Lesson 21: Nucleic Acids in Detail (HL) HL ONLY

This HL extension covers Theme A — nucleic acids in detail (HL only): the molecular architecture of DNA and RNA beyond the SL account, nucleosomes, and the fine structure of replication and gene expression that HL papers probe.

Nucleotide and strand structure in depth

A nucleotide = pentose sugar (deoxyribose in DNA, ribose in RNA — differing by the 2′ –OH group) + phosphate + nitrogenous base. Bases: purines (adenine, guanine — double-ring) always pair with pyrimidines (cytosine, thymine/uracil — single-ring), so the double helix keeps a constant 2 nm diameter; A=T is held by two hydrogen bonds, G≡C by three — so GC-rich DNA is thermally more stable (a fact used in PCR primer design and in explaining extremophile genomes). Nucleotides link by condensation between the phosphate of one and the 3′ carbon of the next sugar, forming the sugar–phosphate backbone with 5′ and 3′ ends; the two strands run antiparallel. Chargaff's rules (A = T, G = C in double-stranded DNA) were a key clue to pairing. Numbering matters in questions: replication and transcription enzymes are described by the carbons they act on (e.g. polymerase extends the free 3′ –OH).

From bases to chromosomes: nucleosomes

Eukaryotic DNA is packaged with histone proteins: ~147 base pairs wrap around an octamer of histones (two each of H2A, H2B, H3, H4) to form a nucleosome, with linker DNA and histone H1 stabilising the "beads on a string" 10 nm fibre, which coils further (30 nm fibre, loops, and ultimately the metaphase chromosome). Packaging is functional, not just storage: tightly packed heterochromatin is transcriptionally silent; looser euchromatin is accessible. Chemical tags change the packing without changing sequence: histone acetylation loosens (activates), DNA methylation (especially at CpG sites in promoters) silences. This is the physical basis of epigenetics — heritable changes in gene expression without changes in DNA sequence — explaining how identical twins diverge with age and how a liver cell and a neurone share a genome yet differ permanently. Some methylation patterns are reset between generations; others (genomic imprinting, e.g. the IGF2/H19 locus) are parent-of-origin specific — a favourite HL discussion of exceptions to simple Mendelian expectations.

Replication detail revisited

At HL you add: DNA primase creates the RNA primer (~10 nucleotides); single-strand binding proteins prevent re-annealing and protect single strands; topoisomerase II / DNA gyrase cuts and reseals DNA ahead of the fork to release supercoiling; the sliding clamp holds polymerase III on the template, hugely increasing processivity. Telomeres: because the lagging strand cannot be completed to the very end (the final primer leaves a gap), chromosomes shorten each division — the end-replication problem. The enzyme telomerase (a reverse transcriptase carrying its own RNA template) extends telomeres in stem cells, germ cells and — pathologically — most cancer cells, linking telomere biology to ageing (cells senesce when telomeres reach a critical length — the Hayflick limit) and to tumour immortality. Dolly the sheep's relatively short telomeres sparked debate about cloned-animal ageing — good evaluation material, with the later evidence mixed.

Gene expression control points (HL)

Eukaryotes regulate at many levels: chromatin accessibility (above), transcription initiation (transcription factors, enhancers/silencers, mediator complex), mRNA processing (alternative splicing — Lesson 7), mRNA stability, translation initiation, and post-translational modification. Only a minority of the genome codes for protein (~1.5% in humans); much of the rest is regulatory sequence, introns, structural DNA (centromeres, telomeres) and the remnants of evolution (pseudogenes) — a corrective to the old "junk DNA" dismissal, which examiners may use as a Nature of Science case: a label that slowed inquiry until evidence (e.g. ENCODE-era findings and conserved non-coding elements) accumulated.

Nature of Science / TOK link

The structure of DNA was solved by model-building from others' data — Franklin's Photo 51 (X-ray diffraction), Chargaff's ratios, and known chemistry — and its discovery story raises enduring TOK issues about data sharing, credit and the interpretation of evidence one did not personally collect. Also note: the "double helix" is a model at several levels — base-pair geometry is measured; the iconic twisted ladder is a representation that hides dynamics (breathing, bending, protein binding) that HL biology must restore.

Common mistakes (from examiner reports)

• Pairing purine with purine or giving A=T three hydrogen bonds.
• Confusing nucleosome components (DNA + histones, not "chromatin proteins" vaguely).
• Claiming telomerase "prevents ageing" generally — it acts in specific cell types; somatic cells mostly lack it, which is linked to senescence.
• Describing methylation as a mutation (sequence is unchanged).

IB Exam Experience

Paper 1 style. 1. How many hydrogen bonds join a G–C base pair? A. One B. Two C. Three D. Four 2. A nucleosome consists of DNA wrapped around… A. ribosomes B. an octamer of histones C. a single polymerase D. a centromere 3. Telomerase is important in cancer cells because it… A. repairs all mutations B. maintains telomeres, allowing unlimited division C. speeds up the cell cycle checkpoints D. produces ATP Answer key. 1 — C. 2 — B. 3 — B. Paper 2 style. A DNA sample contains 18% adenine. (a) Calculate the percentage of guanine. [2] (b) Explain, with reference to base pairing, why GC-rich DNA denatures at a higher temperature than AT-rich DNA. [2] (c) Outline how nucleosomes contribute to the regulation of gene expression. [3] *Marking notes.* (a) A = T = 18%, so A+T = 36%; G+C = 64%; G = 32% [2]. (b) G≡C pairs have three hydrogen bonds vs two in A=T [1]; more bonds require more thermal energy to separate the strands [1]. (c) DNA wound on histones is inaccessible to transcription machinery/RNA polymerase [1]; tight packing (heterochromatin) silences genes [1]; modification such as histone acetylation loosens packing and permits expression (or methylation silences promoters) [1]. IA idea. A database investigation: download GC content and optimal growth temperatures for a set of bacterial genomes and test the hypothesis that thermophiles have GC-richer genomes — evaluating the mixed published evidence critically.

Extended data: chromosome counts and genome sizes — the C-value paradox

Genome size does not track organismal complexity, a result that surprises every cohort and is therefore examined. Haploid genome sizes: *E. coli* ~4.6 Mb; yeast ~12 Mb; *Drosophila* ~180 Mb; human ~3,200 Mb; the lily ~100,000 Mb; the amoeba *Polychaos dubium* reportedly ~670,000 Mb. If genome size equalled complexity, lilies would be thirty times more "advanced" than humans. The resolution is composition: in large genomes, most DNA is non-coding — introns, regulatory regions, repetitive sequences and transposable elements ("jumping genes", ~45% of the human genome derives from them) accumulated to different degrees in different lineages; pufferfish, with a similar gene count to ours, run an unusually compact ~400 Mb genome. The IB takeaway is precise language: gene number (~20,000 in humans) and genome size are different variables; information content relates to regulation and splicing (Lessons 7, 21) more than to raw DNA mass. Data questions present C-values across species and ask for exactly this evaluation — describe the lack of correlation, then explain it compositionally, then note the exception that proves informative (bacteria, under strong streamlining selection, do show tight genome–function coupling).

Epigenetics in the Dutch Hunger Winter — evidence and its limits

In the winter of 1944–45, a Nazi blockade starved the western Netherlands; researchers later studied adults who had been exposed to famine *in utero*. Those exposed in early gestation showed, six decades later, measurably lower methylation at the IGF2 gene locus (a growth-regulating, imprinted gene) than their unexposed same-sex siblings — a durable molecular trace of an environmental exposure, laid down when the epigenome is being established. The study is a model of careful inference: sibling controls reduce genetic confounding; the effect was locus-specific and timing-specific (early, not late, gestation), matching the developmental mechanism proposed. It is equally a model of restraint: effect sizes are small, and headlines claiming "epigenetics proves trauma is inherited" outrun the evidence — human transgenerational epigenetic inheritance (beyond direct exposure of the fetus and its own germ cells) remains contested. Examiners reward students who can hold both: the mechanism is real, the grand claims are unproven. That two-handed grip is the Nature of Science stance this whole HL topic is designed to teach.

One more application: DNA methylation and the smoking signature

Epigenetics is measurable in the clinic: cigarette smoking leaves a reproducible methylation signature in blood DNA — most famously hypomethylation at a specific CpG site in the AHRR gene — which fades gradually after quitting, providing a molecular dosimeter of exposure that outperforms self-reported smoking histories in studies. Forensic and insurance implications follow immediately (a blood sample can reveal lifestyle history its donor did not disclose), which is why this example belongs in the HL classroom: one mechanism (methylation), three domains of knowledge (molecular biology, epidemiology, ethics of genetic privacy). For exam writing, it also corrects a lazy habit: "epigenetic" does not mean vague or Lamarckian — it names specific, assayable chemical marks on DNA and histones with specific inheritance behaviour (mostly reset between generations, stable through mitosis within a lifetime).

Examiner's lens: final drills (nucleic acids HL)

• Bond inventory of DNA, complete: within a nucleotide strand — covalent phosphodiester bonds; between strands — hydrogen bonds (2 per A=T, 3 per G≡C); within chromatin — DNA wound on histone octamers, two full turns ≈ 147 bp per nucleosome.
• Telomere arithmetic, once more: remaining divisions ≈ (current telomere length − critical length) ÷ loss per division. If a stem cell starts at 12 kb, loses 80 bp per cycle and senesces at 4 kb: (12,000 − 4,000) ÷ 80 = 100 divisions.
• Methylation vs mutation, permanently separated: methylation adds –CH₃ groups to bases (usually cytosine) without changing the sequence — expression changes, the code does not; that reversibility is why epigenetic states can reset between generations.
• Self-test: why do PCR primers for a GC-rich template need a higher annealing temperature? (GC pairs have three hydrogen bonds, so primer–template binding is stronger and melts higher.)