Cell Communication and Cell Division

Your body contains tens of trillions of cells, and none of them acts alone: each one is constantly reading chemical messages and deciding whether to grow, divide, change its behavior or die. This chapter explains how cells receive and relay signals, how those signals control the cell cycle, what happens when that control fails in cancer, and how meiosis produces the genetic variety that sexual reproduction depends on.

Section 1Signals, receptors and signal transduction

Why and how cells talk

Cell signaling is ancient. Yeast cells of opposite mating types find each other by secreting chemical signals, and many bacteria use quorum sensing: they release small molecules whose concentration reports population density, and at high density the population switches on genes for biofilm formation, light production or toxin release. The signaling machinery of yeast and mammals is strikingly similar, suggesting it was present in their common ancestor.

In multicellular organisms, signals act over different distances:

• Direct contact. Cells connected by gap junctions (animals) or plasmodesmata (plants) pass small signaling molecules directly through the cytoplasm. In cell to cell recognition, membrane bound molecules on one cell bind receptors on an adjacent cell; immune cells and developing tissues communicate this way.
• Paracrine signaling. A cell secretes a local regulator, such as a growth factor, that acts on nearby target cells.
• Synaptic signaling. A nerve cell releases a neurotransmitter across a narrow synapse to a single target cell, a very fast, specific form of local signaling.
• Autocrine signaling. A cell responds to a signal it secreted itself, as some immune cells and many cancer cells do.
• Endocrine (hormonal) signaling. Specialized cells release hormones that travel through the blood to target cells anywhere in the body. Plants use hormones too, moving them through vascular tissue or diffusing them through the air (ethylene).

Whatever the distance, a cell responds only if it has the right receptor. Insulin floods through the entire bloodstream, but only cells bearing insulin receptors respond. This is the first source of specificity in signaling.

Three stages: reception, transduction and response

Much of what we know about signaling began with studies of how epinephrine (adrenaline) makes liver cells break down glycogen. Epinephrine activated the enzyme glycogen phosphorylase only in intact cells; the hormone never entered the cell, so something at the surface had to relay the message inside. From this work came a three stage model:

1. Reception. The signaling molecule, called a ligand, binds a receptor protein, changing the receptor's shape.
2. Transduction. The change in the receptor sets off a sequence of changes in a series of molecules, the signal transduction pathway, that converts the signal into a form that can bring about a response.
3. Response. The transduced signal triggers a specific cellular activity: activating an enzyme, rearranging the cytoskeleton, or turning on genes.

Receptors in the plasma membrane

Most signaling molecules are water soluble and too large or too polar to cross the membrane, so their receptors are transmembrane proteins. Ligand binding changes the receptor's shape or causes receptors to group together, and that change is passed inside. Three major classes are tested most often.

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors. Each is a single polypeptide that crosses the membrane seven times. On the cytoplasmic side it works with a G protein, a protein that binds the energy-rich nucleotide GTP. When the G protein holds GDP it is inactive. When a ligand binds the receptor, the receptor changes shape and causes the G protein to swap GDP for GTP. The activated G protein (specifically its alpha subunit) moves along the membrane and activates an enzyme, such as adenylyl cyclase. The G protein is also a GTPase: it hydrolyzes its own GTP to GDP within seconds and so turns itself off, which keeps the response brief unless the signal continues. GPCRs detect hormones such as epinephrine and glucagon, neurotransmitters, odors and light (rhodopsin in the eye is a GPCR). About a third of all prescription drugs act on GPCRs.

Receptor tyrosine kinases (RTKs) are membrane receptors with enzymatic activity. A kinase is an enzyme that transfers phosphate groups from ATP to a protein; tyrosine kinases attach them to the amino acid tyrosine. An RTK has a ligand binding site outside the cell, one helix crossing the membrane and a tail inside with several tyrosines. When ligands bind two receptor monomers, the two associate into a dimer. Each tail then phosphorylates tyrosines on the other tail (autophosphorylation). The fully activated receptor is recognized by specific relay proteins, each of which binds a particular phosphorylated tyrosine and becomes activated in turn. Because one RTK can activate ten or more different pathways at once, these receptors suit processes that need several responses together, such as cell growth and division. Insulin and many growth factors act through RTKs, and abnormal RTKs that dimerize without a ligand contribute to some cancers.

Ligand-gated ion channels are receptors that act as gates. When the ligand binds, the channel opens or closes, letting specific ions such as Na⁺, K⁺, Ca²⁺ or Cl⁻ flow through. The resulting change in ion concentration or membrane voltage is itself the signal. These receptors are essential in the nervous system: acetylcholine released at a neuromuscular junction opens such channels in the muscle cell, and the influx of sodium triggers contraction.

Intracellular receptors

Some signals are small or hydrophobic enough to cross the membrane. Steroid hormones (such as testosterone, estrogen and cortisol), thyroid hormones and the gas nitric oxide (NO) bind receptors in the cytoplasm or nucleus. A hormone-receptor complex typically acts as a transcription factor, a protein that binds specific DNA sequences and turns particular genes on or off. Testosterone, for example, enters a cell, binds its receptor in the cytoplasm, and the complex moves into the nucleus to activate genes that produce male sex characteristics. Responses through intracellular receptors are usually slower (hours) but longer lasting than those through membrane receptors, because they require making new proteins.

Transduction: phosphorylation cascades

Transduction usually involves several steps, and at each step a protein changes shape, most often by phosphorylation. In a phosphorylation cascade, an activated protein kinase phosphorylates and activates a second kinase, which activates a third, and so on, until the last protein in the series (often an enzyme or transcription factor) carries out the response. Most cytoplasmic kinases phosphorylate serine or threonine rather than tyrosine. One of the best studied cascades is the MAP kinase pathway, which runs from growth factor RTKs through the small G protein Ras and a three kinase relay to transcription factors that promote cell division.

Signals must be switched off as well as on. Protein phosphatases remove phosphate groups and inactivate kinases, so the activity of each relay protein depends on the balance between its kinase and its phosphatase. When the signal molecule leaves the receptor, the phosphatases win, and the pathway returns to its resting state, ready for the next signal.

Second messengers

Many pathways also use small, nonprotein, water soluble molecules or ions called second messengers (the extracellular ligand being the "first messenger"). Because they are small, they spread quickly through the cytosol.

Cyclic AMP (cAMP) was the first second messenger discovered. Adenylyl cyclase, activated by a G protein, converts ATP to cAMP, and the cAMP concentration can rise twentyfold within seconds. cAMP's main target is protein kinase A (PKA), which phosphorylates other proteins. In the liver, PKA starts a cascade that activates glycogen phosphorylase. The enzyme phosphodiesterase quickly converts cAMP to AMP, ending the signal; caffeine inhibits phosphodiesterase, prolonging cAMP signals. Some G proteins (inhibitory G proteins) lower cAMP instead.

Calcium ions are an even more widely used second messenger. Cells keep cytosolic Ca²⁺ very low by pumping it out of the cell and into the endoplasmic reticulum. In one common pathway, a GPCR activates the enzyme phospholipase C, which cleaves the membrane phospholipid PIP2 into two second messengers: diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 diffuses to the ER and opens a ligand-gated calcium channel, releasing Ca²⁺ into the cytosol. Calcium, often bound to the small protein calmodulin, then activates many proteins, while DAG together with Ca²⁺ activates protein kinase C.

Section 2Cellular responses and apoptosis

Nuclear and cytoplasmic responses

Every signal transduction pathway ends by regulating some activity in the cell. Many pathways end in the nucleus: the final activated molecule is a transcription factor that switches genes on or off, so the cell begins or stops making particular proteins. Growth factors that stimulate cell division typically work this way, through the MAP kinase cascade. Other pathways act in the cytoplasm, changing the activity of proteins that already exist: opening an ion channel, activating a metabolic enzyme such as glycogen phosphorylase, or reorganizing the cytoskeleton. When yeast cells receive mating factor, for example, their cytoskeleton directs growth toward the source of the signal, producing projections called shmoos that grow toward a cell of the opposite mating type.

Amplification

Multistep pathways do something a single switch cannot: they amplify the signal. Each activated enzyme catalyzes many reactions before it is switched off, so the number of activated molecules grows at every step. In the epinephrine pathway, a few hormone molecules activate many G proteins, each adenylyl cyclase makes many cAMP molecules, each PKA phosphorylates many kinases, and so on. In the end, one epinephrine molecule can lead to the release of hundreds of millions of glucose 1-phosphate molecules from glycogen. This is why hormones are effective at extremely low concentrations, often less than a billionth of a mole per liter.

Specificity and coordination

The same signal can produce very different responses in different cells. Epinephrine stimulates glycogen breakdown in the liver, speeds and strengthens the heartbeat, and constricts some blood vessels while dilating others, because each cell type carries a different set of receptors, relay proteins and response proteins. Pathways can branch, converge, and interact with one another (cross talk), and scaffolding proteins hold several relay proteins together, increasing the speed and accuracy of signaling.

A response must also stop. Ligands leave their receptors, G proteins hydrolyze their GTP, phosphodiesterase destroys cAMP, phosphatases remove phosphates and calcium is pumped back into the ER, so the cell always responds to the current level of the signal.

Apoptosis: programmed cell death

One of the most dramatic responses to a signal is the decision to die. Apoptosis is a regulated, orderly self-destruction program. The cell shrinks, its chromatin condenses and its DNA is chopped into fragments, its membrane forms bulges called blebs, and the cell breaks into membrane-enclosed apoptotic bodies. The cell also flips the phospholipid phosphatidylserine to the outer face of its membrane, an "eat me" signal that tells phagocytes to engulf the remains. Because the contents never spill into the surrounding tissue, apoptosis does not cause inflammation.

Apoptosis is essential for normal life:

• Sculpting during development. Cells in the webbing between the developing fingers and toes die by apoptosis; when this fails, the digits remain joined. Many more neurons are produced in the developing brain than survive, and those that fail to make proper connections die.
• Removing dangerous cells. Cells with irreparable DNA damage, virus infected cells, and developing immune cells that would attack the body's own tissues are eliminated.
• Tissue turnover. Billions of cells die by apoptosis every day in an adult and are replaced by cell division.

The molecular basis of apoptosis was first worked out in the nematode Caenorhabditis elegans. Of the 1,090 somatic cells formed during the development of a hermaphrodite worm, exactly 131 die by apoptosis, always the same cells. Researchers identified genes required for this death: ced-3 and ced-4 (ced stands for "cell death") encode proteins that carry out apoptosis, while ced-9 encodes a protein on the outer mitochondrial membrane that acts as a brake. As long as Ced-9 is active, the cell lives; a death signal inactivates Ced-9 and releases the killing machinery. Ced-3 is a caspase, the main type of protease (protein cutting enzyme) that executes apoptosis.

The intrinsic and extrinsic pathways in mammals

Mammals use the same logic with many more players. Their apoptotic signals arrive by two main routes, both of which end by activating caspases.

The intrinsic (mitochondrial) pathway is triggered by signals from inside the cell, such as irreparable DNA damage (often detected through the protein p53), severe stress or the misfolding of proteins in the ER. Proteins of the Bcl-2 family control the outcome. Pro-apoptotic members such as Bax and Bak form pores in the outer mitochondrial membrane, while anti-apoptotic members such as Bcl-2 itself (the mammalian counterpart of Ced-9) block them. When pro-death signals win, cytochrome c leaks from the intermembrane space into the cytosol. There it combines with the protein Apaf-1 (the counterpart of Ced-4) to form a wheel-shaped complex called the apoptosome, which activates the initiator caspase-9. Notice that cytochrome c has two jobs: inside the mitochondrion it carries electrons in respiration (Chapter 3), and outside it triggers death.

The extrinsic (death receptor) pathway is triggered by signals from other cells. Immune cells such as cytotoxic T cells display a ligand (Fas ligand), and cells such as macrophages release tumor necrosis factor; these bind death receptors on the target cell, which recruit adapter proteins and activate the initiator caspase-8.

Both initiator caspases activate the executioner caspases (such as caspase-3), which cut hundreds of cellular proteins, activate nucleases that fragment DNA, and dismantle the cytoskeleton and nuclear lamina. Each caspase is made as an inactive precursor that must itself be cut to become active, and an active caspase can activate many more, so the process, once committed, proceeds rapidly and irreversibly.

Apoptosis compared with necrosis

Not all cell death is programmed. Necrosis is uncontrolled death from severe injury such as loss of blood supply, toxins or trauma. The cell swells, its organelles and membrane rupture, and the spilled contents trigger inflammation. A heart attack kills cardiac muscle mostly by necrosis.

Section 3The cell cycle and mitosis

Why cells divide, and what they must copy

"Every cell from a cell" is one of the founding ideas of biology. Cell division lets a single fertilized egg become a body of trillions of cells, replaces cells lost to wear and injury, and, in single-celled organisms, is reproduction itself. The life of a cell from its formation by division until its own division into two daughter cells is the cell cycle. To divide successfully, a cell must copy its DNA exactly and then separate the two copies so that each daughter cell receives one complete set.

A cell's total DNA is its genome. A human cell holds about 2 meters of DNA, packaged with proteins as chromatin and divided among chromosomes. Human somatic cells contain 46 chromosomes in 23 pairs; gametes (sperm and eggs) contain 23. Chromatin is spread out for most of the cycle and condenses into compact, visible chromosomes as the cell prepares to divide.

Before division, each chromosome is replicated. The duplicated chromosome consists of two identical sister chromatids, held together along their length by protein complexes called cohesins and most tightly at a constricted region called the centromere. On each side of the centromere sits a kinetochore, a protein structure where spindle microtubules attach. Counting is a frequent source of confusion: when sister chromatids are attached, they count as one chromosome. Only when they separate does each become a full chromosome.

Phases of the cell cycle

The cell cycle has two major parts. Interphase, usually about 90 percent of the cycle, is when the cell grows and copies its DNA. The mitotic (M) phase includes mitosis, the division of the nucleus, and cytokinesis, the division of the cytoplasm. Interphase has three subphases:

• G1 phase ("first gap"): the cell grows, makes proteins and organelles, and carries out its normal functions.
• S phase ("synthesis"): DNA is replicated, so each chromosome becomes two sister chromatids. The centrosome is also duplicated.
• G2 phase ("second gap"): the cell continues to grow and prepares for division.

The "gap" names are historical; the cell is busy throughout. For a typical human cell dividing in culture, the full cycle takes about 24 hours: G1 roughly 5 to 6 hours or more, S about 10 to 12, G2 about 4 to 6, and M less than 1 hour. Cells that are not dividing leave the cycle and enter a resting state called G0. Most adult nerve and muscle cells stay in G0 permanently, while liver cells can be called back into the cycle by growth factors after an injury.

The mitotic spindle

Many of the events of mitosis depend on the mitotic spindle, a structure of microtubules and associated proteins. In animal cells, spindle microtubules grow from the centrosome, a microtubule organizing region containing a pair of centrioles (centrioles are not essential; plant cells have centrosomes without them). The centrosome replicates during interphase, and as mitosis begins the two centrosomes move apart, each surrounded by a radial array of short microtubules called an aster. Three groups of microtubules form: kinetochore microtubules attach to chromosomes, nonkinetochore microtubules from opposite poles overlap in the middle of the cell, and astral microtubules anchor the poles to the cell cortex.

The stages of mitosis

Mitosis is a continuous process, but for study it is divided into five stages. The figure and table below summarize them; here is what happens and why.

Prophase. Chromatin fibers condense into discrete chromosomes, each consisting of two sister chromatids. The nucleoli disappear. The mitotic spindle begins to form as the centrosomes move apart.

Prometaphase. The nuclear envelope fragments, letting microtubules invade the nuclear area. Each chromatid now has a kinetochore, and some microtubules attach to them. Because the two sister kinetochores face opposite directions, each chromosome ends up attached to microtubules from both poles, and it is jerked back and forth in a tug of war.

Metaphase. The centrosomes are at opposite poles, and the chromosomes are lined up on the metaphase plate, an imaginary plane midway between the poles. This is usually the longest stage of mitosis, about 20 minutes, and it is the stage at which chromosomes are most condensed, which is why karyotypes are prepared from metaphase cells.

Anaphase. The shortest stage, often only a few minutes, begins when the enzyme separase cleaves the cohesins holding sister chromatids together. Each chromatid becomes a full-fledged chromosome. The kinetochore microtubules shorten by losing tubulin subunits at their kinetochore ends, and motor proteins at the kinetochore "walk" the chromosome toward the pole. At the same time, motor proteins push the overlapping nonkinetochore microtubules apart, elongating the cell. By the end of anaphase, each pole has an equivalent and complete collection of chromosomes.

Telophase. Two daughter nuclei form as nuclear envelopes reassemble from fragments of the parent's envelope and the endomembrane system. Nucleoli reappear, chromosomes decondense, and the spindle microtubules are depolymerized. Mitosis, the division of one nucleus into two genetically identical nuclei, is complete.

Cytokinesis

Cytokinesis usually begins during late telophase. In animal cells it occurs by cleavage. A shallow groove, the cleavage furrow, appears on the cell surface near the old metaphase plate. On the cytoplasmic side lies a contractile ring of actin microfilaments associated with myosin motor proteins. The ring contracts like a drawstring, deepening the furrow until the parent cell is pinched in two. Plant cells, which have rigid cell walls, cannot pinch. Instead, vesicles from the Golgi apparatus move along microtubules to the middle of the cell and fuse into a cell plate, which grows outward until it joins the parent's plasma membrane; a new cell wall forms between the daughter cells from the plate's contents.

Binary fission in prokaryotes

Bacteria and archaea reproduce by binary fission. Replication of the single circular chromosome begins at the origin of replication, and the two copies of the origin move toward opposite ends of the cell as the cell elongates. When replication is complete, the membrane pinches inward and a new wall forms. Prokaryotes have no spindle, but actin-like proteins help move the chromosomes and a tubulin-like protein (FtsZ) forms the dividing ring, hints of how the eukaryotic machinery evolved; some protists, such as dinoflagellates and diatoms, divide by intermediate mechanisms.

Section 4Regulation of the cell cycle and cancer

A control system with checkpoints

Skin and intestinal lining cells divide frequently, liver cells only when needed, and mature neurons not at all. The timing is set by a cell cycle control system of cytoplasmic molecules. Cell fusion experiments revealed it: fusing an S phase cell with a G1 cell made the G1 nucleus start replicating its DNA at once, and fusing an M phase cell with any other cell sent the second nucleus straight into mitosis.

The control system works like a timing device with built-in checkpoints, control points where stop and go signals regulate the cycle. Three are major:

• The G1 checkpoint (called the restriction point in mammals) seems to be the most important. If a cell receives a go-ahead signal here, it usually completes the whole cycle and divides. If not, it exits into G0. The checkpoint checks cell size, nutrients, growth factors and DNA damage.
• The G2 checkpoint checks that DNA replication is complete and that damage has been repaired before mitosis begins.
• The M checkpoint (spindle assembly checkpoint) delays anaphase until every chromosome is attached at its kinetochores to spindle microtubules from both poles. Unattached kinetochores send a "wait" signal that keeps an enzyme complex called the anaphase promoting complex inactive. Once all are attached, the complex triggers the destruction of the protein that has been inhibiting separase, separase cuts the cohesins, and anaphase begins. This checkpoint prevents daughter cells from receiving missing or extra chromosomes.

Cyclins and cyclin-dependent kinases

The cycle is driven by two kinds of regulatory proteins. Cyclin-dependent kinases (Cdks) are protein kinases that are present at fairly constant levels but are active only when attached to a cyclin, a protein named for its cyclically fluctuating concentration. Different cyclin-Cdk pairs act at different points in the cycle. The first to be discovered was MPF (maturation-promoting factor, also read as M-phase promoting factor), a complex of cyclin B and its Cdk. Cyclin is made steadily during interphase and accumulates; as it combines with Cdk, MPF activity rises and peaks at the start of mitosis. MPF phosphorylates many proteins, helping to fragment the nuclear envelope (by phosphorylating the lamins), condense chromosomes and assemble the spindle. During anaphase, MPF switches itself off by triggering the destruction of its own cyclin through the anaphase promoting complex. The Cdk persists, inactive, until new cyclin accumulates in the next cycle.

At the G1 checkpoint, cyclin D and its Cdks, made in response to growth factors, phosphorylate the retinoblastoma protein (Rb). Unphosphorylated Rb binds and holds a transcription factor called E2F; phosphorylated Rb releases it, and E2F switches on the genes needed for S phase. Rb is thus a brake on the cycle, and the cyclin-Cdk complexes release it.

Internal and external signals

The control system responds to signals from inside and outside the cell. A key internal signal is DNA damage. The protein p53 rises when DNA is damaged and acts as a transcription factor that switches on a Cdk inhibitor (p21), halting the cycle at G1; it also activates DNA repair genes and, if the damage is too great, triggers apoptosis. For this reason p53 is often called the "guardian of the genome."

External signals include growth factors, proteins released by certain cells that stimulate other cells to divide. More than 50 are known. Platelet-derived growth factor (PDGF), released by blood platelets at a wound, binds receptor tyrosine kinases on fibroblasts in connective tissue and stimulates them to divide and help heal the wound. Fibroblasts grown in a dish divide only if PDGF is added to the medium.

Two other external controls are visible in cultured cells. In density-dependent inhibition, crowded cells stop dividing: normal cells form a single layer and stop when they touch, and cells bordering a scraped gap divide until it is filled. In anchorage dependence, cells must be attached to a substrate, such as the extracellular matrix, to divide.

Cancer: cells that escape control

Cancer is a group of diseases in which cells escape the normal controls on division. Cancer cells do not show density-dependent inhibition or anchorage dependence; in culture they pile up in layers and keep dividing as long as nutrients are supplied. Many make their own growth factors, have abnormal signaling proteins that send "divide" signals without any factor, or have defective checkpoints. Cancer cells grown in culture can divide indefinitely, whereas normal mammalian cells stop after about 20 to 50 divisions.

The problem begins when a single cell undergoes transformation, the conversion to a cancerous cell. The immune system normally recognizes and destroys such cells, but if one evades destruction it may proliferate into a tumor, a mass of abnormal cells. If the abnormal cells remain at their original site, the lump is a benign tumor, which can usually be removed surgically. A malignant tumor invades surrounding tissues and can undergo metastasis, the spread of cancer cells through blood or lymph to form new tumors in distant parts of the body. Malignant cells often have abnormal chromosome numbers and recruit new blood vessels.

Genes that cause cancer: oncogenes and tumor suppressors

Cancer is fundamentally a disease of genes that control the cell cycle. Two broad classes are involved.

Proto-oncogenes are normal genes that code for proteins that stimulate cell division, such as growth factors, their receptors and relay proteins. A mutation that makes a proto-oncogene's product excessively active or abundant converts it into an oncogene (cancer gene). This can happen in three main ways: (1) a point mutation in the coding sequence produces a hyperactive or degradation-resistant protein; (2) gene amplification produces extra copies of the gene; or (3) a chromosomal translocation moves the gene next to an active promoter, or fuses it with another gene. Because the effect is a gain of function, a mutation in only one of the two copies is enough; oncogenes act like a car's accelerator stuck to the floor. The ras gene, which encodes the Ras G protein in the growth factor pathway, is mutated in about 30 percent of human cancers; the mutant Ras stays active and keeps signaling for division without any growth factor.

Tumor suppressor genes code for proteins that inhibit cell division, repair DNA or trigger apoptosis. Mutations that inactivate them contribute to cancer by a loss of function, so usually both copies must be inactivated before the cell loses control; they act like brakes that fail only when both are cut. The p53 gene (TP53) is mutated in roughly half of all human cancers, more than any other gene. Others include RB, whose loss in childhood causes the eye tumor retinoblastoma, and BRCA1 and BRCA2, which encode proteins needed to repair double-stranded DNA breaks.

Cancer develops in multiple steps

More than one mutation is needed to produce a cancer cell. In the best studied example, colorectal cancer, a normal lining cell first loses the tumor suppressor APC, producing a small benign growth (polyp). Over years, additional mutations, typically activation of the ras oncogene and loss of p53, convert it into a malignant tumor that can invade and metastasize. Cells along the way usually also activate the enzyme telomerase, which prevents the shortening of chromosome ends and lets them divide indefinitely. The requirement for several mutations, each occurring at a low rate, explains why the incidence of most cancers rises sharply with age.

About 5 to 10 percent of cancers involve an inherited predisposition. A person who inherits one mutant copy of a tumor suppressor gene starts with one "hit" already in every cell, so only one more mutation is needed in any cell. Women who inherit a mutant BRCA1 allele, for example, have a lifetime breast cancer risk several times that of the general population. Viruses can contribute too: human papillomavirus, which causes cervical cancer, makes proteins that inactivate p53 and Rb, which is why the HPV vaccine prevents most cervical cancers.

Section 5Meiosis and sexual life cycles

Heredity, genes and two kinds of reproduction

Offspring resemble their parents because they inherit genes, segments of DNA that are the units of heredity, each at a specific locus on a chromosome. In asexual reproduction, one parent passes copies of all its genes to its offspring by mitosis, producing a clone. In sexual reproduction, two parents give rise to offspring with unique combinations of genes, which requires a special division, meiosis, that halves the chromosome number.

Homologous chromosomes, ploidy and the karyotype

A karyotype is an ordered display of the chromosomes of a cell, usually prepared from cells arrested in metaphase and arranged in pairs by size, centromere position and banding pattern. In a human karyotype, the two chromosomes of each pair are homologous chromosomes (homologs): they have the same length, centromere position and staining pattern, and they carry genes for the same characters at the same loci. One homolog of each pair came from the mother and one from the father. The homologs may carry different versions (alleles) of a gene; for example, one may carry an allele for brown eyes and the other an allele for blue.

The two exceptions are the sex chromosomes, X and Y, which determine sex in humans. Females have a homologous pair of X chromosomes; males have one X and one Y, which share only a small region. The other 22 pairs are autosomes.

A cell with two sets of chromosomes is diploid (2n). For humans, n = 23 and 2n = 46. A cell with a single set is haploid (n); human gametes are haploid, containing 22 autosomes plus one sex chromosome. When a haploid sperm fuses with a haploid egg in fertilization, the resulting zygote is diploid. Meiosis is what keeps the chromosome number constant from generation to generation; without it, the number would double every time gametes fused.

Three types of sexual life cycle

All sexual life cycles alternate between meiosis and fertilization, but they differ in when these events occur and which stage is multicellular.

• Animals (gametic meiosis): meiosis in the gonads produces gametes directly, which undergo no further division before fertilization. The only haploid cells are gametes; the multicellular organism is diploid.
• Plants and some algae (alternation of generations): there are both diploid and haploid multicellular stages. The diploid sporophyte produces haploid spores by meiosis. A spore divides by mitosis into a multicellular haploid gametophyte, which makes gametes by mitosis. Fertilization yields a diploid zygote that grows into the next sporophyte.
• Most fungi and many protists (zygotic meiosis): the zygote is the only diploid stage. It undergoes meiosis immediately, producing haploid cells that grow by mitosis into a haploid multicellular (or unicellular) organism, which makes gametes by mitosis.

Note that either haploid or diploid cells can divide by mitosis, depending on the life cycle, but only diploid cells can undergo meiosis, because meiosis requires homologous pairs.

The stages of meiosis

Meiosis is preceded by interphase in which each chromosome replicates into two sister chromatids. It then consists of two consecutive divisions, meiosis I and meiosis II, producing four daughter cells, each with half as many chromosomes as the parent and each genetically unique.

Meiosis I separates homologous chromosomes.

• Prophase I is the longest and most complex phase, occupying 90 percent or more of the time of meiosis. Chromosomes condense, and each homologous pair comes together gene by gene in a process called synapsis, held by a zipper-like protein structure, the synaptonemal complex. The paired homologs (four chromatids in all) are called a bivalent or tetrad. Crossing over occurs: nonsister chromatids exchange corresponding segments of DNA, and the points where they cross remain visible as X-shaped regions called chiasmata after the complex disassembles. In humans, each pair typically has one to three crossovers.
• Metaphase I: the tetrads line up at the metaphase plate, with one homolog facing each pole. Both chromatids of one homolog attach to microtubules from one pole; those of the other homolog attach to the opposite pole.
• Anaphase I: the cohesins along the chromatid arms are cleaved, letting homologs separate and move toward opposite poles. Cohesins at the centromeres are protected, so sister chromatids stay together.
• Telophase I and cytokinesis: each half of the cell has a haploid set of chromosomes, but each chromosome still consists of two (no longer identical, because of crossing over) sister chromatids. In many species no DNA replication occurs before meiosis II.

Meiosis II separates sister chromatids. It closely resembles mitosis: in prophase II a spindle forms; in metaphase II chromosomes line up individually at the plate; in anaphase II the centromere cohesins are finally cleaved and sister chromatids move to opposite poles; in telophase II and cytokinesis, four haploid daughter cells form.

Comparing mitosis and meiosis

Three events are unique to meiosis, and all three occur during meiosis I: synapsis and crossing over in prophase I; the alignment of homologous pairs (rather than individual chromosomes) at the metaphase plate; and the separation of homologs rather than sister chromatids in anaphase I. Because meiosis I reduces the number of chromosome sets from two to one, it is called the reductional division; meiosis II, which separates sister chromatids as mitosis does, is the equational division.

Sources of genetic variation

Mutations are the original source of genetic diversity, creating different alleles. Sexual reproduction then shuffles those alleles into new combinations in three ways.

• Independent assortment of chromosomes. At metaphase I, each homologous pair orients randomly, with the maternal or paternal homolog equally likely to face either pole, independently of every other pair. With n pairs, the number of possible combinations in the gametes is 2ⁿ. For humans, 2²³ is about 8.4 million.
• Crossing over. By exchanging segments between maternal and paternal chromatids, crossing over produces recombinant chromosomes that carry combinations of alleles found in neither parent's original chromosomes. Because crossovers can occur at many points, this multiplies the possible gametes far beyond 8.4 million.
• Random fertilization. Any sperm can fuse with any egg. Even without crossing over, one human couple could produce a zygote with any of about 70 trillion (8.4 million × 8.4 million) chromosome combinations.

This variation is the raw material for natural selection (Chapter 8).

When meiosis goes wrong: nondisjunction

Occasionally the members of a homologous pair fail to separate in meiosis I, or sister chromatids fail to separate in meiosis II. This error is nondisjunction. One resulting gamete receives two copies of a chromosome and another receives none. If such a gamete joins a normal one, the zygote has an abnormal chromosome number, a condition called aneuploidy: a trisomy (2n + 1, three copies of one chromosome) or a monosomy (2n − 1). Most aneuploid embryos do not survive. The most common viable autosomal trisomy is trisomy 21, which causes Down syndrome; its frequency rises with maternal age, partly because human eggs remain arrested in prophase I from before the mother's birth until ovulation, and the cohesins holding the paired homologs together may deteriorate over decades. Aneuploidies of the sex chromosomes, such as XXY (Klinefelter syndrome) and a single X (Turner syndrome), are generally less severe. Chapter 5 returns to these disorders.

Words worth knowing