Genome Structure and Chromosomal Abnormalities

• Exons contain the genetic material.

  Introns are the bits in between that get spliced out.
• Types of DNA sequences in the human genome

  • repetitive DNA that includes transposable elements and related sequences
  • Repetitive DNA unrelated to transposable elements including large-segment duplications
  • introns and regulatory sequences
  • exons (coding DNA)
  • unique noncoding DNA
• Not all changes to DNA cause changes to proteins. Some changes have no effect - synonymous amino acid changes or if they occur in non-functional regions of genome.
• DNA damage occurs in both somatic and germline cells.

  • changes in germline cells cause heritable defects
  • changes in somatic cells cause non-heritable local changes
• Main proteins in chromatin are histones

  • DNA wound around histones to form nucleosomes
  • nucleosomes organise into solenoids
  • solenoids loop up into structure of chromatin
• Meiosis I (46 - 23 chromosome pairs)

  • prophase I
  • metaphase I
  • anaphase I
  • telophase I
• Meiosis II (no change in chromosome number)

  • metaphase II
  • anaphase II
  • telophase II
• Nullisomic gametes result in a monosomic zygote after fertilisation
• Disomic gametes result in a trisomic zygote after fertilisation
• Banding

  • identification of individual chromosomes
  • sub-chromosomal rearrangements
  • 4p (Wolf-Hirschhorn syndrome)
  • 5p (Cri-du-Chat syndrome)
• Fluorescence in situ hybridisation

  • a way of checking the patient's chromosomes for imbalances that cannot be seen with a microscope
  • Di George, Williams syndrome, Prader Willi syndrome
  • have to know what you are looking for
• Aneuploidy - loss or gain of one or more chromosomes
• Monosomy - loss of a single chromosome
• Trisomy or tetrasomy - gain of one or two homologous chromosomes
• Down syndrome

  • affected children show broad range of intellectual ability
  • social skills are relatively well-advanced and most children are happy and very affectionate
  • short stature
  • severe cardiac anomaly leads to early death in some cases
  • shorter life expectancy
  • most affected adults develop Azheimer's disease
• Signs of Down syndrome

  • newborn: hypotonia, sleepy, excess nuchal skin
  • craniofacial: brachycephaly, epicanthic folds, protruding tongue, small ears, upward sloping palpebral fissures
  • limbs: single palmar crease, small middle phalanx of fifth finger, wide gap between first and second toes
  • cardiac: atrial and ventricular septal defects, common atrioventricular canal, PDA
  • anal atresia, duodenal atresia, Hirschsprung disease, short stature, strabismus
• Patau and Edwards syndrome are rare but very severe conditions. Prognosis is poor, with most infants dying during the first days or weeks of life. Many cases are detected prenatally now, often leading to termination. In the unusual event of longer term survival, there are severe learning difficulties and cardiac abnormalities.
• DiGeorge syndrome

  • characterised by heart malformations
  • thymic and parathyroid hypoplasia
  • cleft palate and typical facial features
  • molecular defect is a microdeletion on chromosome 22
  • large proportion develop schizophrenia later in life
• Sex chromosome abnormalities

  • Turner syndrome (X)
  • Trisomy X (XXX)
  • Klinefelter syndrome (XXY)
  • XYY man (XYY)
• Klinefelter's syndrome can be undiagnosed until patients try to conceive (infertility) although they can have female body habitus and gynaecomastia.
• Dysmorphology - looking at pictures of faces and comparing them to those with different syndromes as a diagnostic tool.