Sex determination in humans operates through the XX-XY chromosomal system. Normal human females carry 44 autosomes plus two X chromosomes (44+XX, total 46), while males carry 44 autosomes plus one X and one Y chromosome (44+XY, total 46). The critical point is that mothers always contribute an X chromosome in their eggs, making them homogametic. Fathers contribute either an X chromosome (producing a daughter) or a Y chromosome (producing a son) in their sperm, making them heterogametic. Therefore, the sex of the offspring is determined entirely by which gamete the father contributes — a fact with historical significance in cultures that incorrectly blamed mothers for failing to produce male heirs.

Sex determination is not universal across the animal kingdom. Grasshoppers and cockroaches use the XX-XO system, where females are XX and males carry only one X chromosome with no corresponding sex chromosome (XO). Males in this system have 2n-1 chromosomes — one fewer than females — and produce two types of sperm in equal proportions: X-bearing sperm and O-bearing sperm (carrying no sex chromosome). Birds, butterflies, and certain fish and reptiles use the ZW-ZZ system, which is the mirror image of the human XX-XY system. In birds, males are ZZ (homogametic) and females are ZW (heterogametic), meaning that in these species the mother determines the sex of the offspring rather than the father.

Sex-linked inheritance concerns genes carried on the sex chromosomes, most importantly on the X chromosome. Males are described as hemizygous for X-linked genes because they possess only a single X chromosome with no corresponding allele on the Y to provide a dominant masking effect. Any allele on the male's X chromosome — whether dominant or recessive — is expressed. This hemizygosity explains why X-linked recessive disorders such as haemophilia A and red-green colour blindness are far more common in males than in females. Females require two copies of the recessive allele (homozygous $X^a$ $X^a$) for the disorder to manifest, which necessitates both a carrier or affected mother and an affected father — a statistically uncommon combination.

The standard carrier-female cross ($X^H$ $X^h$ × $X^H$ Y) yields four equally likely outcomes: normal female ($X^H$ $X^H$), carrier female ($X^H$ $X^h$), normal male ($X^H$ Y), and haemophilic male ($X^h$ Y), each at 25%. Among sons, 50% are affected; among daughters, 50% are carriers, and none are affected. The most important rule for pedigree analysis is that fathers pass their Y chromosome to all sons and their X chromosome to all daughters. Consequently, X-linked traits cannot be transmitted from father to son — "no male-to-male transmission" is the definitive pedigree clue for X-linked inheritance. Affected females ($X^h$ $X^h$) can only arise when the father is affected ($X^h$ Y) and the mother is at least a carrier ($X^H$ $X^h$), producing a 25% chance of an affected daughter.

Pedigree analysis is a systematic method of identifying inheritance patterns from family trees. Autosomal dominant traits appear in every generation without skipping, affect both sexes equally, and every affected individual has at least one affected parent. Autosomal recessive traits may skip generations, both parents of an affected individual are typically phenotypically normal carriers, and males and females are equally affected. X-linked recessive traits show a disproportionate number of affected males, no father-to-son transmission, carrier females in each generation, and affected females only when both an affected father and carrier mother contribute. X-linked dominant inheritance is identified by an affected father passing the allele to all daughters but no sons.

Mendelian disorders arise from mutations in single genes and follow predictable Mendelian inheritance ratios. Sickle cell anaemia is caused by a point mutation in the HBB gene on chromosome 11 that changes mRNA codon 6 from GAG (encoding glutamic acid) to GUG (encoding valine). This single amino acid substitution (glutamic acid → valine) at position 6 of the beta-globin chain creates a hydrophobic surface patch on the HbS molecule. Under deoxygenated conditions, this patch promotes HbS polymerization into long fibres that distort red blood cells into a rigid sickle shape. Sickled cells obstruct capillaries (vaso-occlusion) and are rapidly destroyed by the spleen (haemolytic anaemia), causing the hallmark features of the disease. Sickle cell anaemia is autosomal recessive, and heterozygous carriers (HbA/HbS, sickle cell trait) are largely asymptomatic and carry partial protection against severe Plasmodium falciparum malaria in endemic regions.

Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH gene, chromosome 12), leading to accumulation of phenylalanine and consequent neurological damage. Thalassemia encompasses a group of autosomal recessive disorders characterised by reduced synthesis of either alpha-globin (HBA genes, chromosome 16) or beta-globin (HBB gene, chromosome 11) chains. Haemophilia A results from deficiency of clotting factor VIII (F8 gene, X chromosome) and is X-linked recessive, accounting for its high prevalence in males.

Chromosomal disorders arise from aneuploidy — abnormal chromosome number resulting from non-disjunction during meiosis. Down syndrome (trisomy 21, karyotype 47, +21) results from an extra chromosome 21 and presents with intellectual disability, short stature, epicanthic folds, and a broad palm with a simian crease. Turner syndrome (karyotype 45, XO) is monosomy of the X chromosome; the individual is female (no Y chromosome, default female development), presenting with short stature, webbed neck, shield chest, and infertility due to streak gonads. Klinefelter syndrome (karyotype 47, XXY) affects males — despite two X chromosomes, the Y chromosome carries the SRY gene that triggers testicular development, making the individual male. Clinical features include gynaecomastia, tall stature, small testes, and reduced fertility. Super Female syndrome (47, XXX) is often phenotypically normal. Understanding the distinction between Mendelian disorders (single-gene mutations) and chromosomal disorders (aneuploidy, detectable by karyotyping) is fundamental to the NEET syllabus.