Sex Determination, Mutation and Genetic Disorders — Notes

In 1891 Henking traced a specific nuclear structure through spermatogenesis in some insects; half the sperms received it and half did not. He called it the X body; it was later identified as the X chromosome. Chromosomes involved in determining sex are sex chromosomes; the rest are autosomes.

• Male heterogamety, XX–XY: females XX, males XY (humans, Drosophila). Human females are 44 + XX and males 44 + XY. All eggs carry X; sperms carry X or Y in equal numbers, so the sperm decides the sex and each child has a 50 percent chance of either sex.
• Male heterogamety, XX–XO: in many insects such as the grasshopper, females have two X chromosomes and males one X and no Y, so males have one chromosome fewer.
• Female heterogamety, ZW–ZZ: in birds, females are ZW (two kinds of eggs) and males ZZ, so the egg decides the sex.
• Haplodiploidy: in honey bees, a fertilised egg develops into a female (queen or worker, diploid, 32 chromosomes) and an unfertilised egg develops into a male (drone, haploid, 16 chromosomes) by parthenogenesis. Males produce sperms by mitosis; they have no father and cannot have sons, but have a grandfather and can have grandsons.

Genes on the X chromosome (with no counterpart on Y) are X-linked; males, with one X, express any X-linked allele they carry (they are hemizygous).

Drosophila. Morgan found the white-eye allele to be X-linked recessive: red-eyed female × white-eyed male gives all red-eyed F1, and an F2 in which all females are red-eyed but half the males are white-eyed. In the reciprocal cross (white-eyed female × red-eyed male), F1 females are red-eyed and males white-eyed — criss-cross inheritance from mother to son. Yellow body is another X-linked recessive trait.

Haemophilia — X-linked recessive. A single protein involved in the cascade of proteins for blood clotting is affected, so a simple cut may result in non-stop bleeding. Heterozygous females (carriers) may transmit it to sons. Affected females are very rare: the mother must be at least a carrier and the father haemophilic. The family of Queen Victoria, a carrier, shows many haemophilic descendants.

Colour blindness — X-linked recessive mutation in genes for the red or green cones, so the person fails to discriminate red and green. It occurs in about 8 percent of males and only about 0.4 percent of females. A son of a carrier woman has a 50 percent chance of being colour blind; a daughter is colour blind only if her mother is at least a carrier and her father colour blind.

Key rules: a father passes his X to all daughters and his Y to all sons, so fathers never pass X-linked traits to sons; sons get their X from the mother.

Mutation is a phenomenon that results in alteration of DNA sequences and consequently in changes in the genotype and phenotype. Besides recombination, mutation is a source of variation.

• Spontaneous mutations occur naturally, for example through errors in DNA replication.
• Induced mutations are caused by mutagens: physical (UV radiation, X-rays and other ionising radiation) and chemical agents.
• Changes in chromosomes (loss, gain or rearrangement of segments or whole chromosomes) cause chromosomal aberrations, commonly seen in cancer cells.

Gene (point) mutations — change of a single base pair:

• Substitution: a transition replaces a purine by another purine (A ↔ G) or a pyrimidine by another pyrimidine (C ↔ T); a transversion replaces a purine by a pyrimidine or the reverse.
• Insertion or deletion of one or two bases changes the reading frame from that point onward: frameshift mutation. Insertion or deletion of three bases (one codon) adds or removes one amino acid, leaving the reading frame unaltered.
• Sickle-cell anaemia is the classical example of a point mutation: a single base substitution at the sixth codon of the β-globin gene, GAG → GUG, replaces glutamic acid by valine.

Disorders determined by alteration or mutation in a single gene; their pattern of inheritance can be traced in a pedigree.

• Sickle-cell anaemia — autosomal recessive. Caused by substitution of glutamic acid (Glu) by valine (Val) at the sixth position of the β-globin chain (codon GAG → GUG). The mutant haemoglobin (HbS) polymerises under low oxygen tension, changing red cells from biconcave discs to elongated sickle shapes. Only HbSHbS individuals show the disease; HbAHbS individuals are apparently unaffected carriers, with a 50 percent chance of passing on the allele.
• Phenylketonuria — autosomal recessive inborn error of metabolism. The affected person lacks the enzyme that converts the amino acid phenylalanine into tyrosine; phenylalanine accumulates and is converted into phenylpyruvic acid and other derivatives, which accumulate in the brain (mental retardation) and are excreted in urine because of poor absorption by the kidney.
• Thalassaemia — autosomal recessive blood disease caused by mutation or deletion that results in reduced rate of synthesis of one of the globin chains of haemoglobin, causing abnormal haemoglobin and anaemia. α-thalassaemia: production of α-globin affected; controlled by two closely linked genes HBA1 and HBA2 on chromosome 16. β-thalassaemia: production of β-globin affected; controlled by a single gene HBB on chromosome 11. Thalassaemia is a quantitative problem (too few globin molecules), while sickle-cell anaemia is a qualitative problem (an incorrectly functioning globin).
• Colour blindness and haemophilia — X-linked recessive (section 2).

Caused by absence, excess or abnormal arrangement of one or more chromosomes. Failure of segregation of chromatids during cell division results in gain or loss of a chromosome(s): aneuploidy. Failure of cytokinesis after telophase results in an increase in a whole set of chromosomes: polyploidy, often seen in plants. Trisomy is the presence of an additional copy of a chromosome; monosomy, the lack of one chromosome of a pair.

• Down’s syndrome — trisomy of chromosome 21 (47 chromosomes), first described by Langdon Down (1866). Short statured with a small round head, furrowed tongue and partially open mouth; broad palm with a characteristic palm crease; physical, psychomotor and mental development retarded.
• Klinefelter’s syndrome — an additional X chromosome in a male: 47, XXY. Overall masculine development, but feminine development (development of breasts, gynaecomastia) is also expressed; sterile.
• Turner’s syndrome — absence of one X chromosome: 45, X0. Females are sterile, as the ovaries are rudimentary; lack of other secondary sexual characters.