13.2 Genomes and chromosomal abnormalities

Identify normal and simple, abnormal karyotypes

• Normal karyotype

  • 46 chromosomes, 23 pairs: 22 autosomes + 1 sex pair

    • Female: 46, XX

    • Male: 46, XY

• Karyotyping technique

  • G-banding using Giemsa stain during mitosis

  • Sample sources: blood, amniotic fluid, chronic villus, tumour biopsy

  • G-banding ‘addresses’ for chromosomes

• Abnormal karyotype examples

• Aneuploidy: missing or extra chromosomes

  • Trisomy 21 (Down syndrome)

    

  • Trisomy 18 (Edward’s syndrome)

    

  • Trisomy 13 (Patau syndrome)

    

  • Monosomy X (Turner syndrome)

    

  • Klinefelter syndrome

    

  • Triploidy

    

Limitations of traditional chromosome analysis

• Traditional karyotyping

  • Visualisation of chromosomes at metaphase using Giemsa stain (G-banding)

  • Allows for the identification of:

    • Chromosome number

    • large structureal abnormalities

    • Banding pattern

    • Sex chromosomes

  • Common sample types:

    • Peripheral blood (adults)

    • Chorionic villi or amniotic fluid (prenatal)

    • Tumour biopsies (cancer cytogenetics)

• Key limitations

  • Low resolution: Cannot detect small deletions, duplications or point mutations; resolution limited to changes less than 5-10Mb

  • Requires dividing cells: Only metaphase chromosomes can be visualised, so cells must be cultured and arrested—which takes several days

  • Misses mosaicism: If only a subset of cells is abnormal, and not sampled in culture, it may go undetected

  • Not gene-specific: Cannot detect specific gene mutations (e.g. CFTR in cystic fibrosis, BRCA1/2)

  • Labor intensive and time-consuming: Requires skilled technicians and prolonged cell culture

• Modern complementary techniques

Sex chromosome abnormalities and sex determination

• Basic genetics of sex determination

  • Determined by the presence of the SRY gene (Sex-determining region Y)

    • Located on Y chromosome

    • Triggers differentiation of the bipotential gonads into testes

  • Without SRY → ovaries develop

  • Phenotypic sex is determined by:

    • Sex chromosome composition

    • Gene expression patterns

    • Hormonal signalling

• Common sex chromosome aneuploidies

  • Turner syndrome — 45,X

    • Monosomy X – only viable monosomy in humans

    • Phenotypic sex: Female

    • Clinical features:

      • Short stature

      • Webbed neck, broad chest

      • Primary amenorrhoea, streak ovaries → infertility

      • Normal intelligence, may have subtle learning difficulties

      • Increased risk of cardiac defects, horseshoe kidney

  • Klinefelter syndrome — 47,XXY

    • Extra X chromosome in male

    • Phenotypic sex: Male

    • Clinical features:

      • Tall stature, small testes

      • Gynecomastia (man boobs)

      • Infertility due to azoospermia (absences of motile sperm)

      • Feminine body fat distribution

  • XYY syndrome — 47,XYY

    • Male with an extra Y chromosome

    • Usually normal phenotype

    • Tall stature

    • May have mild learning or behavioural difficulties

  • Triple X syndrome — 47,XXX

    • Female with an extra X

    • Often undiagnosed

    • Usually normal phenotype

    • May be taller than average; occasional developmental delays

• Why are the effects milder than autosomal aneuploidies

  • X-inactivation: All but one X chromosome is inactivated in each cell → reduces dosage imbalance.

  • Y chromosome has few genes, many not essential for somatic development.

  • Thus, sex chromosome aneuploidies often have less severe developmental impact than autosomal ones.

Describe: Trisomy, Monosomy, Triploidy, Translocation

• Trisomy

  • Definition: Presence of 3 copies of a specific chromosome (instead of the normal 2)

  • Caused by non-disjunction during meiosis

  • Most common:

    • Trisomy 21 (Down syndrome): Only trisomy compatible with adult life

    • Trisomy 18 (Edwards): Severe congenital anomalies; <1-year survival

    • Trisomy 13 (Patau): Midline defects; survival typically <6 months

  • Effects due to gene dosage imbalance: having 3 copies of dosage-sensitive genes

• Monosomy

  • Definition: Loss of one chromosome (45 chromosomes total)

  • Only viable case: Monosomy X (Turner syndrome)

  • Autosomal monosomies: Lethal very early in embryogenesis

• Triploidy

  • Definition: Three complete sets of chromosomes (69 total)

  • Mechanisms:

    • Dispermy: Fertilisation of one egg by two sperm

    • Diploid gametes due to meiosis failure

  • Outcomes:

    • Most cases miscarry in the first trimester

    • Rare live births → die within days

• Translocation

  • Definition: Rearrangement of chromosome segments between two non-homologous chromosomes

  • Types:

    • Balanced translocation: No genetic material lost or gained → often asymptomatic

    • Unbalanced translocation: Additional or missing genetic material → may cause birth defects or miscarriage

Connect aneuploidies with errors in meiosis and mitosis

• What is aneuploidy

  • Any deviation from the normal number of chromosomes (46)

  • Arises from non-disjunction events: Failure of chromosome separation

• Key mechanisms:

  • Meiosis I non-disjunction

    • Failure of homologous chromosomes to segregate

    • All resulting gametes abnormal: 2 with n+1, 2 with n-1

  • Meiosis II non-disjunction

    • Failure of sister chromatids to separate

    • Results in 2 normal gametes, 1 with n+1, 1 with n-1

  • Mitotic non-disjunction (post-zygotic)

    • Occurs after infertilisation

    • Leads to mosaicism: mixture of normal and abnormal cells

    • Clinical severity depends on:

      • Proportion of affected cells

      • Tissues involved

      • Timing of mutation during development

• Trisomy 21 origins (most cases of trisomy)

  • ~85% of cases from maternal non-disjunction

    • ~65% meiosis I

    • ~20% meiosis II

  • Remaining cases:

    • ~5% paternal meiosis

    • ~5% mitotic error (mosaic)

    • ~4% Robertsonian translocation