Mutation and genetic disorders

A mutation is a change in the DNA sequence, which can change the gene's product. It may affect a whole chromosome piece (deletion, duplication) or just one base pair: a point mutation, as in sickle-cell anaemia. Chemical and physical agents that cause mutations, such as UV radiation, are mutagens.

We cannot do controlled crosses with humans, so geneticists study how a trait runs through a family over several generations, using a family tree: this is pedigree analysis, drawn with standard symbols (squares for males, circles for females, shaded for affected people).

Genetic disorders are of two broad kinds.

Mendelian disorders, caused by a change in one gene, inherited by Mendel's rules:

• Haemophilia (sex-linked recessive): a protein needed for blood clotting is missing, so even a small cut can bleed for a long time. The gene is on the X chromosome, so it is much more common in males. A woman with one faulty copy is a healthy carrier; Queen Victoria was a famous carrier, and many of her descendants had the disease.
• Colour blindness (sex-linked recessive): difficulty telling red from green. It affects about 8% of males but only about 0.4% of females: a male needs only one faulty X, a female needs two.
• Sickle-cell anaemia (autosomal recessive): a single base change makes valine replace glutamic acid at the sixth position of the haemoglobin β chain. Under low oxygen, the faulty haemoglobin clumps and bends red blood cells into a sickle shape. Only HbˢHbˢ people are ill; heterozygotes are carriers.
• Phenylketonuria (autosomal recessive): see the previous lesson.
• Thalassemia (autosomal recessive): the body makes too few globin chains, so haemoglobin is short. Note the difference: thalassemia is a quantity problem (too little globin), sickle-cell anaemia a quality problem (wrong globin).

Chromosomal disorders, caused by extra, missing or rearranged chromosomes. Gaining or losing one chromosome is aneuploidy (from errors when chromosomes separate); having whole extra sets is polyploidy, common in plants.

• Down's syndrome: an extra copy of chromosome 21 (trisomy 21). Short stature, a small round head, a furrowed tongue, partly open mouth, and delayed physical and mental development.
• Klinefelter's syndrome: an extra X in a male, 47, XXY. A tall, sterile male with some female features.
• Turner's syndrome: a missing X in a female, 45, X0. A short, sterile female whose ovaries do not develop.