DNA & Inheritance
Usually weeks 1-3 of an immunology & genetics courseGenetics questions are pattern-recognition questions. The molecular half (replication, transcription, translation, mutation types) is a vocabulary you memorize once; the inheritance half is a small set of pedigree signatures you learn to spot in under ten seconds. Master the four Mendelian patterns and the non-Mendelian exceptions — mitochondrial, imprinting, anticipation — and most stems answer themselves before you read the choices.
This guide is the frame. The exam is written from your lectures— drop this topic's slides on the dashboard to get flashcards and board-style questions from your own course, and quiz them all term (one cumulative exam rewards nothing more than early, repeated self-testing). The immunology & genetics playbook has the weekly loop.
AI-authored study notes, not faculty-reviewed and not medical advice. Verify every mechanism against your course materials and faculty; programs differ in emphasis.
High-Yield Pearl
One instance of male-to-male transmission kills every X-linked answer choice — check for it before you analyze anything else on a pedigree.
What the exam asks
Mechanisms, patterns, and what happens when each one fails.
- DNA and RNA structure. DNA is an antiparallel double helix: purines (A, G) pair with pyrimidines (T, C) — A-T with two hydrogen bonds, G-C with three, so GC-rich DNA melts at a higher temperature. RNA is single-stranded, uses ribose and uracil in place of deoxyribose and thymine, and comes in three working forms: mRNA (the message), tRNA (the adaptor), and rRNA (the ribosome's catalytic core, and the most abundant).
- DNA replication. Semiconservative: each daughter helix keeps one parental strand. Helicase unwinds, primase lays an RNA primer, and DNA polymerase synthesizes only 5'→3' — continuously on the leading strand, in Okazaki fragments on the lagging strand, which ligase seals. Proofreading is the polymerase's 3'→5' exonuclease; telomerase (a reverse transcriptase) rebuilds chromosome ends in germ cells and stem cells.
- Transcription and RNA processing. RNA polymerase II reads the template strand 3'→5' to build mRNA 5'→3'; no primer needed. The eukaryotic pre-mRNA gets a 5' 7-methylguanosine cap, a 3' poly-A tail, and splicing — introns out, exons joined — by the spliceosome (snRNPs, the target of anti-Smith antibodies in lupus). Alternative splicing is why one gene can yield many proteins.
- Translation and the genetic code. Ribosomes read mRNA 5'→3' in triplet codons starting at AUG (methionine); UAA, UAG, and UGA stop. The code is degenerate (most amino acids have several codons, mostly differing at the wobble third position) and essentially universal. tRNA anticodons pair antiparallel with codons; the ribosome's A site accepts, P site holds the peptide, E site exits.
- Mutation classes. Silent: base change, same amino acid (usually third position). Missense: one amino acid substituted — conservative or non-conservative (sickle cell: Glu→Val in beta-globin). Nonsense: premature stop codon, truncated protein. Frameshift: insertion or deletion NOT a multiple of 3 shifts every downstream codon (Duchenne, Tay-Sachs). Splice-site mutations retain introns or drop exons (some beta-thalassemias). Severity generally: frameshift/nonsense > missense > silent.
- Autosomal dominant vs recessive. AD: affected individuals in every generation, male-to-male transmission possible, each child of an affected parent has a 50% risk; classically defects of structural or receptor proteins (Marfan, familial hypercholesterolemia, NF1) — Huntington is the AD exception that works by toxic gain of function. AR: skips generations, unaffected carrier parents, 25% risk per child of two carriers, consanguinity raises the odds; classically enzyme deficiencies (CF, sickle cell, phenylketonuria, Tay-Sachs). Two carriers: 1/4 affected, 1/2 carriers, 1/4 unaffected.
- X-linked inheritance. X-linked recessive: affects mostly males, no male-to-male transmission (a father gives sons his Y), transmitted through carrier mothers — half their sons affected, half their daughters carriers (Duchenne, hemophilia A/B, G6PD deficiency). X-linked dominant: affected fathers pass it to ALL daughters and NO sons (hypophosphatemic rickets); some, like Rett, are typically lethal in males. Skewed lyonization explains symptomatic female carriers.
- Non-Mendelian inheritance. Mitochondrial: transmitted only through the mother, affects offspring of both sexes; variable severity from heteroplasmy (MELAS, LHON). Imprinting: expression depends on parent of origin — deletion of paternal 15q11-13 gives Prader-Willi, deletion of the maternal copy gives Angelman. Trinucleotide repeat expansion with anticipation: earlier, more severe disease each generation (Huntington CAG, fragile X CGG, myotonic dystrophy CTG, Friedreich ataxia GAA).
- Penetrance, expressivity, mosaicism. Penetrance is all-or-none: the fraction of genotype-carriers who show ANY phenotype (incomplete penetrance = an obligate carrier who looks normal). Expressivity is the range of severity among those affected (NF1 is the classic: near-complete penetrance, wildly variable expressivity). Mosaicism means two genetically distinct cell lines from a post-zygotic mutation; germline (gonadal) mosaicism lets two unaffected parents have a second child with a 'new' dominant disease.
Worth drilling · 28 concepts
Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.
- 1Purines — the two-ring bases, adenine and guanine; 'PURe As Gold'
- 2G-C base pair — three hydrogen bonds, so rich regions melt at higher temperature
- 3Helicase — unwinds the double helix at the replication fork
- 4Primase — lays the short RNA primer DNA polymerase needs to start
- 5Okazaki fragments — short lagging-strand pieces later sealed by ligase
- 6Telomerase — reverse transcriptase that rebuilds chromosome ends; active in germ and stem cells
- 7RNA polymerase II — makes eukaryotic mRNA; needs no primer
- 85' cap — 7-methylguanosine added to nascent mRNA; protects and starts translation
- 9Spliceosome — snRNP machine that cuts introns and joins exons
- 10Codon AUG — the start signal; codes methionine
- 11Missense mutation — single base change swaps one amino acid, as in sickle cell
- 12Nonsense mutation — premature stop codon truncates the protein
- 13Frameshift mutation — insertion or deletion not divisible by 3 scrambles everything downstream
- 14Splice-site mutation — intron retained or exon skipped; classic in beta-thalassemia
- 15Autosomal dominant pattern — every generation affected, male-to-male transmission seen
- 16Autosomal recessive pattern — skips generations; two carriers give each child a 25% risk
- 17X-linked recessive pattern — mostly males affected, never father-to-son
- 18X-linked dominant pattern — an affected father's daughters all affected, sons never
- 19Mitochondrial inheritance — passed only by mothers, to children of both sexes
- 20Heteroplasmy — a mixed population of normal and mutant mitochondria explains variable severity
- 21Genomic imprinting — parent-of-origin silencing; Prader-Willi vs Angelman on 15q
- 22Anticipation — trinucleotide repeats expand, so disease starts earlier each generation
- 23Penetrance — the fraction of mutation carriers showing any phenotype at all
- 24Variable expressivity — same genotype, different severity; classic in NF1
- 25Germline mosaicism — mutation confined to a parent's gonads; unaffected parents, recurrent affected children
- 26Lyonization — random X inactivation; skewing makes a female carrier symptomatic
- 27Consanguinity — parental relatedness that raises risk for recessive disease
- 28Pedigree carrier symbol — half-shaded or dotted square/circle marking a heterozygote
Practice it
Active recall over the drill list — flip and claim, match the pairs, produce the answers cold, fill in the diagram, or solve real pedigrees.
Every concept on the drill list, one card at a time — the name up front, the fact that identifies it on the flip. Claim each card honestly and the deck learns what to lead with next time. Progress lives in this browser only.
What everyone misses
The distinctions that lose points on this material, year after year.
- Skipped generation ≠ recessive proof. A generation can look skipped in a dominant disease with incomplete penetrance. Before choosing AR, check the give-away features: male-to-male transmission rules OUT X-linkage but is fine for AD; consanguinity and a 25% recurrence risk point to AR.
- X-linked recessive and 'no male-to-male'. Students see an affected father and affected son and still pick X-linked recessive. A father gives his son a Y — X-linked anything cannot pass father to son. One instance of male-to-male transmission on the pedigree eliminates every X-linked option.
- Carrier-risk arithmetic. Two AR carriers: each pregnancy is independently 1/4 affected — 'they already have one affected child, so the next three are safe' is always wrong. Also, an UNAFFECTED sibling of an AR patient is a carrier with probability 2/3, not 1/2, because the affected genotype has been excluded.
- Frameshift vs in-frame deletion. A 3-base (or any multiple-of-3) deletion removes amino acids but does NOT shift the frame — that's an in-frame deletion (classic CF ΔF508), often milder. Only insertions/deletions NOT divisible by 3 are frameshifts. The exam loves counting the bases for you and watching you ignore the number.
- Penetrance vs expressivity. Penetrance answers 'does the carrier show anything at all?' (yes/no across the population); expressivity answers 'how bad is it in those who do?' (a spectrum). A stem about mild vs severe disease in affected relatives is expressivity; a healthy obligate carrier is incomplete penetrance.
- Mitochondrial ≠ maternal-only victims. Mitochondrial disease is inherited only FROM the mother, but it affects sons and daughters equally — and an affected father transmits to NO children. Students confuse 'maternal transmission' with 'affects only females' and miss the affected sons on the pedigree.
Clinical correlations
Where this topic shows up again — in clinic, on rotations, and on the boards.
- Sickle cell disease. A single missense mutation (Glu→Val, position 6 of beta-globin) makes deoxygenated hemoglobin polymerize — vaso-occlusive pain crises, autosplenectomy, and encapsulated-organism risk. Autosomal recessive; the carrier (trait) state is largely asymptomatic and malaria-protective, the exam's favorite heterozygote-advantage example.
- Cystic fibrosis. AR, most commonly the in-frame ΔF508 deletion misfolding the CFTR chloride channel. Thick secretions produce recurrent sinopulmonary infections, pancreatic insufficiency, and male infertility (absent vas deferens); the diagnostic test is the sweat chloride, elevated because sweat ducts can't reabsorb Cl-.
- Duchenne muscular dystrophy. X-linked recessive frameshift/deletion in dystrophin: a boy with proximal weakness, calf pseudohypertrophy, Gowers sign, and a markedly elevated CK. Becker is the milder in-frame version — the same gene, a preserved reading frame, a partly functional protein.
- Huntington disease. AD CAG-repeat expansion with anticipation — chorea, psychiatric change, and dementia in mid-adult life, striking earlier when inherited from the father (repeats expand more in spermatogenesis). A patient with an affected parent carries a 50% risk, and the repeat count predicts onset.
- Fragile X syndrome. CGG expansion in FMR1 silencing the gene by methylation — the most common inherited cause of intellectual disability: a boy with a long face, large ears, macroorchidism after puberty, and autistic features. X-linked, with premutation carriers who can expand to full mutation in one generation.
- Marfan syndrome. AD fibrillin-1 defect: tall stature, arachnodactyly, upward lens dislocation, and the lethal piece — aortic root dilation and dissection. A connective-tissue structural protein behaving exactly as dominant disorders are supposed to; variable expressivity within one family is the rule.
- Prader-Willi vs Angelman. The imprinting pair. Loss of the PATERNAL 15q11-13 contribution (deletion or maternal uniparental disomy) → Prader-Willi: neonatal hypotonia, then hyperphagia and obesity. Loss of the MATERNAL contribution → Angelman: severe intellectual disability, ataxia, seizures, inappropriate laughter.