Unit 1: Introduction to Genetics, Mendelian Genetics and Chromosomal Basis of Inheritance

I. Orientation: The Vocabulary of Inheritance

Genetics is the study of heredity and variation — how traits pass from parents to offspring and why offspring differ. The field was founded by Gregor Mendel's pea-plant work (1856–1863, published 1866) and reconciled with cytology in the early twentieth century. Every later section rests on the following working definitions.

• Gene: the unit of heredity, a factor controlling a trait; Mendel called these Merkmale (factors).
• Allele: one of the alternative forms of a gene, e.g. T (tall) versus t (dwarf).
• Genotype vs phenotype: the genetic constitution (Tt) versus the observable trait (tall).
• Homozygous vs heterozygous: two identical alleles (TT, tt) versus two different ones (Tt).
• Dominance: the ability of one allele to mask the phenotypic expression of another in the heterozygote; the expressed allele is dominant and is written in uppercase.
• Recessiveness: the state of an allele whose effect is hidden in the heterozygote and appears only when homozygous (tt); written in lowercase.
• P, F₁, F₂: the parental generation, the first filial generation (the cross's offspring), and the second filial generation (from selfing the F₁).

II. Mendelian Genetics — The Laws Derived from Pea Crosses

A. Experimental basis

Mendel chose Pisum sativum for its true-breeding varieties, easily controlled pollination, and seven clearly contrasting traits (seed shape, seed colour, flower colour, pod shape, pod colour, flower position, stem height). He counted large offspring numbers, making his conclusions statistical rather than anecdotal.

B. The Principle of Dominance

In a cross between two contrasting true-breeding parents, only one form of the trait appears in the F₁; that form is dominant.

• Monohybrid cross setup: TT (tall) × tt (dwarf) → all F₁ are Tt.
• F₁ phenotype: every plant is tall — the t allele is present but unexpressed.
• Molecular reason: the dominant allele typically encodes a functional product; a single functional copy suffices, so the recessive (often loss-of-function) allele is masked.
• Exceptions to note: incomplete dominance (heterozygote intermediate, e.g. pink snapdragons) and codominance (both alleles expressed, e.g. AB blood group) show dominance is not universal.

C. The Principle of Segregation

The two alleles of a gene separate during gamete formation so each gamete carries only one.

• Statement: paired factors segregate cleanly, and each gamete receives one member of the pair with equal probability.
• Cytological correlate: separation occurs at anaphase I of meiosis when homologous chromosomes part.
• F₂ result: selfing Tt × Tt restores both alleles.

        T        t
   T   TT       Tt
   t   Tt       tt

• Ratios: genotypic 1 TT : 2 Tt : 1 tt; phenotypic 3 tall : 1 dwarf.
• Worked check: Mendel counted 787 tall : 277 dwarf F₂ (≈2.84 : 1), a close empirical match to 3 : 1.
• Test cross: crossing an unknown dominant to tt reveals its genotype — all tall means TT; a 1 : 1 ratio means Tt.

D. The Principle of Independent Assortment

The alleles of different genes segregate independently of one another during gamete formation.

• Dihybrid cross setup: RRYY (round yellow) × rryy (wrinkled green) → F₁ all RrYy, round yellow.
• Gamete types from F₁: four in equal proportion — RY, Ry, rY, ry.
• F₂ phenotypic ratio: 9 round yellow : 3 round green : 3 wrinkled yellow : 1 wrinkled green (9:3:3:1).
• Underlying rule: the R/r pair assorts without regard to the Y/y pair, giving new combinations (recombinants) such as round green.
• Product rule confirmation: two independent 3:1 ratios multiply to (3:1)(3:1) = 9:3:3:1.
• Cytological limit: independence holds only for genes on different chromosomes (or far apart on one); linked genes violate it — the point Morgan later exploited.

III. The Chromosomal Basis of Inheritance

A. Foundational proposal

By 1900 the rediscovery of Mendel's work coincided with detailed observation of meiosis. Sutton and Boveri independently noted that chromosomes behave exactly as Mendel's factors must, giving rise to the chromosome theory.

B. Chromosomal theory of Inheritance

Genes are carried on chromosomes, whose meiotic behaviour explains Mendel's laws.

• Parallelism of factors and chromosomes: chromosomes, like alleles, occur in homologous pairs; one member of each pair comes from each parent.
• Explains segregation: homologous chromosomes separate at meiosis I, so their alleles separate — Mendel's first law.
• Explains independent assortment: non-homologous chromosome pairs orient randomly at the metaphase I plate, so genes on different chromosomes assort independently — Mendel's second law.
• Continuity: chromosome number is halved in gametes (n) and restored at fertilisation (2n), preserving the diploid state.
• Proponents: Walter Sutton (1902) and Theodor Boveri (1902), hence the Sutton–Boveri theory.

C. Morgan's Drosophila experiment

Thomas Hunt Morgan's fruit-fly work (Columbia University, c. 1910) supplied the physical proof that a gene resides on a specific chromosome.

• Why Drosophila melanogaster: short life cycle (~2 weeks), abundant offspring, only four chromosome pairs, and easily scored mutants.
• The white-eye mutant: a spontaneous white-eyed male appeared among red-eyed (wild-type) flies; red is dominant.
• The reciprocal crosses:
  1. White-eyed male × red-eyed female: F₁ all red-eyed; F₂ showed the 3:1 red:white ratio but all white-eyed flies were male.
  2. Interpretation: the eye-colour gene sits on the X chromosome, so inheritance tracks the sex chromosomes, not the autosomes.
• Notation: X^W (red) dominant to X^w (white); males X^W Y or X^w Y.
• Conclusion: a specific gene was mapped to a specific chromosome (the X), directly confirming the chromosome theory and founding the concept of sex-linked genes. Morgan received the Nobel Prize in 1933.

IV. Patterns of Inheritance

A. Distinguishing framework

Whether a trait follows a simple Mendelian ratio or a sex-dependent pattern depends on which chromosome carries the gene. Traits split into autosomal (chromosomes 1–22 in humans) and sex-linked (X or Y).

B. Autosomal inheritance

Genes on the non-sex chromosomes are inherited identically in both sexes.

1. Autosomal dominant:
   • Pattern: a single dominant allele expresses the trait; affected individuals usually have an affected parent — the trait appears in every generation.
   • Cross: Aa × aa → 1 affected : 1 unaffected; both sexes equally affected.
   • Example: Huntington's disease, achondroplasia.
2. Autosomal recessive:
   • Pattern: the trait appears only in homozygotes (aa); it can skip generations, and two unaffected carriers (Aa) can produce affected children.
   • Cross: Aa × Aa → 3 unaffected : 1 affected (¼ affected, ½ carriers).
   • Example: cystic fibrosis, sickle-cell anaemia.
   • Shared feature: males and females affected in equal proportions, the diagnostic mark separating autosomal from sex-linked traits.

C. Sex linked inheritance

Genes located on the sex chromosomes produce inheritance patterns tied to the offspring's sex.

• Chromosomal setting: females are XX, males XY; the X carries many genes, the Y very few.
• Hemizygosity: males carry only one X, so a single recessive X-linked allele is expressed — there is no second allele to mask it.
• X-linked recessive:
  • Pattern: far commoner in males; an affected male inherits the allele from a carrier mother (X^A X^a).
  • Carrier cross: X^A X^a × X^A Y → daughters all unaffected (half carriers), sons half affected.
  • Example: haemophilia, red–green colour blindness, Drosophila white eye.
• X-linked dominant:
  • Pattern: affected males pass the trait to all daughters and no sons (sons get the Y).
  • Example: hypophosphatemic (vitamin-D-resistant) rickets.
• Y-linked (holandric):
  • Pattern: genes on the Y pass strictly father → son; every son of an affected male is affected, no daughters ever are.
  • Example: genes controlling testis determination (SRY).
• Criss-cross inheritance: a trait passing from an affected grandfather through his unaffected carrier daughter to half his grandsons — the visible signature of X-linkage that Morgan's white-eye data first revealed.