Genetics 7 - Chromosomes and Chromosomal abnormalities

• What are Chromosomal abnormalities the leading cause of?

  Pregnancy loss & intellectual disability
• Euploid - The correct number of chromosomes needed for a healthy cell
• Karyotype

  • individual's complete set of chromsomes
  • 46,XY or 46,XX
• Chromosomes are ordered by :

  • Size - larger first
  • Centromere position : middle- Metacentric , Tip - Acrocentric , between middle and tip - submetacentric
  • Nomenclature : tips = telemore, short arm is p and long arm is q
• Acrocentric chromosomes:

  • centromere near the tip
  • Human 13, 14 , 15 , 21 , 22 , Y
• Short arms (p)

  • fewer genes
  • no essential genetic material
  • Nucleolus organising regions (NOR) -
  • contain rDNA
  • Robertsonian Translocations - involve the exchange of the short arm of one acrocentric chromosome with the long arm of a different acrocentric chromosome. 
• Regions in chromsomes:

  • Q/G Bands - A=T rich
  • R bands
• Cytogenetic location

  • gene reference location
  • Chromosome → Arm→ region → band → sub-band
  • e.g. CFTR gene - Cystic fibrosis transmembrane conductance regulator, location

  -Location

  • 7q31.2
  • chromosome 7, long arm q , region 3, band 1 , sub-band 2
• Ploidy (n)- Number of sets of chromosomes in a genome
• Dna content (c) - amount of DNA in the cell
• Cytogenetics -study of chromosomes and their abnormalities

  Numerical abnormalities

  • Abnormal chromosome number
  • Polyploidy - Total chromosomal copies , Triploidy and Tetraploidy
  • Aneuploidy – Individual chromosomal copies : Monosomy, trisomy , Tetrasomy

  Structural abnormalities

  • Translocations - reciprocal and robertsonian
  • deletions
  • insertions
  • inversions - paracentric, pericentric
  • Rings
  • Isochromosomes
• Polyploidy - Presence of a complete set of extra chromosomes in a cell

  Triploidy (69 chromosomes)

  • Cause: Often fertilisation by two sperm (dispermy)
  • 15% of chromosome abnormalities - many spontaneously aborted
  • very high morbidity
  • many defects

  Tetraploidy (92 chromosomes)

  • cause: mitotic failure in the early embryo
  • very high morbidity
• Aneuploid - Cells containing missing or additional individual chromosomes

  Monosomy

  • only one copy of a chromosome
  • very high morbidity
  • e.g. turner syndrome - monosome of X chromosome (45,X) treated by hormone therapy

  Trisomy

  • three copies of a chromosome
  • less severe
  • e.g. Down syndrome -Trisomy of Ch21 (47,XX,+21 or 47,XY,+21) by nondisjunctions often in egg cells

  Tetrasomy

  • Four copies of a chromosome
  • e.g. Cat eye syndrome (Ch22)
• Conditions caused by Trisomy

  • Klinefelter syndrome - Trisomy of the Sex Chromosomes (47,XXY)
  • Down syndrome - Trisomy of Ch21 (47,XX,+21 or 47,XY,+21)
  • Trisomy 13 (Patau syndrome) - Ch13 (47,XX,+13 or 47,XY,+13)
  • Trisomy 18 (Edwards Syndrome) - Trisomy of Ch18 (47,XX,+18 or 47,XY,+18
• Nondisjunctions

  • Unequal distribution of a chromosome pair in cell division.
  • Nondisjoined During Meiosis - chromosomes are genetically distinct
  • Nondisjoined During Meiosis II - chromosomes are genetically identical
  • Maternal nondisjunction- More common for trisomy
• Structural abnormalities

  • same number of chromosomes
  • caused by unequal crossing over during meiosis and chromosomal breakage

  Types

  1. Balanced - No change in the amount of genetic material
  2. Unbalanced - Gain or loss of chromosomal material, serious consequences
• DNA double strand breaks

  Causes :

  • reactive oxygen species
  • ionising radiation
  • Meiosis

  Repair:

  • Homologous recombination
  • Single-strand annealing
  • Nonhomologous end joining
• Breakage and crossing over between repetitive DNA, can both produce chromosomal rearrangements such as :

  • deletions
  • inversions
  • translocations
• Translocations

  Reciprocal translocations

  • between different chromosomes
  • removal / deletion of DNA

  Robertsonian translocation

  • acrocentric chromsomes
  • Common (65–85%): der(13;14) or der(14;21)

  Sex determination - SRY gene

  • Pseudoautosomal region- PAR1, X and Y chromosomes
  • SRY gene crossover→ XX Males and XY Females
• Deletions

  single break causes a terminal deletion

  • e.g. cri-du-chat syndrome - 46,XY,del(5p) or 46,XX,del(5p)
  • e.g. Wolf-Hirshhorn Syndrome - 46,XY,del(4p) or 46,XX,del(4p)

  Double break - Interstital deletion - the chromosome has broken in two places and the broken ends have fused, leaving out the deleted segment
• Microdeletions

  • need high resolution banding
  • FISH and aCGH techniques

  Prade - Willi syndrome

  • 70% microdeletions of 15q11
  • Including 50% of patients (15q11-q13)

  due to imprinting- ( gene is silenced, and gene from other parent is expressed )

  • Paternal microdeletion ch15 → Prader–Willi syndrome
  • Maternally microdeletion ch15 → Angelman syndrome
• Insertions

  • less serious than deletions
  • causes - offspring of person with reciprocal translocations, Unequal crossover during meiosis
  • e.g. x-linked colour vision, and Charcot-Marie tooth disease
• Inversions

  • Reinsertion of double break
  • Wrong orientation
  • Balanced
  • Mild symptoms
  • Can interfere with meiosis→ Deletions or duplications in offspring
  • Pericentric - centromere inverted
  • Paracentric - no centromere involved
  • e.g. Severe Hemophilia A
• Ring chromosomes

  • breakage at both tips that causes fusion
  • usually de novo - from beginning
  • rarely inherited
  • Most common Ch14 and 22
  • Rings can be lost → Monosomy
  • e.g. Female ring X chromosome 46,X,r(X)
• Isochromosomes

  • Chromosomes divide along wrong axis
  • Chromosomes with two p or q arms
  • r Robertsonian translocation of Ch21q
  • e.g. 46,X,i[Xq] - turner syndrome features
  • isochromosome 18q - Edwards syndrome phenotype
• Abnormalities Nomenclature

  • Mosaic = /
  • Deletion = del
  • Duplication = dup
  • Robertsonian translocation = der (infront of chromosomes that are missing)
  • Translocation = t
  • Inversion = inv
  • Ring chromosome = r
  • Isochromosome = i