Why Haemophilia Is Far More Common in Men Than in Women

Whether a baby is a boy or a girl, and whether it inherits a disorder such as haemophilia or Down's syndrome, depends on chromosomes and the genes they carry. Tracing these through families helps predict risk and plan care.

This part covers sex determination, mutation, pedigree analysis, and Mendelian and chromosomal disorders.

Humans are XX-XY, so the sperm decides sex; birds are ZZ-ZW, so the egg decides; and honey bees are haplodiploid, with diploid females and haploid males.

Humans — XX-XY:

- Females, XX, make only X-carrying eggs — they are homogametic
- Males, XY, make X and Y sperm in equal numbers — they are heterogametic
- The sex chromosome in the sperm decides the child's sex

Birds — ZZ-ZW:

- Females are ZW and heterogametic, making Z and W eggs
- Males are ZZ and homogametic
- The egg decides the sex of the chick

Honey bees — haplodiploidy:

- A fertilised egg, with $2n=32$, develops into a female — a queen or a worker
- An unfertilised egg develops by parthenogenesis into a male drone with $n=16$
- Drones make sperm by mitosis; they have no father and cannot have sons, but have a grandfather and can have grandsons

An everyday example. Poultry farmers raising chicks work with a system in which the hen, not the rooster, determines the sex of the offspring.

The substance. The heterogametic sex decides the offspring's sex — the male in humans, the female in birds.

A mutation is a change in DNA sequence; a point mutation alters a single base pair, as in sickle-cell anaemia, while chromosomal aberrations alter chromosome structure by deletion, duplication, inversion or translocation.

Point mutation — sickle-cell anaemia:

- A single base substitution in the gene for the **$\beta$-globin chain of haemoglobin
- At the sixth position, glutamic acid is replaced by valine
- The mRNA codon changes from GAG to GUG
- Under low oxygen, the altered haemoglobin polymerises and red blood cells become sickle-shaped

Chromosomal aberrations, often seen in cancer cells:

- Deletion — a segment of a chromosome is lost
- Duplication — a segment is repeated
- Inversion — a segment is reversed end to end
- Translocation — a segment moves to a non-homologous chromosome

Mutagens, such as ultraviolet radiation, are agents that cause mutations.

An everyday example. Sunburn from strong ultraviolet light can damage DNA in skin cells, a reminder that UV radiation is a mutagen.

The substance. A single base change can transform a protein** — one altered amino acid among well over a hundred changes how the whole haemoglobin molecule behaves.

A pedigree chart uses standard symbols to show family members and their relationships across generations, and the pattern of affected individuals reveals whether a trait is dominant or recessive and whether it is autosomal or sex-linked.

Standard symbols:

- Square — male; circle — female
- Shaded symbol — affected individual
- Horizontal line between a male and a female — mating
- Double line — consanguineous mating, between relatives
- Vertical line down to the offspring, shown in birth order from left to right

Clues for common patterns:

- Autosomal dominant — affected individuals usually have an affected parent, the trait appears in every generation, and both sexes are affected equally
- Autosomal recessive — the trait can skip generations, two unaffected carriers can have an affected child, and both sexes are affected, as in sickle-cell anaemia
- X-linked recessive — mostly males are affected, the allele passes from carrier mothers to sons, and it is never passed from father to son, as in haemophilia

Worked example. Two unaffected parents have an affected daughter. The trait cannot be dominant, since neither parent shows it, and it cannot be X-linked recessive, since an affected daughter would need an affected father. It must be autosomal recessive, with both parents carriers (Aa), so each further child has a $\frac{1}{4}$ chance of being affected.

An everyday example. Genetic counsellors draw pedigrees for families in which a disorder such as thalassaemia has appeared, to advise relatives about their risk.

The substance. Human genetics relies on pedigrees because controlled crosses, like those used with peas, are impossible in people.

Mendelian disorders come from a change in a single gene and follow Mendel's patterns, while chromosomal disorders come from missing, extra or rearranged chromosomes, often after chromatids fail to separate.

Mendelian disorders:

- Haemophilia — X-linked recessive; a missing clotting protein makes even a small cut bleed for a long time; carrier females are rarely affected
- Colour blindness — X-linked recessive; defects in the red or green cones of the eye
- Sickle-cell anaemia — autosomal recessive; Hb${}^S$Hb${}^S$ individuals have the disease, while Hb${}^A$Hb${}^S$ carriers are usually healthy
- Phenylketonuria — autosomal recessive; lack of the enzyme that converts phenylalanine to tyrosine lets phenylalanine accumulate
- Thalassaemia — autosomal recessive; reduced synthesis of $\alpha$ or $\beta$ globin chains causes anaemia

Chromosomal disorders:

- Down's syndrome — trisomy 21; short stature, a small round head, a furrowed tongue and delayed development
- Klinefelter's syndrome — XXY, $47$ chromosomes; masculine development with some feminine features and sterility
- Turner's syndrome — XO, $45$ chromosomes; sterile females with rudimentary ovaries and underdeveloped secondary sexual characters

Worked example. A carrier mother, X${}^H$X${}^h$, and an unaffected father give each son a $\frac{1}{2}$ chance of haemophilia, while daughters are at most carriers.

An everyday example. Screening for thalassaemia carriers is encouraged for couples in India, so that children do not inherit two defective alleles.

The substance. Mendelian and chromosomal disorders differ in scale — one gene altered, against a whole chromosome gained or lost.