Chromosomal Structure

Introduction

Chromosomal structure refers to the organization and arrangement of DNA molecules within chromosomes. Chromosomes are thread-like structures found in the nucleus of cells that carry genetic information in the form of genes. Each chromosome consists of a single, long DNA molecule that is wrapped around proteins called histones. The DNA and histones together form a structure called chromatin.

The chromatin within a chromosome is organized into distinct regions based on how tightly the DNA is packaged. Regions of chromatin that are tightly packed are called heterochromatin, while regions that are less densely packed are called euchromatin. Heterochromatin is generally associated with genes that are inactive or silenced, while euchromatin is associated with active genes that are actively transcribed and expressed.

Overview

• Centromere
  • holds sister chromatids together
  • attachment of mitotic spindle fibers
    • allows chromosomes to be pulled to opposite poles during anaphase
  • variations in position
    • metacentric
      • centromere in the middle
    • submetacentric
      • centromere offset slightly towards one end
    • acrocentric
      • near complete displacement of centromere to one end
• Nomenclature
  • long = q
  • short = p
    • remember: p = petite
  • translocation = t
• deletion = del

Types of chromosomal alterations

• Nondisjunction 
  • homologous chromatids do not separate properly during meiosis
    • stage of nondisjunction affects gamete production outcome
      • nondisjunction in meiosis I results in 2 gametes with x 2 and 2 gametes x 0
      • nondisjunction in meiosis II results in 2 normal gametes, 1 gamete x 2 and 1 gamete x 0
    • zygote receiving 3 copies = trisomy
    • zygote receiving 1 copy = monosomy
  • risk greatly ↑ with ↑ in maternal age
    • more common in oogenesis than spermatogenesis
• Translocation
  • exchange genetic info between nonhomologous chromosomes by breakage and repair
    • balanced
      • where exchanged fragment is still functional on another chromosome
    • unbalanced
      • where exchanged fragment cannot function properly
  • common in cancers
  • types
    • Robertsonian
      • balanced
      • always involve two acrocentric chromosomes
        • 13, 14, 15, 21, 22
      • results in loss of short arm and fusion of two long arms of different chromosomes
      • no clinical presentation because short arms of acrocentrics contain no vital info
        • is a translocation carrier
        • problems with gametogenesis and therefore reproduction
          • miscarriage, aneuploidy
          • depends on how chromosomes segregate during homologous pair separation
    • reciprocal
      • exchange of DNA between two non-homologous chromosomes
        • as long as no DNA is lost the phenotype is normal for that generation
          • is a translocation carrier
• Inversion
  • type of rearrangement where part of chromosome is inverted in orientation
  • types
    • pericentric
      • inverted chromosomal segment includes centromere
      • remember: pericentric involves centromere
    • paracentric
      • inverted chromosomal segment does not include centromere
• Ring chromosomes
  • causes
    • product of two breakage sites on the chromosome and the segment lost circularizes
    • ends of chromosomes join circularizing entire chromosome
  • usually lost during gametogenesis → monosomy
• Isochromosome
  • replication of one arm of a chromosome with loss of the other
    • p-q → p-p’
  • lethal for autosomes
    • can be observed on sex chromosomes
• Deletions
  • loss of chromosome segment
  • types
    • terminal
      • end of chromosome
    • interstitial
• within the chromosome

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Symptoms

• Down Syndrome: Down Syndrome is caused by an extra copy of chromosome 21, leading to a total of 47 chromosomes instead of the usual 46. This can lead to developmental delays, intellectual disability, distinctive facial features, and an increased risk of heart defects, hearing and vision problems, and other health issues.
• Turner Syndrome: Turner Syndrome is caused by a missing or incomplete X chromosome, leading to a total of 45 chromosomes instead of 46. This can lead to short stature, infertility, heart defects, hearing loss, and other health issues.
• Klinefelter Syndrome: Klinefelter Syndrome is caused by an extra X chromosome in males, leading to a total of 47 chromosomes instead of 46. This can lead to infertility, breast development, reduced muscle mass, and other health issues.
• Cri du chat Syndrome: Cri du chat Syndrome is caused by a deletion in chromosome 5, leading to a range of symptoms including intellectual disability, delayed development, distinctive facial features, and a high-pitched cry that sounds like a cat.

Studies

• A study published in the journal Nature Genetics found that changes in chromatin structure can influence the development of cancer by altering the expression of key genes involved in cell growth and division.
• Another study published in the journal Science found that variations in chromosomal structure can impact the development of neurological disorders such as schizophrenia and autism spectrum disorder.
• A study published in the journal Cell Reports found that changes in chromatin structure can influence the development of diabetes by altering the expression of genes involved in glucose metabolism.
• Researchers have also studied the relationship between chromosomal structure and aging, with some studies suggesting that changes in chromatin structure may contribute to age-related decline in cellular function and the development of age-related diseases.

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