Chapter 15 – Chromosomal Basis of Inheritance (Comprehensive Notes)

Gene Localization on Chromosomes

• Mendel’s “hereditary factors” ≈ modern genes.
• Genes occupy specific loci on chromosomes; cytological evidence via fluorescent in-situ hybridization (FISH).
• Improved microscopy (post-1875) revealed mitosis parallels with Mendel’s laws.
• Sutton & Boveri (≈1902) formalized the Chromosome Theory of Inheritance.

Mendel’s Laws Revisited Cytologically

• Law of Segregation: homologous chromosome pairs separate during meiosis I ➔ each gamete gets one allele.
• Law of Independent Assortment: non-homologous chromosomes align randomly at metaphase I.
• Dihybrid cross (seed color/shape; YYRR \times yyrr) ➔ F$1$ YyRr; F$2$ phenotypic ratio 9:3:3:1 via gamete types \tfrac14 each (YR, Yr, yR, yr).

Morgan’s Pioneering Work

• Model: Drosophila melanogaster (fast generation ~2 weeks, many offspring, 4 chromosome pairs).
• Wild type = common phenotype; mutants = alternatives.
• White-eye mutation study:
  • P: white-eyed male (X$^w$Y) × red-eyed female (X$^{w+}$X$^{w+}$).
  • F$1$: all red-eyed. F$2$: 3:1 red:white but all whites male.
  • Conclusion: eye-color gene lies on X; first gene-to-chromosome assignment.

Sex Chromosomes & Sex Determination

• Humans: XX (female), XY (male); Y chromosome pairs only at pseudo-autosomal ends with X.
• Other systems:
  • X-0 (e.g., grasshoppers): XX female, X0 male.
  • Z-W (birds, some fish): ZW female, ZZ male.
  • Haplo-diploid (bees/ants): diploid female (2n), haploid male (n).
• SRY gene on Y triggers testes development.

Sex-Linked Inheritance

• Sex-linked gene = locus on sex chromosome.
• X-linked recessive expression:
  • Female: needs two mutant alleles (homozygous) to express.
  • Male: hemizygous; one allele suffices.
• Human X-linked disorders: color blindness, Duchenne muscular dystrophy, hemophilia.
• X-inactivation in females → Barr body; heterozygous females are mosaics (e.g., tortoiseshell cats).

Linked Genes & Genetic Recombination

• Linked genes = same chromosome, tend to co-inherit.
• Morgan’s body-color (b/b$^+$) & wing-size (vg/vg$^+$) dihybrid cross:
  • Parental phenotypes predominated.
  • Non-parental (recombinant) phenotypes appeared → linkage incomplete.
  • Crossing-over in prophase I explains physical breakage/rejoining.
  • Recombination frequency example: \tfrac{391}{2300} \times 100 = 17\%.
• Terminology:
  • Parental type = phenotype identical to parent.
  • Recombinant = new combination.
  • 50\% recombination implies genes on different chromosomes or far apart on same.

Linkage Mapping (Sturtevant)

• Recombination frequency proportional to physical distance.
• Map unit (centimorgan, cM) = 1\% recombination.
• Example chromosome: gene order b—(9 cM)—cn—(9.5 cM)—vg; total 17\% b–vg.
• Four linkage groups in Drosophila ≈ 4 chromosome pairs.

Chromosomal Abnormalities

Number Changes

• Nondisjunction: homologues (meiosis I) or sister chromatids (meiosis II) fail to separate.
• Gamete outcomes: n+1, n-1, or normal.
• Fertilization consequences:
  • Aneuploidy = abnormal single chromosome number.
  – Monosomy: 2n-1 (e.g., X0 Turner syndrome).
  – Trisomy: 2n+1 (e.g., Trisomy 21 Down syndrome; incidence ≈ \tfrac{1}{700} births, maternal-age related).
  • Polyploidy = >2 sets (3n triploid, 4n tetraploid); frequent in plants, generally viable.

Structural Changes

• Deletion, duplication, inversion, translocation (reciprocal or non-reciprocal).
• Examples:
  • Cri du chat: deletion on chromosome 5.
  • CML: Philadelphia chromosome t(9;22).

Aneuploidy of Sex Chromosomes

• XXX (triplo-X): phenotypically female, fertile.
• XXY: Klinefelter male, sterile, some feminization.
• X0: Turner female, sterile, only viable monosomy.

Exceptions to Standard Mendelian Inheritance

Genomic Imprinting

• Parent-of-origin effect; allele expression silenced via DNA methylation.
• Example: Igf2 in mice—only paternal allele active; paternal mutant ⇒ dwarf phenotype.

Extranuclear (Cytoplasmic) Genes

• Mitochondria & chloroplasts carry circular DNA.
• Inheritance is maternal (egg cytoplasm).
• Evidence: variegated leaves (green/white) in plants.
• Human mitochondrial disorders: mitochondrial myopathy, Leber’s hereditary optic neuropathy (defective ATP production).

Genetic Variation & Evolutionary Significance

• Crossing-over + independent assortment + random fertilization ➔ myriad allele combinations.
• Recombinant chromosomes introduce novel genetic variation → substrate for natural selection.

Key Numerical & Statistical References

• F$_2$ dihybrid ratio: 9:3:3:1.
• Recombination ≥50\% ⇒ genes unlinked.
• Map unit: 1\% recombination = 1 cM.
• Down syndrome frequency: \approx\tfrac{1}{700} US births.
• Morgan’s recombination frequency example: 17\%.

Historical Timeline Snapshot

• 1875: Mitosis described.
• 1902: Sutton & Boveri propose Chromosome Theory.
• Early 1900s: Morgan’s Drosophila experiments.
• Sturtevant develops first genetic linkage map.