Chromosome Abnormalities and Nondisjunction

Euploidy

• Cells are euploid when they have a complete set of chromosomes. The number of chromosomes is a multiple of the number of chromosomes in the set (e.g., n = 23, 2n=46, 3n=69).
• Chromosome size and shape is a unique species characteristic.

Aneuploidy

• Cells are aneuploid if they do not have a complete set of chromosomes.
• They have more or fewer chromosomes than a euploid cell.
• Aneuploidy is caused by chromosome nondisjunction.
• Chromosome nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division.

Chromosome Nondisjunction in Somatic Cells

• Somatic cells with nondisjunction result in 2 daughter cells.
• One cell has an extra chromosome (2n+1), and the other is missing a chromosome (2n-1).
• Aneuploidy in somatic cells can cause cancer.

Chromosome Nondisjunction in Germ-Line Cells

• Germ-line cell nondisjunction results in an aneuploid egg or sperm (n+1 or n-1).
• When an aneuploid gamete fuses with a normal gamete, it produces either a trisomic (2n+1) or monosomic (2n-1) offspring.

Gene Dosage and Balance

• The relative number of genes in a chromosome and their expression level can lead to imbalances.
• Most animals are sensitive to gene dosage changes.
• Plants often tolerate gene dosage changes more readily.

Aneuploidy in Humans

• Humans are very sensitive to gene dosage changes, and aneuploidy is not typically tolerated.
• Only trisomies of chromosomes 8, 13, 18, and 21 are observed in newborns and no autosomal monosomies.
• Trisomy 21 is the only autosomal trisomy with a life expectancy exceeding 6 months.
• Multiple types of sex chromosome trisomies and one type of monosomy are known to occur.

Aneuploidy in Human Pregnancies

• Trisomies and monosomies other than those found in newborns are known to occur.
• In human pregnancies, about 50% spontaneously abort during the first trimester.
• Approximately 50% of these miscarriages (25% of all conceptions) have chromosome number or structure abnormalities.
• ~2-13% of male sperm are aneuploid.
• Frequency of aneuploidy increases with female age.

Polyploidy

• Polyploidy is the presence of more than two sets of chromosomes in a cell.
• Polyploids are named for the number of sets of chromosomes they possess (e.g. triploid, tetraploid, pentaploid, hexaploid).
• Polyploidy can be caused by duplication of chromosome sets within a species (autopolyploidy).
• Autopolyploidy can arise via multiple fertilization or nondisjunction.
• Polyploidy can also occur from combining chromosome sets of different species (allopolyploidy).
• Allopolyploidy arises during hybridization.

Polyploidy and Evolution

• Polyploidy doubles the genome of an organism.
• It creates a duplicated set of all genes.
• Because of relaxed selection on duplicated genes, there is more freedom to accumulate mutations.
• Duplicated genes can become inactive and degrade, but they can also acquire new functions.
• Genes originating from genome duplication events often share similar sequence and structure, and are spatially associated with other syntenic genes. These are called paralogs, and form gene families.

Chromosome Breakage

• Mutations that result in the loss or gain of chromosome segments can cause abnormalities due to gene dosage imbalances.
• The changes can be large enough to detect microscopically (>100 kb), or smaller changes that only molecular methods can detect.
• Large changes affect many genes, while smaller changes affect few genes.

Partial Chromosome Deletion

• When a chromosome breaks, both DNA strands are severed at a chromosome break point.
• The broken chromosome ends can adhere to other broken chromosome ends, or the ends of intact chromosomes.
• An acentric fragment of a broken chromosome lacking a centromere may be lost during cell division.

Larger Chromosome Deletions

• Terminal deletions occur when a chromosome arm detaches. The fragment is lost during cell division because it lacks a centromere.
• Interstitial deletions occur when a portion of a chromosome is deleted. They result from two chromosome breaks.

Unequal Cross-Over

• During recombination in meiosis, some homologous chromosomes can undergo unequal cross over.
• It results in duplication on one chromosome and deletion on the other.
• Unequal cross over happens when repetitive regions of homologous chromosomes misalign.

Gene Duplications

• Gene dosage imbalance caused by duplication can result in abnormal development.
• Duplication and divergence are a major factor in evolution.
• They contribute to larger and more complex genomes.

Chromosome Inversion

• Chromosome breakage may lead to the reattachment of the wrong broken ends.
• Chromosome inversion occurs when the broken ends reattach in reverse orientation.
• There are two types of chromosome inversion:
  • Paracentric inversion: The centromere is outside of the inverted region.
  • Pericentric inversion: The centromere is included within the inverted region.

Chromosome Translocation

• Translocations occur when the broken ends of non-homologous chromosomes are reattached.
• There are three types of translocations:
  • Unbalanced translocations: A piece of one chromosome is translocated onto a non-homologous chromosome, and there is no reciprocal event.
  • Reciprocal balanced translocations: When there is a reciprocal switch of pieces between two non-homologous chromosomes.
  • Robertsonian translocations (chromosome fusions): Fusions between two non-homologous chromosomes.

Robertsonian Translocations (Chromosome Fusions)

• Involves fusion of two non-homologous chromosomes at the centromere.
• Often occurs in human chromosome pairs 13,14, 14, 15, 15, 21, 21, 22, and 22.
• Most frequent cause of trisomy 21 (Down Syndrome).

Human Chromosome 2

• The human chromosome 2 is thought to have originated from a fusion of two separate chromosomes in an ancestor.
• Fusion of these two ancestral chromosomes is thought to have happened in the evolutionary lineage of humans.
• Other primates have two chromosomes that correspond to the two ancestral chromosomes that merged to form human chromosome 2.

Explore the concepts of euploidy and aneuploidy, including the effects of chromosome nondisjunction in somatic and germ-line cells. Understand how these abnormalities can lead to cancer and affect reproductive cells. Test your knowledge on the importance of chromosome sets in biology.