense further and the nuclear envelope breaks down.

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Meiosis is like sorting a deck of cards into four smaller hands. First the deck is copied once, and then the paired cards line up and swap a few pieces with each other. The pairs are then split between two piles, and each pile splits its copies one more time, so the deck ends as four piles that each hold half the original cards. Each final pile holds a different mix, which is why children of the same parents can differ from one another.

Crossing Over and Independent Assortment as Sources of Variation

Two mechanisms in meiosis generate genetic variation among gametes. The first, crossing over, exchanges segments between nonsister chromatids during prophase I, producing chromatids with new allele combinations, so one chromatid can mix maternal and paternal alleles. The second, independent assortment, is the random orientation of homologous chromosome pairs at metaphase I: each pair orients independently, so the number of possible chromosome combinations in gametes is 2^n, where n is the haploid number. For humans, 2^23 = 8,388,608, roughly 8.4 million combinations, and crossing over multiplies the possibilities far beyond that.

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Think of building a sandwich from a menu of ingredients. Independent assortment decides which bread, filling, and topping you pick, and crossing over is like swapping a slice from one sandwich with a slice from another before packing it. Both processes mix the ingredients in new ways, so nearly every sandwich comes out a little different. That is why two siblings, even with the same parents, are not identical.

Mitosis vs Meiosis Comparison

Mitosis and meiosis share the same core machinery but serve different purposes. Mitosis produces two genetically identical diploid cells for growth and repair; meiosis produces four genetically distinct haploid gametes. The differences are in the table.

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Mitosis is like making two photocopies of a page, and meiosis is like cutting the page into cards and shuffling them into four new hands. The photocopies are exactly like the original, while the card hands each hold half the page and come out mixed in different ways. Both processes start by copying the page once, but they divide it differently afterward.

Chromatin and Nucleosome Structure

The human genome is about 2 meters of DNA packed into a 10 micrometer nucleus, so packaging is essential. Chromatin is the DNA protein complex that fills the nucleus, and its repeating unit is the nucleosome: about 147 base pairs of DNA wrapped around a core of eight histone proteins, two each of H2A, H2B, H3, and H4, with linker histone H1 binding the DNA between nucleosomes. Nucleosome strings coil into a 30 nanometer fiber, which folds into the mitotic chromosome. Chromatin exists in two states: euchromatin, the less condensed form where genes are generally active, and heterochromatin, the more condensed, generally silent form that includes most centromeric and telomeric DNA. Chromatin state is controlled by chemical marks, including DNA methylation, maintained through division by DNA methyltransferase 1 (gene DNMT1, chromosome 19p13.2). A striking example is X chromosome inactivation in female cells, initiated by the long noncoding RNA from XIST (chromosome Xq13.2), which silences most genes on one X chromosome.

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Chromatin packaging is like winding a very long ribbon around many small spools. Each spool, the nucleosome, holds a short stretch of ribbon, and the spools line up along the ribbon like beads on a string. When the cell must divide, the beaded string is twisted and folded into a compact bundle, and when it needs to read a gene, that part of the string is loosened. The same ribbon is used, but how tightly it is wound controls what can be read.

Telomeres and Centromeres

Every chromosome carries two specialized regions with different jobs. Telomeres are the repeated sequences at the chromosome ends that protect the ends from degradation and from being mistaken for broken DNA. Because the replication machinery cannot copy the ends of linear DNA molecules, telomeres shorten with each division in most somatic cells. The enzyme telomerase counteracts this in germ cells and some stem cells: its RNA component (gene TERC, chromosome 3q26.2) carries the template for the repeats, and its catalytic reverse transcriptase (gene TERT, chromosome 5p15.33) elongates the telomere.

The centromere is the primary constriction of the chromosome, where sister chromatids stay attached and the kinetochore assembles during division. Its position is used for classification: metacentric (centromere near the middle), submetacentric (slightly off center), acrocentric (near one end), and telocentric (at the very end, not present in normal human chromosomes).

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A telomere is like the plastic tip on a shoelace, the aglet that stops the lace from fraying at the end. Every time the shoe is worn, the tips wear down a little, and telomeres wear down the same way with each cell division. The centromere, by contrast, is like the handle of a shopping bag, the one spot where the bag is meant to be lifted, which is exactly where the cell grabs the chromosome to pull it apart during division.

Karyotyping and Banding

A karyotype is an organized display of an individual's chromosomes, prepared from cells arrested at metaphase, when chromosomes are most condensed. Chromosomes are photographed through a microscope and arranged in homologous pairs by size and shape, with the sex chromosomes last. Banding techniques, such as Giemsa staining (G banding), produce light and dark stripes, called chromosome bands, unique to each chromosome, allowing identification, breakpoint assignment, and detection of deletions, duplications, inversions, and translocations. Karyotype notation lists total chromosome number and sex chromosomes: 46,XY for a typical male, 46,XX for a typical female, and forms such as 47,XXY and 45,X described next.

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Making a karyotype is like sorting a box of crayons by color and size before drawing. The cell is stopped at the moment its chromosomes are shortest and thickest, so they can be photographed clearly, and then each one is matched with its identical partner. The stripes on each chromosome, the bands, are like the pattern on a candy wrapper, unique to each kind, so a crayon with a missing stripe or an extra piece can be spotted easily.

Nondisjunction and Aneuploidy

Errors in chromosome segregation produce cells with the wrong chromosome number. Nondisjunction is the failure of chromosomes or sister chromatids to separate properly during anaphase. If it happens in meiosis I, both homologs move to the same pole, so one gamete receives both and the other receives none, a reciprocal pair of outcomes in a 1:1 ratio (sums to 2). If it happens in meiosis II, sister chromatids fail to separate, with the same net result.

Aneuploidy is a chromosome number that is not an exact multiple of the haploid number, such as a monosomy (one missing chromosome) or a trisomy (one extra chromosome). The most common viable autosomal aneuploidy is trisomy 21, the cause of Down syndrome, a chromosomal condition with intellectual disability, characteristic facies, and congenital heart disease. Trisomies of larger autosomes are usually lethal: Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) cause severe malformations and early lethality. Sex chromosome aneuploidies are tolerated much better: Turner syndrome (45,X) is a monosomy X with short stature and ovarian failure, and Klinefelter syndrome (47,XXY) carries an extra X chromosome with tall stature, small testes, and infertility. Most aneuploid embryos do not survive.

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Nondisjunction is like a mishap in a line dance. When the dancers are supposed to split left and right, sometimes the partners hold on too long and both end up on the same side, leaving the other side empty. If this happens while an egg or sperm is being made, one gamete gets two copies of a chromosome and the other gets none. A baby built from such a gamete has the wrong number of that chromosome.

Worked Example

Problem: A human cell with 2n = 46 completes a division. How many chromosomes does each daughter cell have after mitosis, and how many does each gamete have after a complete meiosis?

Given: Diploid number 2n = 46. Mitosis preserves the chromosome number; meiosis halves it.

Plan: For mitosis, each daughter receives the parental chromosome number. For meiosis, halve the diploid number, because two divisions follow one replication.

Solution: Mitosis: each daughter cell has 46 chromosomes, and with 2 daughters the total is 2 x 46 = 92. Meiosis: n = 2n / 2 = 46 / 2 = 23 chromosomes per gamete, and with 4 gametes the total is 4 x 23 = 92.

Answer: After mitosis each daughter cell has 46 chromosomes; after meiosis each gamete has 23.

Worked Example

Problem: Ignoring crossing over, how many chromosome combinations can one human produce in gametes by independent assortment?

Given: Human haploid number n = 23; each chromosome pair orients independently at metaphase I.

Plan: The number of combinations is 2^n, because each pair has two orientations.

Solution: 2^23 = 8,388,608, about 8.4 million. Crossing over multiplies this far beyond.

Answer: 8,388,608 combinations, about 8.4 million.

High-Yield:

• DNA replicates once before both mitosis and meiosis; the number of divisions that follow is what differs.
• Mitosis preserves chromosome number (2n to 2n); meiosis halves it (2n to n) because homologous chromosomes separate in meiosis I.
• Sister chromatids separate in anaphase of mitosis and in anaphase II of meiosis; homologs separate in anaphase I.
• The checkpoints to know are G1/S (is DNA intact), G2/M (is replication complete), and the spindle assembly checkpoint (are all chromosomes attached to the spindle).
• Nondisjunction yields disomic and nullisomic gametes; trisomy 21 (Down syndrome), Turner syndrome (45,X), and Klinefelter syndrome (47,XXY) are the classic viable outcomes.

Quick Review

• The cell cycle runs G1, S, G2, and M, with G0 as a resting state; DNA replicates once, in S phase.
• Cyclins activate CDKs: CDK2 drives entry into S phase and CDK1 drives entry into mitosis; p53, ATM, and RB are checkpoint regulators that halt the cycle on DNA damage.
• Mitosis runs prophase, prometaphase, metaphase, anaphase, and telophase, plus cytokinesis, producing two identical diploid cells.
• Meiosis runs two divisions with five prophase I substages, leptotene through diakinesis, producing four haploid gametes.
• Crossing over and independent assortment create variation; independent assortment alone gives 2^23 = 8,388,608 combinations, about 8.4 million.
• Nucleosomes wrap 147 base pairs of DNA around a histone octamer; telomeres protect chromosome ends, and telomerase (from TERC and TERT) extends them.
• A karyotype is a banded, ordered display of metaphase chromosomes; 46,XY and 46,XX are the typical human constitutions.
• Nondisjunction causes aneuploidy: trisomy 21 is Down syndrome, 45,X is Turner syndrome, and 47,XXY is Klinefelter syndrome.