(a) Give a detailed account on sex linked inheritance ? (20 marks) (b) Explain the structural variations of chromosomes and…

(a) Sex-linked inheritance (20 marks)

Sex-linked inheritance is the inheritance of genes located on the sex chromosomes. Because the X and Y chromosomes differ in gene content, the inheritance of such genes differs in the two sexes.

Types:

• X-linked (the commonest): genes on the X chromosome with no counterpart on the Y, so males are hemizygous and express even a recessive allele. Examples in humans are red-green colour blindness, haemophilia A, and Duchenne muscular dystrophy (recessive), and hypophosphataemic rickets (dominant).
• Y-linked (holandric): genes on the Y chromosome pass only from father to son, as SRY, the male-determining gene.
• Genes in the pseudoautosomal regions, which are homologous on X and Y, behave like autosomal genes.
• In birds, moths and some reptiles females are ZW and males ZZ, and Z-linked genes, such as the barred plumage gene in Plymouth Rock fowl, show a reversed pattern.

Morgan's experiment (1910). In Drosophila, a white-eyed male crossed with a red-eyed female gave red-eyed F1, and the F2 had red and white eyes in a 3 : 1 ratio, with all the white-eyed flies male. In the reciprocal cross, a white-eyed female crossed with a red-eyed male gave red-eyed daughters and white-eyed sons in F1, and a 1 : 1 : 1 : 1 ratio in F2. This shows criss-cross inheritance and that the eye-colour gene lies on the X chromosome. Bridges' study of non-disjunction later gave strong support to the chromosome theory.

Characteristics of X-linked recessive inheritance:

• Males are affected more often than females.
• An affected father passes the gene to all his daughters, who become carriers, and to none of his sons.
• A carrier mother passes it to half of her sons, who are affected, and half of her daughters, who are carriers.
• Traits skip a generation, moving from a grandfather through a carrier daughter to a grandson.

Examples. A colour-blind man and a normal woman produce normal sons and carrier daughters. A carrier woman and a normal man produce, in equal proportion, a normal daughter, a carrier daughter, a normal son and a colour-blind son. Haemophilia A (factor VIII deficiency) appeared in the descendants of Queen Victoria.

Females have two X chromosomes but one is inactivated (Barr body, the Lyon hypothesis), so gene dosage is equal in the two sexes and heterozygous females are mosaics. Sex-linked genes should not be confused with sex-limited genes, expressed only in one sex, or sex-influenced genes, whose expression depends on the sex, such as baldness.

(b) Structural variations of chromosomes and their significance (15 marks)

Structural variations are changes in the structure of a chromosome, from breakage and faulty rejoining, that alter the number or order of genes. There are four types:

• Deletion (deficiency): loss of a segment, terminal or interstitial. In a heterozygote, the normal chromosome forms a loop at pachytene. Homozygous deletions are usually lethal. Examples are cri-du-chat syndrome (deletion of 5p) and Notch in Drosophila. Deletions help to map genes and cause pseudodominance.
• Duplication: a segment is repeated, tandem or displaced. The Bar eye of Drosophila is due to a duplication of band 16A. Duplications supply extra genes that may evolve new functions, as in the globin gene families.
• Inversion: a segment is reversed, paracentric (excluding the centromere) or pericentric (including it). In heterozygotes an inversion loop forms; crossing over in it gives dicentric bridges and acentric fragments in the paracentric type, so recombination is suppressed. Inversions maintain gene combinations and are important in the evolution of Drosophila species.
• Translocation: a segment is shifted to a non-homologous chromosome, simple or reciprocal; a Robertsonian translocation joins two acrocentrics. In a reciprocal translocation heterozygote the meiotic configuration is a ring or a chain of four, and gametes are often unbalanced, so there is semi-sterility. The Philadelphia chromosome, t(9;22), produces the BCR-ABL gene in chronic myeloid leukaemia, and familial Down syndrome can arise from a 14;21 translocation.

Significance:

• They are a source of variation for evolution and speciation, and change the karyotype.
• They cause genetic disease and cancer.
• They are tools for gene mapping, and balancer chromosomes with inversions maintain lethal genes.
• In breeding, translocations transfer alien genes, as in wheat-rye 1BL.1RS lines and leaf rust resistance from Aegilops and Agropyron.

(c) Role of the biochemical and molecular basis of mutation (15 marks)

Biochemical basis. Garrod and later Beadle and Tatum (Neurospora, 1941) showed that a mutation changes a gene, and hence an enzyme, causing a block in a metabolic pathway: inborn errors such as alkaptonuria, phenylketonuria (phenylalanine hydroxylase) and albinism (tyrosinase). Ingram showed in 1957 that sickle-cell disease is a single amino acid change in beta globin (glutamic acid to valine, from a single base change, GAG to GUG). Biochemical mutants (auxotrophs) have been used to work out pathways, and the Ames test uses Salmonella his⁻ reversion to detect mutagens.

Molecular basis:

• Base substitutions are transitions (purine to purine or pyrimidine to pyrimidine) or transversions, and deletions and insertions cause frameshifts.
• Spontaneous mutation comes from rare tautomeric shifts causing mismatches, depurination, deamination of cytosine to uracil and of 5-methylcytosine to thymine (CpG hotspots), replication slippage, oxidative damage (8-oxoguanine), and insertion of transposons.
• Induced mutation is caused by base analogues (5-bromouracil, 2-aminopurine, giving transitions), nitrous acid (deamination), hydroxylamine, alkylating agents such as EMS (O⁶-ethylguanine pairing with thymine), intercalating agents such as acridines (frameshifts), UV light (thymine dimers) and ionising radiation (breaks).
• DNA repair (photoreactivation, excision repair, mismatch repair, recombination repair) corrects most damage, and failure of repair (xeroderma pigmentosum) leaves mutations.

Role of this knowledge:

• Understanding genetic diseases and cancer (RAS point mutation, TP53).
• Induced mutation breeding of crops, such as Sharbati Sonora wheat and many other varieties.
• Screening of mutagens and carcinogens, and design of site-directed mutagenesis and genome editing.
• Explaining the source of variation in evolution.