Unit 3: Chromosomal Variations and Mutations

I. Orientation: The Genome and Its Heritable Alterations

The chromosome is the physical vehicle of heredity, and any stable change to its structure, number, or nucleotide sequence is a heritable variation transmitted through cell division. This unit divides such changes into two scales: gross chromosomal rearrangements visible cytologically, and mutations at the level of the DNA sequence.

• Karyotype: the complete chromosome complement of a cell, described as 2n = 46 in humans (22 autosome pairs + XX or XY).
• Euploid vs. aneuploid: euploid genomes carry exact multiples of the haploid set (n); aneuploid genomes gain or lose individual chromosomes.
• Balanced vs. unbalanced: balanced rearrangements retain the full gene dosage; unbalanced ones alter it, usually with phenotypic consequence.
• Genotype–phenotype link: dosage-sensitive genes mean that added or missing segments frequently produce disease, while balanced carriers may be normal.

II. Variation in Chromosome Structure

Structural changes arise when a chromosome breaks and rejoins abnormally, altering the amount or arrangement of genetic material without changing chromosome number.

A. Deletion

Loss of a chromosomal segment and the genes it carries.

• Types: terminal deletion (break at chromosome end) versus interstitial deletion (two internal breaks, middle segment lost).
• Dosage effect: heterozygous deletion leaves one copy, causing haploinsufficiency of the missing genes.
• Example: Cri-du-chat syndrome from deletion of the short arm of chromosome 5 (5p−); infants produce a cat-like cry, with microcephaly and intellectual disability.
• Cytology: in meiosis the normal homolog forms a deletion loop to pair with the deleted partner.

B. Duplication

Presence of an extra copy of a chromosomal segment.

• Origin: unequal crossing over between misaligned homologs generates one duplicated and one deleted product.
• Dosage effect: three doses of the duplicated genes; generally less harmful than deletion.
• Example: Bar eye in Drosophila — tandem duplication of region 16A on the X reduces facet number; the classic dosage-effect phenotype.

C. Inversion

A segment breaks, rotates 180°, and reinserts, reversing gene order.

1. Paracentric: both breaks on the same arm, centromere outside the inverted segment.
2. Pericentric: breaks flank the centromere, which lies inside the inverted segment.
   • Meiotic behaviour: heterozygotes form an inversion loop; crossing over within it yields inviable gametes, so inversions act as crossover suppressors.
   • Product difference: paracentric crossovers produce dicentric and acentric fragments; pericentric crossovers produce duplication–deletion chromatids.

D. Translocation

Transfer of a segment to a non-homologous chromosome.

1. Reciprocal: two chromosomes exchange segments; balanced carriers are healthy but produce unbalanced gametes.
2. Robertsonian: two acrocentric chromosomes fuse at the centromere, reducing chromosome number (e.g., 45 chromosomes).
   • Clinical link: Robertsonian fusion of chromosome 21 causes familial Down syndrome; the Philadelphia chromosome t(9;22) fuses BCR–ABL and drives chronic myeloid leukaemia.

III. Variation in Chromosome Number

Whole chromosomes are gained or lost when segregation fails during cell division.

A. Non-disjunction and Aneuploidy

Failure of chromosomes to separate normally, producing cells with abnormal counts.

• Mechanism: homologs fail to separate at meiosis I, or sister chromatids fail at meiosis II (or in mitotic non-disjunction, producing mosaics).
• Products: one gamete gains a chromosome (n + 1), the other lacks it (n − 1).
• Aneuploid classes: monosomy (2n − 1), trisomy (2n + 1), nullisomy (2n − 2).
• Maternal age effect: prolonged arrest of oocytes in meiosis I raises non-disjunction risk sharply with age.

IV. Autosomal Trisomies

An extra copy of a single autosome; viability decreases as the extra chromosome carries more genes.

A. Trisomy 21 — Down Syndrome

Three copies of chromosome 21 (47,XX/XY,+21).

• Cause: ~95% maternal non-disjunction; ~4% Robertsonian translocation; rare mosaicism.
• Phenotype: intellectual disability, epicanthic folds, single palmar crease, congenital heart defects; the most common viable autosomal trisomy.

B. Trisomy 18 — Edwards Syndrome

Three copies of chromosome 18.

• Phenotype: clenched fists with overlapping fingers, rocker-bottom feet, severe cardiac and renal defects; most die within the first year.

C. Trisomy 13 — Patau Syndrome

Three copies of chromosome 13.

• Phenotype: cleft lip/palate, polydactyly, holoprosencephaly, microphthalmia; survival is usually only days to weeks.

V. Sex-Linked Aneuploidies

Non-disjunction of sex chromosomes; often milder than autosomal aneuploidies because of X-inactivation and the gene-poor Y.

A. Turner Syndrome

Monosomy X (45,X) — the only viable human monosomy.

• Phenotype: short stature, webbed neck, streak gonads with sterility, broad "shield" chest; normal intelligence.
• Basis: absence of the second sex chromosome removes genes escaping X-inactivation needed for ovarian and skeletal development.

B. Klinefelter Syndrome

47,XXY — an extra X in males.

• Phenotype: tall stature, small testes, reduced testosterone, gynaecomastia, infertility.
• Cytology: the inactivated extra X forms a Barr body, absent in normal males.

C. Superfemales

47,XXX (metafemales / triple-X).

• Phenotype: usually near-normal fertile females; tall stature, sometimes mild learning delay.
• Barr bodies: two are present (one per extra X), since all but one X inactivate.

VI. Polyploidy

Possession of complete extra chromosome sets (3n, 4n, ...), euploid but multiplied.

A. Polyploidy in Plants

Whole-genome multiplication is common and often advantageous in plants.

1. Autopolyploidy: multiple sets from one species (e.g., autotetraploid 4n); arises by failed cytokinesis or unreduced gametes.
2. Allopolyploidy: sets from two species combined via hybridisation then chromosome doubling; restores fertile pairing.
   • Example: bread wheat Triticum aestivum is an allohexaploid (6n = 42) from three ancestral genomes (AABBDD).
   • Traits: larger cells, organs, and seeds — the "gigas" effect exploited in crops; colchicine induces doubling by blocking spindle formation.

B. Polyploidy in Animals

Rare and usually lethal in animals owing to sex-determination and dosage constraints.

• Barriers: disrupted X:autosome balance breaks sex determination; established chromosomal sex systems tolerate polyploidy poorly.
• Exceptions: some fish, amphibians (e.g., Xenopus), and parthenogenetic lizards and insects sustain polyploidy; certain mammalian tissues (liver hepatocytes) are polyploid somatically.

VII. Mutations

Heritable changes in DNA sequence, the ultimate source of genetic variation and the raw material of evolution.

A. Definition

A permanent, heritable alteration in the nucleotide sequence of the genome.

• Somatic vs. germline: somatic mutations affect only the individual; germline mutations pass to offspring.
• Spontaneous vs. induced: arising from replication errors versus caused by external mutagens.

B. Types of Mutation

Classified by the scale and nature of the sequence change.

• Point mutation: single base substitution.
  • Transition: purine↔purine or pyrimidine↔pyrimidine.
  • Transversion: purine↔pyrimidine.
• Frameshift: insertion or deletion not in multiples of three, shifting the reading frame downstream.

C. Phenotypic Effects

The consequence of a mutation depends on where and how it alters coding.

• Silent: codon change encodes the same amino acid (e.g., GAA→GAG, both Glu).
• Missense: one amino acid replaces another; sickle-cell GAG→GTG substitutes valine for glutamate at β-globin position 6.
• Nonsense: codon becomes a stop (e.g., UAC→UAA), truncating the protein.
• Loss vs. gain of function: null alleles abolish activity; gain-of-function alleles produce new or excess activity.

D. Molecular Basis of Mutation

Mutations trace to specific chemical events in DNA.

• Tautomeric shift: bases briefly adopt rare imino/enol forms, mispairing during replication (A–C, G–T).
• Depurination: loss of a purine base leaves an abasic site read as any base.
• Deamination: cytosine → uracil, generating C→T transitions if unrepaired.
• Repair link: proofreading and mismatch repair correct most errors; failure fixes the mutation permanently.

E. Radiation and Chemically Induced Mutation

External agents raise mutation rates far above spontaneous levels.

1. Radiation-induced:
   • Ionising (X-rays, γ-rays): break sugar–phosphate backbones, causing deletions and chromosome breaks.
   • UV light: forms pyrimidine (thymine) dimers that distort the helix and block replication.
2. Chemically induced:
   • Base analogs: 5-bromouracil mimics thymine but mispairs with guanine, causing transitions.
   • Alkylating agents: ethyl methanesulfonate (EMS) adds alkyl groups, altering base pairing.
   • Intercalating agents: acridine dyes wedge between bases, producing frameshift insertions/deletions.
   • Dose relationship: mutation frequency rises roughly linearly with ionising-radiation dose, with no threshold.