5.1 about 34 minDeep Learning viewL5 p.2–6

Mutations and Mendelian inheritance

A mutation is a permanent change in DNA. Whether it reaches the next generation, what it does to the protein, and how it travels through a family decide who is affected and what the risk is for the next child.

Germline and somatic mutations

L5 p.2

A mutation is a permanent change in the nucleotide sequence or arrangement of DNA. Where it happens decides who can inherit it. A germline mutation is present in an egg or sperm (or the cells that make them), so it can pass to children and is then present in every cell of the child's body. A somatic mutation arises in a body cell after conception; it is copied only into that cell's descendants and is not transmitted to offspring.

Germline

  • In gametes or their precursors
  • Every cell of the offspring carries it
  • Causes inherited (familial) disease
  • Example: a CFTR allele passed from a carrier parent

Somatic

  • Arises in one body cell after conception
  • Only that cell's clone carries it (a mosaic)
  • Not passed to children
  • Example: most cancer-driving mutations; an early embryonic error gives mosaicism (5.2)
L5 p.2

What a mutation does to the message

L5 p.3–4

The ribosome reads mRNA three bases at a time from a fixed start. A mutation's effect depends on what it does to that reading frame and to the codon it hits. A point mutation replaces one base: it can be silent (same amino acid, usually a third-position change), missense (a different amino acid) or nonsense (a premature stop codon, so the protein is truncated and the mRNA is often destroyed). An insertion or deletion of a number of bases not divisible by three shifts the frame: every codon downstream is misread until a stop codon appears (frameshift). Losing or adding a multiple of three keeps the frame and removes or adds whole amino acids (in-frame). Splice-site mutations alter the signals that mark exon borders, so an exon is skipped or an intron retained.

Teaching schematic

Normal β-globin

codons 5–8

CCUProGAGGluGAGGluAAGLys

Normal protein

Silent

GAG → GAA

CCUProGAAGluGAGGluAAGLys

Same amino acid (third-base wobble)

Missense (HbS)

GAG → GUG

CCUProGUGValGAGGluAAGLys

Glu6Val: HbS polymerizes when deoxygenated

Nonsense

GAG → UAG

CCUProUAGStopGAG·AAG·

Premature stop: truncated protein, mRNA decay

Frameshift (+1)

an A inserted

CCUProAGAArgGGAGlyGAAGlu

Every codon downstream is misread until a stop appears (e.g., Tay–Sachs 4-bp insertion)

In-frame deletion (CFTR ΔF508)

3 bases (CTT) lost

AUCIleAUUIle—Phe lostGGUGly

Frame kept; one residue missing → misfolded CFTR degraded in the ER

Splice-site mutations change the GT…AG signals at exon–intron borders, so an exon is skipped or an intron retained (many β-thalassemias). A codon change can also create a new splice site: the “silent” LMNA change in progeria (5.6).

One stretch of β-globin (codons 5–8) read normally and after each kind of mutation, plus the CFTR in-frame deletion. Pink = changed codon.L5 p.3–4

The lecture's examples, mechanism firstL5 p.3

  • Sickle cell disease

    Mutation
    Missense: GAG → GTG at β-globin codon 6 (Glu → Val)
    What happens to the protein
    HbS is made in normal amounts but polymerizes when deoxygenated; red cells sickle

  • Cystic fibrosis (ΔF508)

    Mutation
    In-frame deletion of 3 bases: phenylalanine 508 lost
    What happens to the protein
    Full-length CFTR misfolds, is retained in the ER and degraded; little channel reaches the apical membrane

  • Tay–Sachs disease

    Mutation
    Frameshift: 4-base insertion in HEXA (the common Ashkenazi allele)
    What happens to the protein
    No functional hexosaminidase A; GM2 ganglioside accumulates in neurons

  • β⁰-thalassemia (example)

    Mutation
    Nonsense or splice-site mutations in β-globin
    What happens to the protein
    No β chain made; unpaired α chains precipitate

Worked case · Same gene, different damage

Two children have mutations in the same gene. In child A a single base change converts a glutamate codon (GAG) to a stop codon (UAG). In child B a single base is inserted near the start of the coding sequence.

Which child is more likely to make some protein, and why are both likely to be severe?

Trinucleotide repeats and anticipation

L5 p.3Ch. V cases p.12

Some genes contain a short run of a repeated triplet. Above a threshold the run becomes unstable: it tends to lengthen when passed to the next generation. Longer repeats cause earlier and more severe disease, so the disorder appears to worsen down the family: anticipation. Where the repeat sits in the gene decides the mechanism.

The four repeat disorders in the lectureL5 p.3

  • Huntington disease

    Repeat and location
    CAG, coding region of HTT (4p)
    Inheritance
    AD
    Mechanism and key findings
    Polyglutamine protein aggregates (gain of function) → caudate and putamen atrophy: chorea, psychiatric change, dementia
    Expansion mostly through
    Father (spermatogenesis)

  • Myotonic dystrophy type 1

    Repeat and location
    CTG, 3′ untranslated region of DMPK (19q)
    Inheritance
    AD
    Mechanism and key findings
    Toxic RNA traps splicing regulators → myotonia, distal weakness, temporal wasting, frontal balding, cataracts, testicular atrophy, cardiac conduction block
    Expansion mostly through
    Mother for the severe congenital form

  • Fragile X syndrome

    Repeat and location
    CGG, 5′ untranslated region of FMR1 (Xq27.3)
    Inheritance
    X-linked (lecture: XD)
    Mechanism and key findings
    Hypermethylation silences the gene → no FMRP (5.3)
    Expansion mostly through
    Mother

  • Friedreich ataxia

    Repeat and location
    GAA, intron 1 of FXN (9q)
    Inheritance
    AR
    Mechanism and key findings
    Too little frataxin → mitochondrial iron overload, oxidative damage → ataxia, hypertrophic cardiomyopathy, diabetes
    Expansion mostly through
    Little anticipation (recessive)

Worked case · A son worse than his father

A 16-year-old faints; his pulse is 43/min. He has frontal balding, temporal wasting, small testes, bilateral foot drop and weak hand muscles. His father developed cataracts and frontal balding in his twenties but has no heart disease (Ch. V Q11).

Which genetic property explains why the son is more severely affected?

Ch. V cases p.12

Reading a pedigree: four Mendelian patterns

L5 p.5–6

A pedigree is evidence. Each pattern leaves a signature that follows from two facts: autosomes come in pairs in both sexes, while a male has one X (from his mother) and passes his X to every daughter and his Y to every son. So the most powerful single observation is father-to-son transmission: it is possible only for autosomal (or Y-linked) traits and excludes anything carried on the X or in mitochondria.

Teaching schematic

Autosomal dominant

Autosomal dominant pedigreeIIIIIII-1I-2II-1II-2II-3II-4III-1III-2

Every generation; affected parent → ½ of children; male-to-male transmission

Autosomal recessive

Autosomal recessive pedigreeIIII-1I-2II-1II-2II-3II-4

Unaffected carrier parents; ¼ of children affected; both sexes; often consanguinity

X-linked recessive

X-linked recessive pedigreeIIIIIII-1I-2II-1II-2II-3III-1III-2

Mostly males, linked through carrier females; no male-to-male transmission

X-linked dominant

X-linked dominant pedigreeIIII-1I-2II-1II-2II-3II-4

Affected father → all daughters, no sons; affected mother → ½ of either sex

Mitochondrial

Mitochondrial pedigreeIIIIIII-1I-2II-0II-1II-2II-3III-1III-2III-3III-4

Affected mother → all children (variable severity); affected father → none

  • male
  • female
  • affected
  • known carrier
  • proband
Canonical pedigrees with the clue that identifies each pattern. Filled = affected; dot = known carrier; double line = consanguineous mating.L5 p.5–6, 21

Signatures and the lecture's disease examplesL5 p.5–6

  • Autosomal dominant

    Signature
    Vertical: every generation; affected parent → each child 1/2; both sexes; male-to-male transmission possible
    Lecture examples
    Marfan, osteogenesis imperfecta, familial hypercholesterolemia, von Willebrand disease, Huntington disease

  • Autosomal recessive

    Signature
    Horizontal: affected siblings of unaffected carrier parents; 1/4 per child; consanguinity raises risk
    Lecture examples
    Cystic fibrosis, sickle cell disease, most metabolic disorders (PKU), lysosomal storage diseases (Tay–Sachs)

  • X-linked recessive

    Signature
    Mostly males; passed through carrier women (each son 1/2); affected father → all daughters carriers, no sons affected
    Lecture examples
    Hemophilia A and B, chronic granulomatous disease

  • X-linked dominant

    Signature
    Affected father → all daughters, no sons; affected mother → 1/2 of children of either sex; more females affected
    Lecture examples
    Hypophosphatemic (vitamin D–resistant) rickets, Alport syndrome, fragile X (lecture classification)

What each example disease does (mechanism in one line)L5 p.5–6

  • Marfan syndrome

    Gene / product
    FBN1 (fibrillin-1), chr 15
    Why it causes disease
    Defective microfibrils and excess TGF-β signaling: tall stature, arachnodactyly, upward lens dislocation, aortic root dilation and dissection

  • Osteogenesis imperfecta

    Gene / product
    COL1A1/COL1A2 (type I collagen)
    Why it causes disease
    Abnormal collagen weakens bone, sclera, dentin: fractures, blue sclerae, hearing loss

  • Familial hypercholesterolemia

    Gene / product
    LDLR (LDL receptor)
    Why it causes disease
    Liver cannot clear LDL: very high LDL, xanthomas, early coronary disease; homozygotes far worse (gene dose)

  • von Willebrand disease

    Gene / product
    VWF
    Why it causes disease
    Poor platelet adhesion and less factor VIII carrier: mucosal bleeding

  • Cystic fibrosis

    Gene / product
    CFTR, chr 7
    Why it causes disease
    Defective chloride channel: thick secretions in lungs, pancreas, vas deferens; salty sweat

  • Sickle cell disease

    Gene / product
    HBB Glu6Val
    Why it causes disease
    HbS polymerizes when deoxygenated: hemolysis and vaso-occlusion

  • Hemophilia A / B

    Gene / product
    F8 / F9
    Why it causes disease
    Factor VIII / IX deficiency: deep tissue and joint bleeding

  • Chronic granulomatous disease

    Gene / product
    CYBB (NADPH oxidase, X-linked form)
    Why it causes disease
    No respiratory burst: infections by catalase-positive organisms, granulomas

  • Hypophosphatemic rickets

    Gene / product
    PHEX → ↑ FGF23
    Why it causes disease
    Proximal tubule wastes phosphate: rickets despite vitamin D

  • Alport syndrome

    Gene / product
    COL4A5 (type IV collagen α5)
    Why it causes disease
    Defective basement membranes: hematuria → renal failure, sensorineural deafness, lens defects. (Goodpasture is autoimmune anti-GBM disease, not inherited.)

Lecture slide

Two pedigrees from the lecture: on the left an autosomal recessive family with half-shaded carriers and fully shaded affected children; on the right an autosomal dominant family with half-shaded heterozygotes in every generation.
The lecture's AR and AD pedigrees. Watch the shading: in the AR pedigree a half-shaded symbol is a healthy carrier, while in the AD pedigree a half-shaded symbol is an affected heterozygote and a fully shaded one a (rare, severe) homozygote.L5 p.5

Lecture slide

Lecture pedigrees: left, an X-linked recessive family with genotypes XY and XX marked and affected males in red; right, an X-linked dominant family in which an affected father has only affected daughters.
Left: X-linked recessive (affected males red, carrier females outlined red). Right: X-linked dominant; the affected father in generation I has affected daughters and unaffected sons.L5 p.6

Case image

Three-generation pedigree: unaffected grandparents; an affected son in generation II whose two sons are unaffected; his unaffected sister has an affected son, the arrowed proband.
Ch. V Q12: a boy who cannot sort colors (arrow). His maternal uncle is affected, his uncle's sons are not, and his mother is healthy. Only males, through a healthy woman, no male-to-male transmission: X-linked recessive (red–green color blindness).Ch. V cases p.13

Turning a pedigree into a probability

L5 p.5–6

Every risk calculation has the same three steps: fix the genotypes that are certain (affected people and obligate carriers, whose children prove what they carry), list the equally likely outcomes of each mating, and then remove the outcomes the facts exclude. The last step is the one students skip, and it is the source of the famous 2/3.

Worked calculation · Healthy sibling of a child with an autosomal recessive disease

Parents
both carriers (+/m) — proven by the affected child
Outcomes per child
+/+, +/m, m/+, m/m (each 1/4)
Known about the sibling
healthy, so not m/m

Formula

P(carrier | healthy) = P(+/m) ÷ P(healthy) = (1/2) ÷ (3/4)

Ref. · Thompson & Thompson, risk calculation

Worked calculation · Sister of a boy with an X-linked recessive disease

Mother
obligate carrier X⁺Xᵐ (affected son, healthy husband, affected brother)
Father
X⁺Y
Question
risk that the sister's next son is affected

Formula

P(sister carrier) × P(son receives Xᵐ)

Risks to each child, by patternL5 p.5–6, 21

  • AD: affected heterozygote × unaffected

    Sons
    1/2 affected
    Daughters
    1/2 affected

  • AR: carrier × carrier

    Sons
    1/4 affected, 1/2 carriers
    Daughters
    1/4 affected, 1/2 carriers

  • XLR: carrier mother × normal father

    Sons
    1/2 affected
    Daughters
    1/2 carriers

  • XLR: affected father × normal mother

    Sons
    None affected
    Daughters
    All carriers

  • XLD: affected father × normal mother

    Sons
    None affected
    Daughters
    All affected

  • XLD: affected (heterozygous) mother × normal father

    Sons
    1/2 affected
    Daughters
    1/2 affected

  • Mitochondrial: affected mother

    Sons
    All inherit (variable severity)
    Daughters
    All inherit

  • Mitochondrial: affected father

    Sons
    None
    Daughters
    None

Pedigree Lab

L5 p.5–10, 21, 23

Five families, one method. Pick the pattern and the clue that proves it, genotype the marked people by tapping them, then compute a risk. The second and third tabs carry the same logic into chromosomes: a 46-chromosome child with Down syndrome, and six children whose chromosome 15 tells a parent-of-origin story.

Centerpiece · Pedigree Lab

Pedigree Lab

Read the family, not the disease name. For each pedigree: pick the pattern and the clue that proves it, genotype the marked people, then compute a risk. Two more exercises follow the same logic into chromosomes: a 46-chromosome Down syndrome and the parent-of-origin puzzles of chromosome 15.

A daughter with cystic fibrosis

III-1 has cystic fibrosis. Her parents and siblings are healthy, and so is the rest of the family. Her sister III-2 wants to know whether she could be a carrier.

Pedigree: A daughter with cystic fibrosisIIIIIII-1I-2II-1II-2?II-3?III-1?III-2?III-3
  • male
  • female
  • affected
  • proband

Cystic fibrosis (CFTR) · dashed rings mark the people you will genotype in step 2.

Step 1

Inheritance pattern and the decisive clue

Pick the pattern.

Which observation decides it?

Step 2

Assign genotypes

Settle the pattern in step 1 first: genotypes depend on it.

Tap a person with a dashed ring, then tap the genotype that is certain for them. Use “+/?” when the data cannot decide.

People

Genotypes

Tap a person (here or on the pedigree), then a genotype, or the other way round.

Step 3

Compute the probability

Finish the genotypes first: the calculation starts from them.

III-2 is healthy. What is the probability that she is a carrier?

Penetrance, expressivity and pleiotropy

L5 p.5Ch. V cases p.4

Three words describe how a genotype shows up, and they answer different questions. Penetrance asks whether: the proportion of people with the genotype who show any sign of it. Most recessive and metabolic disorders are fully penetrant (the lecture's point); some dominant ones are not, so a carrier can look healthy and the disease seems to skip a generation. Expressivity asks how much: among affected people, how severe and in which organs. Pleiotropy asks how many places: one gene affecting several apparently unrelated systems.

  • Penetrance

    Question it answers
    Does a person with the genotype show the trait at all?
    Example
    Huntington: near-complete; BRCA1 or retinoblastoma: incomplete → apparent skipped generation

  • Expressivity

    Question it answers
    How severely, and with which features?
    Example
    Marfan: one relative has only long fingers, another an aortic dissection; NF1

  • Pleiotropy

    Question it answers
    How many organs does one gene affect?
    Example
    Marfan (skeleton, eye, aorta); PKU (brain, pigment, odor); myotonic dystrophy (muscle, lens, heart, gonads)

  • Anticipation

    Question it answers
    Why is the next generation worse?
    Example
    Repeat expansion: Huntington, myotonic dystrophy

Case image

Hand photographs: thumb projecting beyond the palm in a closed fist, and thumb overlapping the little finger around the wrist.
Ch. V Q3: the thumb sign (a) and wrist sign (b) of arachnodactyly in a tall man who later had an aortic dissection: Marfan syndrome, autosomal dominant.Ch. V cases p.4

Marfan syndrome shows all three ideas. FBN1 encodes fibrillin-1, a scaffold for elastic fibers that also holds TGF-β inactive. Abnormal fibrillin weakens connective tissue and releases excess TGF-β: long bones overgrow (tall stature, arachnodactyly, pectus), the suspensory ligament of the lens fails (upward lens dislocation), the mitral valve becomes floppy, and the aortic media degenerates (cystic medial degeneration), so the aortic root dilates and can dissect. Penetrance is high, expressivity variable, and about a quarter of cases are new mutations.

Two recessive diseases from the cases: CF and PKU

Ch. V cases p.5–7L5 p.3, 5

Cystic fibrosis (CFTR, chromosome 7) is the most common lethal autosomal recessive disease in people of European ancestry; about 1 in 25 are carriers. CFTR is an apical chloride (and bicarbonate) channel. Without it, epithelia secrete too little chloride and water, while airway cells absorb extra sodium, so secretions become thick. The sweat duct cannot reabsorb chloride, which is why sweat is salty and the sweat chloride test is diagnostic.

One channel, many organsCh. V cases p.5

  • Pancreas (85–90%)

    What thick secretions do
    Ducts plug; acini atrophy and fibrose
    Clinical result
    No lipase reaches the gut → steatorrhea, failure to thrive, deficiency of vitamins A, D, E, K; later CF-related diabetes

  • Intestine

    What thick secretions do
    Inspissated meconium
    Clinical result
    Meconium ileus in newborns

  • Airways

    What thick secretions do
    Mucus is not cleared
    Clinical result
    Recurrent infection (S. aureus, P. aeruginosa), bronchiectasis, respiratory failure

  • Liver

    What thick secretions do
    Bile plugs ductules
    Clinical result
    Focal biliary cirrhosis

  • Male reproductive tract

    What thick secretions do
    Vas deferens fails to form or is obstructed
    Clinical result
    Infertility (azoospermia)

  • Sweat glands

    What thick secretions do
    Cl⁻ not reabsorbed
    Clinical result
    Salty sweat, salt depletion in heat

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

A 4-year-old with a positive sweat chloride test has greasy, foul-smelling stools (Ch. V Q4). Complete the chain from mutation to malabsorption.

  1. Both CFTR alleles carry ΔF508 (3-base, in-frame deletion: Phe508 lost)
  4. less Cl⁻ and HCO₃⁻ secreted, so less water follows into the duct
  5. Thick, dehydrated secretions in pancreatic ducts

Cards

Tap or drag a card. Placing a used card moves it.

Phenylketonuria (PKU) is an autosomal recessive deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. The unmetabolized substrate accumulates: high phenylalanine impairs myelination and competes with other large neutral amino acids for transport into the brain, lowering serotonin and dopamine synthesis. Untreated infants look normal at birth, then develop intellectual disability, seizures and a musty (“mousy”) odor from phenylacetate. Less tyrosine means less melanin: fair skin, blond hair, blue eyes. Tyrosine becomes an essential amino acid.

Worked case · A boy adopted from an orphanage

A 10-month-old adopted from an orphanage is missing milestones. He is fair-skinned and blond with a mousy odor. Tests show an inborn error of amino acid metabolism (Ch. V Q5–Q6, one case with two questions).

Which amino acid must his diet restrict, and why is his brain injured?

Ch. V cases p.6–7

Knowledge check · 5.1

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 8 correct
  1. Q1Marfan syndrome: autosomal dominantCh. V cases p.4L5 p.5

    A 25-year-old man is 6 ft 5 in tall with the hand findings shown. A year later he suffers a dissecting aortic aneurysm (Ch. V Q3).

    Case image

    Two photographs of a hand: (a) the thumb, folded into a closed fist, projects beyond the ulnar border of the palm; (b) the thumb and little finger overlap when wrapped around the opposite wrist.

    What type of inheritance is characteristic of his disease?

  2. Q2CF: pancreatic insufficiencyCh. V cases p.5

    A 4-year-old boy is admitted with pneumonia. His stools are greasy and foul-smelling, and a sweat chloride test is positive (Ch. V Q4).

    What mechanism most likely causes his steatorrhea?

  3. Q3PKU: phenylalanine restrictionCh. V cases p.6

    A 10-month-old boy adopted from an orphanage is fair-skinned and blond, has a mousy odor and is missing milestones. An inborn error of amino acid metabolism is found (Ch. V Q5).

    To prevent further intellectual disability, his diet should lack which essential amino acid?

  4. Q4PKU: substrate accumulationCh. V cases p.7

    Same patient as the previous question (Ch. V Q6).

    Which best describes the pathogenesis of his intellectual disability?

  5. Q5Pedigree: X-linked recessiveCh. V cases p.13L5 p.6

    A 4-year-old boy cannot sort colored balls into matching baskets. His mother mentions an eye condition that runs in the family. The pedigree is shown; the proband is arrowed (Ch. V Q12).

    Pedigree from case Q12: affected II-4 and proband III-5IIIIIII-1I-2II-1II-2II-3II-4II-5II-6III-1III-2III-3III-4III-5III-6
    • male
    • female
    • affected
    • proband

    Which mode of inheritance best explains his vision problem?

  6. Q6Anticipation (CTG expansion)Ch. V cases p.12L5 p.3

    A 16-year-old with syncope, a pulse of 43/min, frontal balding, temporal wasting, testicular atrophy and distal weakness has myotonic dystrophy. His father had cataracts and frontal balding in his twenties only (Ch. V Q11).

    The son's greater severity is best explained by which genetic property?

  7. Q7In-frame deletion vs frameshiftL5 p.3

    The common CFTR allele deletes three nucleotides. What is the main consequence for the protein?

  8. Q82/3 carrier riskL5 p.5

    A healthy 24-year-old woman's brother has cystic fibrosis; her parents are healthy. Her partner has no family history and has not been tested.

    What is the probability that she is a carrier?

Chapter startNext5.2 Chromosomal syndromes