Human Genetics — Chromosomes, Inheritance Patterns and Genetic Disorders

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Human genetics is a high-yield topic in INI CET, frequently appearing in clinical scenarios and problem-based questions. Focus on Mendelian inheritance patterns, chromosomal abnormalities, and the difference between autosomal and sex-linked disorders.

High-Yield Facts for INI CET:

• Human diploid number: 46 chromosomes (23 pairs); haploid: 23
• Karyotype: 22 autosomal pairs + XX (female) or XY (male)
• Autosomal dominant:achondroplasia, Huntington’s disease; Autosomal recessive: cystic fibrosis, sickle cell anaemia, phenylketonuria
• X-linked recessive: Haemophilia A, Duchenne muscular dystrophy, red-green colour blindness

⚡ Exam tip: For inheritance pattern questions, always check whether both sexes are affected equally (autosomal) or if males are predominantly affected (X-linked recessive). Remember that X-linked recessive disorders almost never affect females unless they are homozygous or have Turner syndrome.

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Chromosomes and the Human Karyotype:

Normal Human Karyotype

• Total: 46 chromosomes — 22 pairs of autosomes + 1 pair of sex chromosomes
• Female: 46, XX — one X inherited from mother, one X from father
• Male: 46, XY — X from mother, Y from father
• Chromosomes are numbered 1-22 by decreasing size (chromosome 1 is largest)
• Chromosome banding (G-banding, Q-banding) is used to identify and characterise chromosomes

Chromosome Structure:

• Each chromosome consists of two chromatids joined at the centromere
• Centromere position determines chromosome type:
  • Metacentric: Centromere at centre (chromosomes 1, 3, 16, 19, 20)
  • Submetacentric: Centromere off-centre (most autosomes)
  • Acrocentric: Centromere near one end (chromosomes 13, 14, 15, 21, 22 — satellite chromosomes with stalks and satellites)
• Short arm = p arm; Long arm = q arm

Chromosomal Nomenclature:

• Short arm = p; Long arm = q
• Location written as: chromosome number + arm + region + band
• Example: 5p15.2 = short arm of chromosome 5, region 1, band 5, sub-band 2

The Cell Cycle and Meiosis

Mitosis: Somatic cell division — produces two genetically identical diploid daughter cells Meiosis: Germ cell division — produces four genetically unique haploid gametes

• Meiosis I: Prophase I (crossing over/recombination at chiasmata), Metaphase I (homologous pairs align), Anaphase I (homologues separate), Telophase I
• Meiosis II: Like mitosis — sister chromatids separate

Crossing Over: Exchange of genetic material between non-sister chromatids of homologous chromosomes during Prophase I — creates genetic diversity.

Mendelian Inheritance Patterns:

Autosomal Dominant

• Affected individual has at least one mutant allele
• Every affected person has at least one affected parent (unless due to new mutation)
• Affected male/female transmit to male/female equally
• Examples: Achondroplasia, Huntington’s disease, Marfan syndrome, familial hypercholesterolaemia, hereditary spherocytosis

Achondroplasia: Dwarfism (short limbs, normal torso); heterozygous dominant (aa = lethal, Aa = affected); 80% of cases are new mutations; father age > 40 associated with increased mutation rate.

Autosomal Recessive

• Affected individual must be homozygous (aa)
• Both carrier parents are unaffected (Aa × Aa)
• 25% chance of affected child, 50% chance carrier, 25% chance normal
• Examples: Cystic fibrosis, sickle cell anaemia, phenylketonuria, Tay-Sachs disease, galactosemia, thalassaemia

Cystic Fibrosis: Autosomal recessive; mutation in CFTR gene on chromosome 7; thick mucus in lungs (recurrent infections), pancreas (malabsorption), sweat (elevated Cl⁻); most common lethal genetic disease in Caucasians; carrier frequency ~1/25 in Europeans; diagnosed by sweat chloride test.

X-Linked Recessive

• Mutant allele on X chromosome; no corresponding locus on Y
• Males (XY) are affected if they have one mutant X (XᴬY)
• Females (XX) are affected only if homozygous (XᴬXᴬ)
• Carrier females (XᴬX) are usually unaffected
• Males transmit to all daughters (who become carriers) but to no sons
• Affected males cannot transmit to sons (they give Y to sons)
• Examples: Haemophilia A (Factor VIII deficiency), Duchenne muscular dystrophy, red-green colour blindness, G6PD deficiency

Haemophilia A: X-linked recessive; deficiency of Factor VIII; prolonged bleeding, haemarthrosis (joint bleeds), muscle haematomas; diagnosed by PTT (activated partial thromboplastin time) prolonged, Factor VIII assay low; treated with recombinant Factor VIII; royal families (Queen Victoria lineage) — affected males in European royal families.

X-Linked Dominant

• Both males and females affected; but more females (some affected males die in utero)
• Affected male transmits to all daughters (no sons)
• Example: Vitamin D-resistant rickets (X-linked hypophosphataemia), Rett syndrome

Mitochondrial Inheritance

• Mitochondrial DNA is inherited exclusively from mother (maternal inheritance)
• All children of affected mother are affected; no transmission from father
• mtDNA codes for: 13 proteins (all part of electron transport chain), 2 rRNAs, 22 tRNAs
• Mutations cause: Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS)

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Chromosomal Abnormalities:

Trisomies (Autosomal)

• Down syndrome (Trisomy 21): 47, XY+21 or 47, XX+21; extra chromosome 21; risk increases with maternal age; features: flat facies, epicanthal folds, single palmar crease, hypotonia, intellectual disability, congenital heart defects (AV canal defect), increased risk of leukaemia, early Alzheimer disease; karyotype confirms diagnosis

• Edwards syndrome (Trisomy 18): 47, XY+18 or 47, XX+18; features: micrognathia, clenched fists, rocker-bottom feet, severe intellectual disability, congenital heart defects; most die within first year; less common than Down syndrome

• Patau syndrome (Trisomy 13): 47, XY+13 or 47, XX+13; features: holoprosencephaly, cleft lip/palate, polydactyly, severe intellectual disability, congenital heart defects; most die within first year

Sex Chromosome Abnormalities

• Klinefelter syndrome: 47, XXY (or 48, XXXY); tall male, small firm testes, azoospermia (infertile), gynaecomastia, reduced testosterone; most common male hypogonadism; often diagnosed in adulthood for infertility; some mosaic forms (46, XY/47, XXY) exist

• Turner syndrome: 45, XO (or variants 46, Xi(Xq), 45, X/46, XX mosaicism); short stature female, streak gonads (non-functional), coarctation of aorta, webbed neck, shield chest, lymphoedema; primary amenorrhoea, infertility; intelligence usually normal; some cases diagnosed in infancy (webbed neck, lymphoedema), others at adolescence (delayed puberty)

• XYY syndrome: 47, XYY; tall male, may have learning difficulties; normal fertility; historically associated with criminal behaviour (misunderstood/stigmatised association — not accurate)

• Triple X syndrome: 47, XXX; female; often normal phenotype, may have tall stature, mild learning difficulties; fertile

Structural Chromosomal Abnormalities

• Translocations: Robertsonian translocation (most common) — two acrocentric chromosomes fuse at centromere; common in ~1/900 births; balanced carriers are phenotypically normal but at risk of producing offspring with unbalanced translocations (e.g., familial Down syndrome via t(14;21))
• Deletions: 5p deletion (cri du chat syndrome — deletion of short arm of chromosome 5; features: microcephaly, cat-like cry, intellectual disability)
• Duplications, inversions (inversions usually phenotypically normal unless involve genes), ring chromosomes

Pedigree Analysis:

Key symbols:

• Square = male; Circle = female
• Filled = affected; Unfilled = unaffected
• Half-filled = carrier (for autosomal dominant where heterozygous is affected, half-filled may denote carrier for recessive)

Reading a pedigree:

• Determine inheritance pattern: autosomal vs X-linked, dominant vs recessive
• Autosomal dominant: vertical transmission (parent to child), both sexes affected
• Autosomal recessive: horizontal transmission (affected siblings with unaffected parents), affected may be absent in one generation
• X-linked recessive: predominantly affected males; no male-to-male transmission; carrier females
• X-linked dominant: affected males transmit to all daughters; affected females transmit to both sexes

DNA Structure and Replication:

DNA Double Helix:

• Discovered by Watson and Crick (1953) — based on X-ray crystallography by Rosalind Franklin
• Sugar-phosphate backbone (covalent bonds); nitrogenous bases face inward (hydrogen bonds)
• Base pairing: A=T (2 hydrogen bonds); G≡C (3 hydrogen bonds)
• Antiparallel strands: 5’→3’ direction on one strand vs 3’→5’ on complementary strand
• Major groove and minor groove — regulatory proteins bind to major groove

DNA Replication:

• Semi-conservative (each new DNA molecule has one old strand, one new strand)
• Origins of replication: Multiple origins in eukaryotes; replication forks move bidirectional
• Enzymes: Helicase (unwinds DNA), Primase (synthesises RNA primer), DNA Polymerase III (synthesises new strand in 5’→3’ direction), DNA Polymerase I (removes RNA primer, fills gaps), DNA Ligase (joins Okazaki fragments)
• Leading strand: Synthesised continuously (toward replication fork)
• Lagging strand: Synthesised discontinuously in short Okazaki fragments (away from replication fork); larger fragments needed because polymerase can only add nucleotides 5’→3’
• Telomeres: Repetitive sequences (TTAGGG in humans) at chromosome ends; telomerase (reverse transcriptase with RNA template) adds repeats; somatic cells lack telomerase → telomeres shorten with age → replicative senescence

The Genetic Code:

• Codon: 3 nucleotide sequence specifying one amino acid
• 64 codons (4³); 61 code for amino acids; 3 are stop codons (UAA, UAG, UGA); AUG is start codon (also codes for methionine)
• Degenerate/redundant: Multiple codons can code for the same amino acid (e.g., leucine has 6 codons)
• Non-overlapping and universal (almost — mitochondria use slight variations)

Gene Expression:

• Transcription: DNA → mRNA (in nucleus); RNA polymerase II transcribes structural genes; promoter (TATA box), enhancer elements; splicing removes introns; 5’ cap (7-methylguanosine) and 3’ poly-A tail added
• Translation: mRNA → protein (in cytoplasm at ribosome); tRNA carries amino acids; ribosome has A, P, E sites; initiation factors, elongation factors, release factors; stop codon enters A site → release factor binds → polypeptide released

Epigenetics:

• DNA methylation (CpG islands in promoters → gene silencing)
• Histone modifications (acetylation → open chromatin → transcription; methylation → closed chromatin)
• Genomic imprinting (parent-of-origin-specific gene expression — e.g., IGF2, H19)
• X-chromosome inactivation (in females, one X is inactivated early in development — forms Barr body)