Mutation Genetic Disorders

5.11 Mutation

Mutation is a sudden, heritable change in the DNA sequence or chromosomal structure of an organism. Mutations are the ultimate source of all new genetic variation upon which natural selection acts.

5.11.1 Types of Mutation

5.11.2 Mutagens

Agents that cause mutations are called mutagens. They include:

• Physical mutagens: UV radiation, X-rays, gamma rays.
• Chemical mutagens: Base analogues (5-bromouracil), alkylating agents, intercalating dyes (ethidium bromide).
• Biological mutagens: Some viruses and transposons.

5.12 Genetic Disorders

Genetic disorders are broadly grouped into Mendelian disorders (caused by single-gene mutations) and Chromosomal disorders (caused by changes in chromosome number or structure).

5.12.1 Mendelian Disorders

a) Haemophilia (X-linked recessive)

A blood-clotting disorder caused by a defect in clotting factors (commonly factor VIII for haemophilia A, or factor IX for haemophilia B). The X-linked recessive allele means:

• Affected males (X^hY) cannot clot blood properly — even minor cuts cause prolonged bleeding.
• Heterozygous females (X^HX^h) are carriers — they don't have the disorder but can pass it to sons.
• Homozygous females (X^hX^h) are very rare because they'd need two haemophilic alleles — usually fatal in pre-modern times.

b) Sickle Cell Anaemia (Autosomal recessive)

Sickle cell anaemia is caused by a substitution mutation: glutamic acid (Glu) is replaced by valine (Val) at position 6 of the β-globin chain. The mutated haemoglobin (HbS) polymerises under low oxygen, causing red blood cells to assume a sickle shape.

• HbA HbA (homozygous normal): unaffected.
• HbA HbS (heterozygous, sickle-cell trait): mildly affected; partly malaria-resistant.
• HbS HbS (homozygous): full sickle cell anaemia; severe anaemia, organ damage.

c) Thalassemia (Autosomal recessive)

Thalassemia is caused by mutations that reduce the production of either α-globin (α-thalassemia) or β-globin (β-thalassemia) chains. Unlike sickle cell where haemoglobin is made but defective, in thalassemia haemoglobin is not made in adequate amounts. Patients require regular blood transfusions.

d) Phenylketonuria (Autosomal recessive)

An autosomal recessive disorder where the enzyme that converts phenylalanine to tyrosine is defective. Phenylalanine accumulates and is converted to phenylpyruvic acid, which damages the developing brain — leading to mental retardation if untreated. Detected at birth and managed by a phenylalanine-restricted diet.

5.12.2 Chromosomal Disorders

These are caused by changes in chromosome number — usually due to non-disjunction (failure of chromosomes to separate during meiosis).

a) Down Syndrome (Trisomy 21)

Caused by an extra copy of chromosome 21 → karyotype 2n + 1 = 47 (47, XX or XY, +21). First described by Langdon Down (1866). Features: short stature, characteristic facial features (epicanthic folds, broad palm, simian crease), intellectual disability, congenital heart defects, mostly delayed mental and physical development.

b) Klinefelter Syndrome (47, XXY)

Caused by an extra X chromosome in males → XXY (47 chromosomes). Features: tall stature, mild gynaecomastia (breast development), small testes, sterility, sometimes mild learning difficulties. Phenotypically male but with some feminine features.

c) Turner Syndrome (45, XO)

Caused by absence of one X chromosome in females → XO (45 chromosomes). Features: short stature, webbed neck, broad chest, underdeveloped ovaries (sterility), no menstrual cycle, often normal intelligence.

Worked Examples