An E. coli cell carries about 4300 genes, but making every protein all the time would waste energy and raw materials. When lactose becomes available, the cell starts making lactose-digesting enzymes within minutes; when the lactose is gone, it stops. Your own cells take this much further. Every cell in your body has the same genome, yet a pancreatic beta cell makes insulin and a developing red blood cell makes hemoglobin, because each cell type expresses a different subset of its genes. Gene regulation is how a cell decides which genes to express, when, and how much. The second half of this topic looks at what happens when the DNA sequence itself changes. A mutation is any permanent change in the DNA sequence. Most are harmless, some are harmful and a few are beneficial; together they are the raw material of evolution and the root cause of genetic disease and cancer.
Operons: gene control in prokaryotes
In bacteria, genes that work together are often grouped into an operon: a cluster of genes transcribed together as one mRNA and controlled by a single switch. An operon has a promoter (where RNA polymerase binds), an operator (a short DNA sequence between the promoter and the genes that acts as the on-off switch), and the structural genes themselves. A separate regulatory gene, with its own promoter, makes a repressor protein that can bind the operator and physically block RNA polymerase. The lac operon controls lactose use. Its three genes code for β-galactosidase (lacZ, which splits lactose into glucose and galactose), permease (lacY, which brings lactose into the cell) and transacetylase (lacA). With no lactose around, the repressor is active and sits on the operator, so transcription is off. When lactose is present, some of it is converted to allolactose, which binds the repressor and changes its shape so it can no longer grip the operator. RNA polymerase is now free to transcribe the genes. Because the substrate switches the genes on, the lac operon is inducible, and allolactose is its inducer.
| Glucose | Lactose | Repressor | CAP–cAMP | lac transcription |
|---|---|---|---|---|
| High | Absent | Bound to operator | Not bound (cAMP low) | Off |
| High | Present | Released by allolactose | Not bound (cAMP low) | Low |
| Low | Present | Released by allolactose | Bound (cAMP high) | High |
| Low | Absent | Bound to operator | Bound (cAMP high) | Off (the repressor still blocks) |
- Genes break down lactose (a catabolic pathway)
- Normally off
- Repressor is made in its active form and binds the operator on its own
- The inducer (allolactose) inactivates the repressor, switching the genes on
- Logic: make the enzymes only when there is lactose to digest
- Five genes (trpE, D, C, B, A) build the amino acid tryptophan (an anabolic pathway)
- Normally on
- Repressor is made in an inactive form and cannot bind the operator alone
- Tryptophan acts as a corepressor: it binds and activates the repressor, switching the genes off
- Logic: stop making tryptophan when there is already plenty
Gene regulation in eukaryotes
| Level | How it works | Example |
|---|---|---|
| Chromatin structure | Genes packed tightly in heterochromatin cannot be reached by RNA polymerase. Histone acetylation (adding acetyl groups) loosens packing and turns genes on. DNA methylation (adding methyl groups to cytosines) and removing acetyl groups tighten packing and silence genes. These epigenetic marks pass to daughter cells without changing the DNA sequence. | In female mammals one X chromosome in each body cell is condensed and silenced (a Barr body). |
| Transcription | General transcription factors must assemble at the promoter (for example at the TATA box). Specific activators bind distant enhancer sequences and loop the DNA to boost transcription; repressors bind silencers. Each cell type has its own mix of transcription factors. | Steroid hormones such as estrogen enter cells and bind receptor proteins that act as transcription factors. |
| RNA processing and mRNA lifetime | Alternative splicing makes different mRNAs from one gene. How long an mRNA survives in the cytoplasm also varies, and small RNAs (microRNAs) can bind an mRNA and block it or mark it for destruction. | One gene produces different forms of the muscle protein tropomyosin in different tissues. |
| Translation | Proteins or small RNAs bound to an mRNA can stop ribosomes from starting; initiation factors can be switched on or off. | When iron is scarce, a protein binds ferritin mRNA and blocks its translation, so the cell does not make iron-storage protein it cannot fill. |
| After translation | Many proteins are made inactive and must be cut, folded or chemically modified (for example, by adding phosphate) before they work. Proteins tagged with ubiquitin are destroyed by proteasomes, which controls how long they last. | Insulin is made as inactive proinsulin and is cut into its active form. |
Mutations
A point mutation changes a single nucleotide pair. A substitution swaps one base for another, and its effect depends on what happens to the codon: it is silent if the new codon codes for the same amino acid (thanks to redundancy), missense if it codes for a different amino acid, and nonsense if it becomes a stop codon and cuts the protein short. Insertions and deletions add or remove nucleotides. Because the code is read in non-overlapping triplets from a fixed start, adding or removing one or two bases shifts the reading frame: every codon after the change is misread, which usually produces a garbled protein and an early stop codon. This is a frameshift mutation. Inserting or deleting exactly three bases (or any multiple of three) keeps the frame, so the protein simply gains or loses one amino acid. The most common cystic fibrosis allele, ΔF508, is a three-base deletion that removes one phenylalanine; the protein misfolds, but the rest of its sequence is intact.
| Type | Coding strand (normal: ATG GCA TGG CAG TTA) | Polypeptide (normal: Met–Ala–Trp–Gln–Leu) | Usual impact |
|---|---|---|---|
| Silent substitution | ATG GCG TGG CAG TTA | GCG is still Ala: Met–Ala–Trp–Gln–Leu | None |
| Missense substitution | ATG ACA TGG CAG TTA | ACA is Thr: Met–Thr–Trp–Gln–Leu | None to severe, depending on the new amino acid and where it sits |
| Nonsense substitution | ATG GCA TAG CAG TTA | TAG gives the stop codon UAG: Met–Ala, then stop | Usually severe: a shortened protein |
| Frameshift (insertion) | ATG GGC ATG GCA GTT A… | Met–Gly–Met–Ala–Val…: every codon after the insertion changes | Usually severe |
| Frameshift (deletion) | ATG CAT GGC AGT TA… (first G of GCA deleted) | Met–His–Gly–Ser… | Usually severe |
| In-frame deletion | ATG GCA CAG TTA (TGG deleted) | Met–Ala–Gln–Leu: one amino acid lost, the rest unchanged | Variable |
Larger changes are chromosomal mutations: a deletion loses a chromosome segment, a duplication repeats one, an inversion flips a segment end to end, and a translocation moves a segment onto a non-homologous chromosome. (In chronic myeloid leukemia, a swap between chromosomes 9 and 22 fuses two genes into one cancer-driving gene.) Mutations are spontaneous when they arise from normal cell processes, such as replication errors that escape proofreading or bases that change chemically on their own. They are induced when an outside agent, a mutagen, causes them. UV radiation makes adjacent thymines on the same strand bond to each other (thymine dimers), kinking the helix. Ionizing radiation (X-rays, gamma rays) breaks DNA strands and creates reactive free radicals. Chemical mutagens include compounds in tobacco smoke (such as benzo[a]pyrene, which binds to guanine), base analogues such as 5-bromouracil that resemble a normal base but mispair during replication, and intercalating agents that slip between base pairs and cause frameshifts. Location matters too: a somatic mutation affects only the descendants of one body cell and is not inherited, while a germ-line mutation in cells that make gametes can be passed to offspring.