Principles of Inheritance and Variation

Genetics is the study of inheritance and variation, and its foundations were laid by Gregor Mendel, who worked on the garden pea (Pisum sativum). The pea was an excellent choice: it has several clear contrasting traits (he studied seven, such as tall/dwarf and round/wrinkled seeds), it is naturally self-pollinating (so true-breeding lines are easy to keep), it has a short life cycle and produces many offspring for statistical analysis.

In a monohybrid cross Mendel crossed two true-breeding parents differing in one trait, e.g. tall (TT) × dwarf (tt). The whole F1 generation was tall (Tt) — the dwarf character had not blended or disappeared but was simply masked. This is the Law of Dominance: in a hybrid, one allele (the dominant, T) expresses itself and the other (the recessive, t) stays hidden.

When the F1 plants were self-pollinated, the F2 generation showed both tall and dwarf plants in a 3:1 phenotypic ratio (and a 1:2:1 genotypic ratio: 1 TT : 2 Tt : 1 tt). The dwarf trait reappeared, proving that the recessive allele had been present but hidden in the F1. To explain this Mendel proposed the Law of Segregation (Law of Purity of Gametes): the two alleles of a trait separate during gamete formation, so each gamete carries only one allele; a gamete is therefore always 'pure' for the trait.

To find the genotype of a tall plant (TT or Tt?), Mendel used a test cross — crossing the unknown with the homozygous recessive (tt). If the tall plant is TT, all offspring are tall; if it is Tt, the offspring are 1 tall : 1 dwarf (1:1). For NEET, fix why the pea was chosen, the monohybrid F2 ratios (3:1 phenotype, 1:2:1 genotype), the Laws of Dominance and Segregation, and the test-cross logic (1:1 reveals a heterozygote).

In a dihybrid cross Mendel followed two traits at once, e.g. round-yellow (RRYY) × wrinkled-green (rryy). The F1 were all round-yellow (RrYy). On selfing, the F2 showed four phenotypes in the famous 9:3:3:1 ratio (9 round-yellow : 3 round-green : 3 wrinkled-yellow : 1 wrinkled-green). The appearance of the two new combinations (round-green and wrinkled-yellow) showed that the two traits were inherited independently. This is the Law of Independent Assortment: during gamete formation, the alleles of one trait assort independently of the alleles of another.

Later work showed that not all inheritance follows simple dominance — these are the extensions of Mendelism. In incomplete dominance, the heterozygote shows a blended, intermediate phenotype. The classic example is the snapdragon (Antirrhinum) or 4-o'clock plant: red (RR) × white (rr) gives pink (Rr) in F1, and the F2 ratio is 1 red : 2 pink : 1 white — i.e. the phenotypic ratio equals the genotypic ratio (1:2:1) because each genotype looks different.

In codominance, both alleles are fully and equally expressed in the heterozygote, so both characters appear together (not blended). The best example is the human ABO blood group: a person with genotype I^A I^B has blood group AB, showing both A and B antigens.

The ABO system also illustrates multiple alleles — a gene with more than two alleles in the population. Here three alleles exist: I^A and I^B (codominant to each other, both dominant over i) and i (recessive), giving blood groups A, B, AB and O. Another extension is pleiotropy, where a single gene affects several traits (e.g. phenylketonuria, sickle-cell anaemia). For NEET, fix the dihybrid 9:3:3:1 and Independent Assortment, and clearly separate incomplete dominance (blended; pink; F2 1:2:1) from codominance (both expressed; AB blood) and multiple alleles (I^A, I^B, i).

Mendel's 'factors' were later identified with genes on chromosomes. The chromosomal theory of inheritance, proposed by Sutton and Boveri, noted that the behaviour of chromosomes during meiosis (pairing, segregation and independent assortment) exactly parallels Mendel's laws — so genes must be located on chromosomes.

If genes are on chromosomes, then genes on the same chromosome should be inherited together. This is linkage, discovered by Thomas Hunt Morgan working on the fruit fly Drosophila melanogaster. Linked genes do not assort independently; instead they tend to stay together. The strength of linkage depends on the distance between the genes: genes that are close together are tightly linked (rarely separated), while genes far apart are separated more often by recombination (crossing over). Morgan's student Sturtevant used recombination frequency to build the first genetic maps of chromosomes.

Whether an organism is male or female is fixed by sex determination, which often involves special sex chromosomes. In the XX–XY type (humans and Drosophila), the female is XX and the male is XY; here the male is heterogametic (makes X- and Y-bearing gametes). In the XX–XO type (some insects like grasshoppers), females are XX and males have a single X (XO). In the ZZ–ZW type (birds), the situation is reversed — the female is heterogametic (ZW) and the male is ZZ.

In humans, each cell has 23 pairs of chromosomes — 22 pairs of autosomes plus one pair of sex chromosomes (XX in females, XY in males). Because the female always contributes an X but the male contributes either an X or a Y, it is the father's sperm that determines the sex of the child. For NEET, fix Sutton & Boveri (chromosomal theory), Morgan's linkage/recombination on Drosophila, and the sex-determination systems with which sex is heterogametic in each.

Variation can also arise suddenly through mutation — a change in the genetic material (DNA). A point (gene) mutation changes a single base pair; the classic example is sickle-cell anaemia, caused by the substitution of a single base that changes one amino acid (glutamic acid → valine, Glu→Val) at the sixth position of the haemoglobin β-chain. A frameshift mutation (insertion or deletion of bases) shifts the reading frame and alters everything downstream. Mutations are the raw material of variation and evolution but can also cause disease.

Human genetic disorders are of two broad kinds. Mendelian disorders are caused by an alteration in a single gene and follow Mendelian inheritance. Important X-linked recessive disorders are haemophilia (blood fails to clot) and colour blindness (red-green) — both are far more common in males, who need only one defective X. Important autosomal recessive disorders include sickle-cell anaemia and thalassaemia (defective haemoglobin) and phenylketonuria (PKU) (a metabolic disorder where phenylalanine cannot be broken down). Thalassaemia is a quantitative problem (too little globin made), whereas sickle-cell is a qualitative one (abnormal globin).

Chromosomal disorders are caused by the absence, excess or abnormal arrangement of chromosomes, usually due to non-disjunction (failure of chromosomes to separate in meiosis). Down's syndrome is a trisomy of chromosome 21 (an extra 21), with characteristic features and intellectual disability. Klinefelter's syndrome is 47, XXY — an individual who is overall male but with some feminine features and usually sterile. Turner's syndrome is 45, X0 (one X missing) — a female who is sterile with underdeveloped ovaries.

So mutations underlie variation, single-gene changes cause Mendelian disorders, and changes in chromosome number cause chromosomal disorders. For NEET, fix the sickle-cell point mutation (Glu→Val, single base), the inheritance pattern of each Mendelian disorder (haemophilia & colour blindness = X-linked recessive; sickle-cell, thalassaemia, PKU = autosomal recessive), and the three chromosomal disorders with their karyotypes (Down's = trisomy 21; Klinefelter's = XXY; Turner's = X0).