Chromosomal Basis of Inheritance, Sex Linkage & Genetic Disorders

Sex in humans is determined by the XX-XY chromosome system: females carry two X chromosomes (44+XX) while males carry one X and one Y (44+XY). The father's gamete determines the sex of the offspring, since mothers contribute only X chromosomes while fathers contribute either X or Y. Alternative sex determination systems exist across the animal kingdom. Grasshoppers use the XX-XO system, where females are XX and males carry only a single X with no corresponding sex chromosome. Birds, butterflies, and some reptiles follow the ZW-ZZ system, where males are homogametic (ZZ) and females are heterogametic (ZW), the exact reverse of the human pattern.

Sex-linked inheritance refers to genes located on the X chromosome. X-linked recessive traits, such as haemophilia and red-green colour blindness, are far more common in males because males are hemizygous for X-linked genes, possessing only a single X chromosome with no corresponding allele on the Y to mask recessive alleles. A worked example illustrates this clearly: when a carrier female (X^H X^h) is crossed with a normal male (X^H Y), the expected offspring are X^H X^H (normal female), X^H X^h (carrier female), X^H Y (normal male), and X^h Y (haemophilic male). Thus, 50% of the sons are affected and 50% of the daughters are carriers, while none of the daughters exhibit the disease. An affected female (X^h X^h) would require both a carrier mother and an affected father, making this exceptionally rare.

Pedigree analysis enables identification of inheritance patterns from family trees. Key indicators include: autosomal dominant traits affect both sexes equally and appear in every generation; autosomal recessive traits may skip generations and affected individuals often have unaffected parents; X-linked recessive traits show more affected males, no male-to-male transmission, and carrier females.

Mendelian disorders are caused by mutations in single genes. Sickle cell anemia results from a point mutation where glutamic acid at position 6 of the $\beta$-globin chain is replaced by valine (GAG to GUG in mRNA), causing HbS to polymerize under low oxygen. Phenylketonuria (PKU) is an autosomal recessive deficiency of phenylalanine hydroxylase. Thalassemia involves reduced or absent synthesis of $\alpha$ or $\beta$ globin chains.

Chromosomal disorders arise from aneuploidy. Down syndrome (trisomy 21, karyotype 47, +21) results from non-disjunction and presents with intellectual disability, short stature, and characteristic facial features. Turner syndrome (45, XO) affects females with short stature, webbed neck, and infertility. Klinefelter syndrome (47, XXY) affects males, who despite having two X chromosomes are male due to the presence of the Y chromosome, and show gynaecomastia and reduced fertility. The key testable concept is understanding why X-linked recessive disorders appear predominantly in males (hemizygosity) and correctly identifying chromosomal disorder karyotypes and their associated sex.