DNA & Inheritance

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.

Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.

1. 1Purines — the two-ring bases, adenine and guanine; 'PURe As Gold'
2. 2G-C base pair — three hydrogen bonds, so rich regions melt at higher temperature
3. 3Helicase — unwinds the double helix at the replication fork
4. 4Primase — lays the short RNA primer DNA polymerase needs to start
5. 5Okazaki fragments — short lagging-strand pieces later sealed by ligase
6. 6Telomerase — reverse transcriptase that rebuilds chromosome ends; active in germ and stem cells
7. 7RNA polymerase II — makes eukaryotic mRNA; needs no primer
8. 85' cap — 7-methylguanosine added to nascent mRNA; protects and starts translation
9. 9Spliceosome — snRNP machine that cuts introns and joins exons
10. 10Codon AUG — the start signal; codes methionine
11. 11Missense mutation — single base change swaps one amino acid, as in sickle cell
12. 12Nonsense mutation — premature stop codon truncates the protein
13. 13Frameshift mutation — insertion or deletion not divisible by 3 scrambles everything downstream
14. 14Splice-site mutation — intron retained or exon skipped; classic in beta-thalassemia
15. 15Autosomal dominant pattern — every generation affected, male-to-male transmission seen
16. 16Autosomal recessive pattern — skips generations; two carriers give each child a 25% risk
17. 17X-linked recessive pattern — mostly males affected, never father-to-son
18. 18X-linked dominant pattern — an affected father's daughters all affected, sons never
19. 19Mitochondrial inheritance — passed only by mothers, to children of both sexes
20. 20Heteroplasmy — a mixed population of normal and mutant mitochondria explains variable severity
21. 21Genomic imprinting — parent-of-origin silencing; Prader-Willi vs Angelman on 15q
22. 22Anticipation — trinucleotide repeats expand, so disease starts earlier each generation
23. 23Penetrance — the fraction of mutation carriers showing any phenotype at all
24. 24Variable expressivity — same genotype, different severity; classic in NF1
25. 25Germline mosaicism — mutation confined to a parent's gonads; unaffected parents, recurrent affected children
26. 26Lyonization — random X inactivation; skewing makes a female carrier symptomatic
27. 27Consanguinity — parental relatedness that raises risk for recessive disease
28. 28Pedigree carrier symbol — half-shaded or dotted square/circle marking a heterozygote

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.

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.