Chromosome Mutations and Aberrations

Chromosome Mutations

• Chromosome mutations are disruptions in the normal chromosomal content of a cell.
• A major cause of genetic conditions in humans, such as Down syndrome.
• Includes changes in the total number of chromosomes, deletion or duplication of genes or segments of a chromosome, and rearrangements of genetic material.
• Variations in chromosome numbers include aneuploidy and polyploidy.

Aneuploidy

• An organism gains or loses one or more chromosomes, but not a complete set.
• Types include:
  • Monosomy: 2n - 1
  • Trisomy: 2n + 1
  • Tetrasomy: 2n + 2
  • Pentasomy: 2n + 3

Polyploidy

• More than two multiples of the haploid chromosome set are found.
• Types include:
  • Triploid: 3n chromosomes
  • Tetraploid: 4n chromosomes
  • Pentaploid: 5n chromosomes

Non-disjunction

• The failure of homologous chromosomes to separate during anaphase.
• Can produce eggs with two X chromosomes or none instead of one.

Sex Chromosomes Aberrations

Klinefelter Syndrome

• "XXY Males" or "47, XXY Males"
• The most common sex chromosome disorder.
• Occurs in 2 out of every 1,000 males.
• Individuals are sterile, have longer arms and legs, and are taller than their peers.
• Characterized by microorchidism (small testicles), hypogonadism (decreased testicular hormone), gynecomastia (breast enlargement), rounded hips, and below-normal IQ.
• Higher incidence of speech delay and dyslexia.

Turner Syndrome

• 45, X0 condition.
• Occurs in 1 in 2,000 female births.

Jacob Syndrome

• 47, XYY condition.
• Individuals are above average height (over 6 ft tall) and have subnormal intelligence.
• Controversial - Criminal Syndrome: Although many males do not exhibit antisocial behavior and lead normal lives, there is a high incidence of correlation between the extra Y chromosome and a predisposition to behavioral problems.

Metafemale Syndrome

• 47, XXX condition
• Occurs in 1 in 1,200 female births.
• Individuals have underdeveloped secondary sex characteristics, menstrual irregularities, and early onset of menopause.
• There's a tendency towards learning disabilities.

Autosome Aberrations

Cri-du-chat Syndrome

• "Chromosome 5p deletion syndrome", "5p minus syndrome" or "Lejeune’s syndrome"
• 46,5p- condition.
• A French term meaning "cat-cry or call of the cat" referring to the characteristic cry of affected children.
• Genetic disorder due to a missing part of chromosome 5 (segmental deletion).
• Occurs in 1 in 20,000 to 1 in 50,000 births.
• The chromosome carrying the deletion is often inherited from the father.
• Signs and symptoms include small size at birth, respiratory problems, an unusual cat-like cry due to larynx development issues, microcephaly (small head), an unusually round face, a small chin, widely set eyes, folds of skin over the eyes, a small bridge of the nose, heart defects, muscular or skeletal problems, and hearing or sight problems.

Down Syndrome

• Trisomy 21
• 47,21+
• Discovered in 1866 by Langdon Down.
• Occurs in 1 in every 800 births.

Polyploidy

• The addition of one or more extra sets of chromosomes, identical to the normal haploid complement of the same species (Autopolyploidy).
• The combination of chromosome sets from different species (Allopolyploidy).

Autopolyploidy

• Additional set of chromosomes are identical to the parent species.
• Causes:
  • Failure of all chromosomes to segregate during meiotic division.
  • Autotriploids - 3n chromosomes
  • Autotetraploids - 4n chromosomes.

Value of Autopolyploidy

• Commercial Value:
  • Plants - Horticultural value: increased size of fruits and flowers.
  • Autopolyploids are larger than their diploid relatives (larger in cell size, not in cell number).
• Experiment:
  • Tetraploids can be produced from diploids by applying cold or heat shock to meiotic cells or by applying colchicine to somatic cells undergoing mitosis.
• Colchicine: an alkaloid that interferes with spindle formation, preventing replicated chromosomes from separating during anaphase.
• Economically Important Triploid Plants: potato, bananas, seedless watermelons, apples, and strawberries.

Allopolyploidy

• Hybridization of two closely related species.
• Hybrid species resulting chromosome sets may be sterile due to the inability to produce viable gametes.
• Allotetraploid or Amphidiploid: Diploid for two genomes derived from different species.

Amphidiploid

• Potential to form balanced gametes, making them reproductively successful.
• Amphidiploid plants:
  • Cabbage and raddish (unsuccessful)
  • Wheat and rye (grass family): wheat with high yield and rye with growth tolerance in unfavorable environments.

Variation in Chromosome Structure and Arrangement

Deletion

• A chromosome breaks in one or more places and a portion is lost.
• Types:
  • Terminal deletion: near the end of the chromosome.
  • Intercalary deletion: interior of the chromosome.

Duplication

• Any part of the genetic material, a single locus or a large piece of chromosome, is present more than once in the genome.

Significance of Duplication

• Gene Redundancy: Ribosomal RNA genes support protein synthesis and development after fertilization.
• Phenotypic Variation: Exhibited in Bar-eyed fruit flies.
• Important source of genetic variability during evolution.

Inversion

• A segment of a chromosome is turned around 180 degrees within the chromosome.
• Does not involve a loss of genetic information but simply rearranges the linear gene sequence.
• Usually does not cause abnormalities in carriers as long as the rearrangement is balanced.
• Individuals heterozygous for an inversion may have an increased production of abnormal chromatids, leading to lowered fertility due to unbalanced gametes.
• The most common inversion in humans is on chromosome 9, at inv(9)(p11q12), increasing the risk of miscarriage for about 30% of affected couples.

Translocation

• The movement of a chromosomal segment to a new location in the genome.
• Balanced translocation: pieces of chromosomes are rearranged, but no genetic material is gained or lost.
• Unbalanced translocation occurs when a child inherits a chromosome with extra or missing genetic material from a parent with a balanced translocation.

Chromosomal Fragile Sites

• Specific heritable points on a chromosome that tend to form a gap or constriction and may tend to break when the cell is exposed to partial replication stress.
• Over 120 fragile sites have been identified in the human genome.

Types of Fragile Sites

• Common: Part of normal chromosome structure, present in all or nearly all individuals.
• Rare: Found in less than 5% of the population, often composed of two- or three-nucleotide repeats.

Common Fragile Sites

• Not especially prone to spontaneous breaks under normal conditions.
• Of interest in cancer studies because they are frequently affected in cancer and can be found in healthy individuals.

Rare Fragile Sites

• Susceptible to spontaneous breakage during replication, often affecting neighboring genes.

FRAXA: Fragile X Syndrome or Martin-Bell Syndrome

• Most common cause of hereditary mental retardation.
• Occurs in 1 in 1,250 males, 1 in 2,500 females.
• A dominant trait.
• Male expression rate is higher than females (80% vs. 30%).
• Phenotypes: mentally retarded, long narrow faces, protruding chins, enlarged ears, and increased testicular size.

FMR-1 Gene

• Responsible for FRAXA syndrome.
• Trinucleotide repeat: a phenomenon that repeats a cluster of three nucleotides, expanding gene size and resulting in a disease phenotype.
• Number of repeats correlates with the expression of fragile X syndrome:
  • 6-54 repeats: Normal
  • 55-200 repeats: "Carriers" of the disorder.

  • 200 repeats: Express the syndrome.

Genetic Anticipation

• A phenomenon showing a continuous increase in the number of repeats in future generations until a threshold is reached (200 repeats), leading to the expression of illness or disease.

Fragile Sites and Cancer

• FHIT: Fragile Histidine Triad
  • Located within a fragile site on chromosome 3.
  • Altered in cells taken from tumors in individuals with lung cancer.
  • Is also a part of another fragile region, FRA3B, which is linked to other cancers (e.g., esophagus, colon, and stomach).

FHIT

• Highly susceptible to induced breaks in DNA.
• Sensitive to carcinogen-induced damage, creating susceptibility to cancer.