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Cellular Control

Part of Module 6: Genetics, evolution and ecosystems.

Every cell in an organism carries the same genome, yet a liver cell looks and behaves completely differently from a neurone. The explanation lies in gene expression — which genes are switched on or off at any given moment. This topic covers the mechanisms that control gene expression at multiple levels, from changes in the DNA sequence itself (mutations) through to post-translational protein modification. It also covers programmed cell death (apoptosis), which is as important to normal development as cell division.

Learning Objectives

ID Official specification wording Main teaching sections
6.1.1-lo-1 (a) types of gene mutations and their possible effects on protein production and function Gene Mutations
6.1.1-lo-2 (b) the regulatory mechanisms that control gene expression at the transcriptional level, post- transcriptional level and post-translational level Control of Gene Expression
6.1.1-lo-3 (c) the genetic control of the development of body plans in different organisms Homeobox Genes and Body Plan Control
6.1.1-lo-4 (d) the importance of mitosis and apoptosis as mechanisms controlling the development of body form. Apoptosis

Gene Mutations

A gene mutation is a change in the base sequence of DNA in a gene. Mutations can occur spontaneously during DNA replication or be induced by mutagens (e.g. ionising radiation, certain chemicals).

Types of Mutation

Type Description Effect on protein
Substitution (point mutation) One base pair is replaced by another Depends on which codon is affected
Insertion One or more base pairs are added to the sequence Frameshift — all codons downstream of the insertion are altered
Deletion One or more base pairs are removed Frameshift — all codons downstream of the deletion are altered

Insertions and deletions of one or two bases cause a frameshift: the reading frame is shifted, and every codon from that point onwards changes, usually producing a non-functional protein. Insertions or deletions of three bases add or remove one amino acid but do not cause a frameshift.

Categories of Substitution Mutation

Category Definition Example
Missense mutation Codon change results in a different amino acid being incorporated Sickle-cell anaemia: GAG → GTG in the β-globin gene; glutamic acid replaced by valine
Nonsense mutation Codon change introduces a premature stop codon mRNA translation terminates early → truncated, non-functional polypeptide
Silent mutation Codon change does not change the amino acid (due to degeneracy of the genetic code) Third base of codon is often interchangeable; same amino acid is coded for

Why Silent Mutations Are Possible

The genetic code is degenerate — most amino acids are coded for by more than one codon (e.g. leucine has six codons: UUA, UUG, CUU, CUC, CUA, CUG). A substitution at the third position of such a codon often codes for the same amino acid. A silent mutation therefore has no effect on the polypeptide sequence.

Effects of Mutations

Effect When it occurs
Neutral Mutation in non-coding DNA (introns, regulatory regions with no essential function); silent mutation; change in amino acid that does not affect protein function
Harmful Amino acid change alters protein structure → loss of function or gain of toxic function (e.g. cystic fibrosis: mutation in CFTR protein → misfolded protein retained in ER)
Beneficial Amino acid change improves protein function in a given environment (e.g. mutations that confer antibiotic resistance in bacteria; trichromatic vision in humans)

Whether a mutation is beneficial or harmful depends on the environment — the same mutation may be neutral in one context and advantageous or harmful in another.

Control of Gene Expression

Gene expression can be controlled at several levels: transcriptional, post-transcriptional and post-translational.

Transcriptional Control: The Lac Operon

The lac operon in E. coli is the classic example of transcriptional gene regulation. It controls expression of the enzymes needed to metabolise lactose only when lactose is available and glucose is absent.

Structure of the lac operon:

Component Location Function
Regulator gene Upstream of operon Codes for the repressor protein; constitutively expressed
Promoter 5' end of operon Binding site for RNA polymerase to initiate transcription
Operator Between promoter and structural genes Binding site for the repressor; blocks RNA polymerase when occupied
Structural genes lacZ, lacY, lacA Code for β-galactosidase (lactose hydrolysis), lactose permease (uptake), transacetylase

Regulation:

Situation 1 — High glucose, low lactose (genes OFF): - Repressor protein binds to the operator, blocking RNA polymerase from accessing the structural genes - No transcription; no lactose-metabolising enzymes produced

Situation 2 — Low glucose, high lactose (genes ON): - Lactose (acting as an inducer) binds to the repressor protein, changing its shape (allosteric change) - The modified repressor can no longer bind to the operator - RNA polymerase binds to the promoter and transcribes the structural genes - β-galactosidase and lactose permease are produced

The lac operon illustrates how inducible gene expression works: the gene is only expressed when its product is needed.

Catabolite repression — glucose suppresses the lac operon:

When glucose is present, E. coli preferentially uses it. The presence of glucose keeps cyclic AMP (cAMP) levels low. cAMP is required to activate the cAMP receptor protein (CRP) (also called catabolite activator protein, CAP). The CRP-cAMP complex binds to the promoter and greatly enhances RNA polymerase binding.

  • Glucose present, lactose absent: repressor bound to operator; cAMP low; CRP inactive → no transcription
  • Glucose absent, lactose present: repressor released by lactose; cAMP high; CRP-cAMP activates promoter → maximum transcription
  • Both glucose and lactose present: repressor released (lactose present), but cAMP still low → transcription occurs at only a low rate

Transcriptional Control: Transcription Factors

Transcription factors are proteins that bind to specific DNA sequences (particularly the promoter region) and either activate or inhibit transcription:

  • Activator transcription factors enhance binding of RNA polymerase, increasing transcription rate
  • Repressor transcription factors block RNA polymerase binding, decreasing transcription

Many developmental and environmental signals (hormones, growth factors) work by activating or inactivating specific transcription factors. For example, steroid hormones (which are lipid-soluble and can cross the plasma membrane) bind to intracellular receptor proteins that then act as transcription factors.

Epigenetics and Chromatin Remodelling

In eukaryotes, DNA is wrapped around histone proteins to form chromatin. The accessibility of DNA to RNA polymerase and transcription factors depends on how tightly chromatin is packed:

Form Description Effect on transcription
Heterochromatin Tightly packed chromatin Prevents RNA polymerase access; gene silenced
Euchromatin Loosely packed chromatin RNA polymerase accessible; active transcription

Histone modifications alter chromatin structure without changing the DNA sequence (this is epigenetic regulation):

Modification Effect on histone charge Effect on chromatin Effect on transcription
Acetylation Reduces positive charge Looser chromatin (euchromatin) Increased
Phosphorylation Reduces positive charge Looser chromatin Increased
Methylation No charge change; increases hydrophobic interactions Tighter chromatin (heterochromatin) Decreased

Histone modifications are reversible and allow gene expression to be dynamically regulated in response to signals without altering the DNA sequence itself.

Post-Transcriptional Control: mRNA Processing

After transcription, the primary mRNA transcript (pre-mRNA) is processed before it is translated:

  1. Capping: a 5' cap (modified guanosine) is added — protects mRNA from degradation and aids ribosome binding
  2. Polyadenylation: a poly-A tail is added to the 3' end — aids stability
  3. Splicing: non-coding regions (introns) are removed; coding regions (exons) are joined together to produce the mature mRNA

Alternative splicing allows different combinations of exons to be joined, producing different protein isoforms from the same gene — a major source of protein diversity.

Post-Translational Control

After translation, polypeptides can be modified to activate or inactivate them:

  • Phosphorylation: kinase enzymes add phosphate groups to specific amino acid residues, changing protein shape and activity (e.g. enzyme activation cascades triggered by cAMP)
  • Cleavage: inactive precursor proteins (zymogens, proproteins) are cleaved to produce the active form (e.g. proinsulin → insulin)
  • Glycosylation: carbohydrate groups added in the Golgi apparatus

Homeobox Genes and Body Plan Control

Homeobox (Hox) genes are a family of genes found in all animals that control the development of the body plan — the anterior-posterior axis, the formation of body segments and limbs.

  • Homeobox genes code for transcription factors containing a specific DNA-binding domain (the homeodomain, encoded by the ~180-nucleotide homeobox sequence)
  • These transcription factors bind to promoters of target genes and switch them on or off, determining which structures develop in which body region
  • In Drosophila and vertebrates, Hox genes are arranged in clusters with a spatial collinearity — genes at the 3' end of the cluster are expressed in anterior regions; genes at the 5' end in posterior regions
  • Mutations in Hox genes cause dramatic homeotic transformations — e.g. antennae developing where legs should be in Drosophila

Homeobox genes are highly conserved across animal phyla, suggesting they arose early in animal evolution and have been maintained by strong purifying selection.

Why homeobox genes are so conserved: a mutation would have large effects by altering the organism's body plan; many downstream genes would also be affected; such mutations are typically lethal and strongly selected against.

Why fruit flies (Drosophila) are used as model organisms for Hox gene research: - Fewer ethical concerns than using vertebrates - Low cost - Genetics and development are well understood - Rapid reproduction rate allows many generations in a short time - Simple body plan with clear segmentation - Mutations visible under a low-powered microscope

Apoptosis

Apoptosis is programmed cell death — an ordered, tightly regulated process of self-destruction. It is distinct from necrosis, which is accidental cell death resulting from physical or chemical damage.

Why Apoptosis Is Necessary

  • Development: Fingers and toes are sculpted by apoptosis — the web-like tissue between digits undergoes programmed death
  • Tissue homeostasis: Cell number must be kept constant; cells that have divided must be matched by cells dying
  • Immune system: Autoreactive T-lymphocytes that could attack self-tissue are eliminated by apoptosis during development
  • Cancer prevention: Cells with DNA damage are eliminated before they can proliferate; failure of apoptosis contributes to cancer

Process of Apoptosis

  1. The cell receives an intrinsic (DNA damage, mitochondrial dysfunction) or extrinsic (death receptor activation by death ligands) death signal
  2. Caspase protease enzymes are activated in a cascade
  3. Caspases break down the cytoskeleton and nuclear proteins
  4. DNA is fragmented by DNases (nucleosomal ladder pattern on gel electrophoresis)
  5. The cell shrinks and the plasma membrane blebs (forms vesicle-like protrusions)
  6. The cell fragments into apoptotic bodies — membrane-enclosed packages of cellular content
  7. Apoptotic bodies are engulfed by phagocytes (macrophages) and digested; there is no inflammatory response

Key distinction from necrosis: in apoptosis, the plasma membrane remains intact until the cell is phagocytosed, so cellular contents are not released. In necrosis, the plasma membrane ruptures and cytoplasmic enzymes are released, triggering inflammation.

Key Terms

  • Gene mutation: change in the base sequence of DNA within a gene.
  • Frameshift mutation: mutation caused by insertion or deletion that shifts the reading frame of downstream codons.
  • Missense mutation: substitution mutation that changes one amino acid in the polypeptide.
  • Nonsense mutation: substitution mutation that creates a stop codon and truncates translation.
  • Silent mutation: substitution mutation that does not change the amino acid sequence because of code degeneracy.
  • Lac operon: inducible gene-control system in E. coli that regulates lactose-metabolising enzymes.
  • Repressor protein: regulatory protein that binds to an operator and blocks transcription.
  • Transcription factor: protein that binds specific DNA sequences to increase or decrease transcription.
  • Alternative splicing: production of different mature mRNA molecules from the same pre-mRNA by joining different exon combinations.
  • Epigenetics: changes in gene expression that do not involve changes to the DNA sequence, such as histone modification.
  • Heterochromatin: tightly packed chromatin that blocks transcription.
  • Euchromatin: loosely packed chromatin that allows active transcription.
  • Histone acetylation: addition of acetyl groups to histones, reducing positive charge, loosening chromatin and increasing transcription.
  • Histone methylation: addition of methyl groups to histones, tightening chromatin and reducing transcription.
  • CRP (cAMP receptor protein): protein that, when bound to cAMP, activates transcription of the lac operon; mediates catabolite repression by glucose.
  • Post-translational modification: chemical change to a polypeptide after translation that alters its activity or function.
  • Homeobox gene: developmental control gene that codes for a transcription factor determining body plan.
  • Apoptosis: programmed, controlled cell death.
  • Caspase: protease enzyme that drives the ordered breakdown of the cell during apoptosis.

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