How Two Metres of DNA Fit Inside a Tiny Nucleus

Every cell in your body carries instructions written in DNA and passed from parents to children. Its structure, the way it is packed, and the experiments that proved it is the genetic material form the foundation of modern biology.

This part covers the double helix, DNA packaging, the evidence that DNA is the genetic material, and why DNA rather than RNA stores genetic information.

DNA is a polymer of nucleotides joined by phosphodiester bonds into a sugar-phosphate backbone; in the double helix two antiparallel chains are held together by hydrogen bonds between complementary bases — adenine with thymine and guanine with cytosine — and coil right-handedly with a pitch of 3.4 nm and a rise of 0.34 nm per base pair.

Polynucleotide chain:

- Each nucleotide has a nitrogenous base, a pentose sugar (deoxyribose in DNA) and a phosphate group
- Nucleotides join by 3'-5' phosphodiester bonds, giving a chain with a 5' phosphate end and a 3' OH end

The double helix:

- The two chains are antiparallel — one runs 5' to 3', the other 3' to 5'
- A pairs with T through two hydrogen bonds; G pairs with C through three
- One right-handed turn has about 10 base pairs, a pitch of 3.4 nm and a rise of 0.34 nm per base pair
- This explains Chargaff's rule: A equals T and G equals C

Worked example. Human diploid DNA has about $6.6\times 10^9$ base pairs, so its length is

$$6.6\times 10^9\times 0.34\times 10^{-9}\text{ m}\approx 2.2\text{ m}$$

An everyday example. A twisted rope ladder is a good picture — the sugar-phosphate backbones are the side ropes and the base pairs are the rungs.

The substance. G-C rich DNA is harder to separate, because each G-C pair holds three hydrogen bonds instead of two.

In prokaryotes, negatively charged DNA is held by positively charged proteins in a region called the nucleoid, while in eukaryotes DNA wraps around positively charged histone octamers to form nucleosomes, which coil further into chromatin — loosely packed, active euchromatin and densely packed, largely inactive heterochromatin.

Prokaryotes. There is no nucleus; DNA is organised in large loops held by proteins in the nucleoid.

Eukaryotes:

- Histones are rich in the basic amino acids lysine and arginine, so their positive charge binds negatively charged DNA
- Eight histone molecules form a histone octamer
- About 200 base pairs of DNA wrap around each octamer to form a nucleosome
- Further coiling, helped by non-histone chromosomal proteins, forms chromatin and, at metaphase, chromosomes

Euchromatin versus heterochromatin:

- Euchromatin — loosely packed, stains lightly, transcriptionally active
- Heterochromatin — densely packed, stains darkly, largely inactive

An everyday example. Winding a long thread neatly onto spools lets it fit into a small sewing box — histones act as the spools for DNA.

The substance. Packing also controls gene activity — genes locked in tightly packed heterochromatin are generally switched off.

Griffith showed that something from heat-killed virulent bacteria could transform harmless bacteria, Avery, MacLeod and McCarty identified that transforming principle as DNA by destroying other molecules with enzymes, and Hershey and Chase showed that only viral DNA, not protein, enters bacteria when viruses infect them.

Griffith's transforming principle in Streptococcus pneumoniae:

- The S strain, with a capsule, kills mice; the R strain, without one, does not
- Heat-killed S mixed with live R kills mice, and live S bacteria are recovered
- Some transforming principle from the dead S cells changed R bacteria into S

Avery, MacLeod and McCarty:

- Purified proteins, RNA and DNA from heat-killed S cells
- Proteases and RNases did not stop transformation, but DNase did
- So the transforming principle was DNA

Hershey and Chase with bacteriophages:

- One batch of viruses was grown with **radioactive phosphorus, ${}^{32}$P, labelling DNA; another with radioactive sulphur, ${}^{35}$S, labelling protein
- After infection, blending removed the viral coats and centrifugation** separated the bacteria
- Bacteria infected by ${}^{32}$P viruses were radioactive; those infected by ${}^{35}$S viruses were not
- So DNA enters the bacterium as the genetic material

An everyday example. A new instruction sheet slipped into a factory changes what the workers build — just as DNA entering a bacterium changes what the cell makes.

The substance. Sulphur labels protein and phosphorus labels DNA because proteins contain sulphur but no phosphorus, while DNA has phosphorus but no sulphur.

An ideal genetic material must replicate, stay chemically and structurally stable, allow slow change through mutation, and express itself as traits; RNA was probably the first genetic material, but DNA, being more stable, took over information storage while RNA kept its roles in expression and catalysis.

Criteria for genetic material:

- Able to replicate accurately
- Chemically and structurally stable
- Able to mutate slowly, providing variation for evolution
- Able to express itself as Mendelian characters

Why DNA is more stable than RNA:

- RNA's 2'-OH group on every ribose makes it reactive and easily broken
- DNA's complementary double strands resist damage and allow repair
- DNA contains thymine instead of uracil, adding stability

RNA world hypothesis:

- RNA can both store information and catalyse reactions, so it was probably the first genetic material
- DNA evolved from RNA through chemical changes that made it more stable

An everyday example. Keeping important certificates in a laminated file protects them, while photocopies are used for daily work — DNA is the laminated original, RNA the working copy.

The substance. RNA suits expression and DNA suits storage — the reactivity that makes RNA a good catalyst makes it a poor long-term archive.