Why do X-linked recessive disorders predominantly affect males?

Step 1 — Structure: Males have one X chromosome (from mother) and one Y chromosome (from father). The Y chromosome is small and does not carry most of the genes present on X.

Step 2 — Hemizygosity: For genes on the X chromosome, males have only ONE copy (hemizygous). There is no corresponding allele on Y to provide a backup or masking effect.

Step 3 — Expression: Any allele on the male's single X chromosome — whether dominant or recessive — is expressed. A recessive allele that would be masked in a female (heterozygous $X^A$ $X^a$) is fully expressed in a male ($X^a$ Y).

Step 4 — Female Protection: Females have TWO X chromosomes. If one X carries the recessive allele ($X^a$) but the other carries the dominant allele ($X^A$), the dominant allele masks the recessive → female is phenotypically normal (carrier). Two copies of the recessive allele ($X^a$ $X^a$) are required for a female to be affected — requiring the rare combination of a carrier/affected mother + affected father.

Step 5 — Population Level: Because male expression frequency = allele frequency (q), while female expression frequency = $q^{2}$ (much smaller for rare alleles), X-linked recessive conditions are always more prevalent in males.

Why is sickle cell haemoglobin (HbS) harmful only under low oxygen conditions?

Step 1: Normal HbA: glutamic acid at position 6 of beta-globin is hydrophilic and charged. It sits on the surface of the haemoglobin molecule and does not interact with adjacent haemoglobin molecules.

Step 2: HbS mutation: valine (hydrophobic, non-charged) replaces glutamic acid at position 6. This creates a surface hydrophobic "sticky patch" on the beta-globin subunit.

Step 3: Under oxygenated conditions: haemoglobin is in the "oxy" conformation (R-state, round shape). In this conformation, the hydrophobic sticky patch is partially buried and cannot readily interact with neighbouring HbS molecules.

Step 4: Under deoxygenated conditions: haemoglobin switches to "deoxy" conformation (T-state, tense shape). This conformational change exposes a complementary hydrophobic pocket on another HbS molecule, allowing the sticky patch to dock into it.

Step 5: Polymerization: Multiple HbS molecules chain together via these hydrophobic interactions, forming long fibres (tactoids) that distort the RBC membrane into a rigid sickle shape.

Step 6 — Clinical impact: Sickled RBCs are rigid (cannot deform to pass through capillaries), block small vessels (vaso-occlusion), and are destroyed rapidly by the spleen (haemolytic anaemia).