The three major single-chromosome mutations: deletion (1), duplication (2) and inversion (3).
The two major two-chromosome mutations: insertion (1) and Translocation (2)
A chromosomal disorder, anomaly, aberration, or mutation is a missing, extra, or irregular portion of chromosomal DNA. It can be from a typical number of chromosomes or a structural abnormality in one or more chromosomes. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. The term "karyotype" refers to the full set of chromosomes from an individual; this can be compared to a "normal" karyotype for the species via genetic testing.
A chromosome anomaly may be detected or confirmed in this manner.
Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. There are many types of chromosome anomalies. They can be organized into two basic groups, numerical and structural anomalies.
Numerical disorders
This is called aneuploidy
(an abnormal number of chromosomes), and occurs when an individual
either is missing a chromosome from a pair (monosomy) or has more than
two chromosomes of a pair (trisomy, tetrasomy, etc.).
An example of trisomy in humans is Down syndrome,
which is a developmental disorder caused by an extra copy of chromosome
21; the disorder is therefore also called trisomy 21. Having an extra
copy of this chromosome means that individuals have three copies of each
of its genes instead of two, making it difficult for cells to properly
control how much protein is made. Producing too much or too little
protein can have serious consequences. Genes on chromosome 21 that
specifically contribute to the various symptoms of Down syndrome are now
being identified. The frequency of Trisomy 21 has been determined to be
a function of advanced maternal age.
An example of monosomy is Turner syndrome, where the individual is born with only one sex chromosome, an X.
Sperm aneuploidy
Exposure of males to certain lifestyle, environmental and/or occupational hazards may increase the risk of aneuploid spermatozoa. In particular, risk of aneuploidy is increased by tobacco smoking, and occupational exposure to benzene, insecticides, and perfluorinated compounds. Increased aneuploidy is often associated with increased DNA damage in spermatozoa.
Structural abnormalities
When the chromosome's structure is altered, this can take several forms:
- Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.
- Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A, which may be caused by duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17.
- Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocations:
- Reciprocal translocation: Segments from two different chromosomes have been exchanged.
- Robertsonian translocation: An entire chromosome has attached to another at the centromere - in humans these only occur with chromosomes 13, 14, 15, 21, and 22.
- Inversions: A portion of the chromosome has broken off, turned upside down, and reattached, therefore the genetic material is inverted.
- Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.
- Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
- Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere.
Chromosome instability syndromes
are a group of disorders characterized by chromosomal instability and
breakage. They often lead to an increased tendency to develop certain
types of malignancies.
Inheritance
Most
chromosome abnormalities occur as an accident in the egg cell or sperm,
and therefore the anomaly is present in every cell of the body. Some
anomalies, however, can happen after conception, resulting in Mosaicism (where some cells have the anomaly and some do not). Chromosome anomalies can be inherited from a parent or be "de novo".
This is why chromosome studies are often performed on parents when a
child is found to have an anomaly. If the parents do not possess the
abnormality it was not initially inherited; however it may be transmitted to subsequent generations.
Acquired chromosome abnormalities
Most cancers, if not all, could cause chromosome abnormalities,
with either the formation of hybrid genes and fusion proteins,
deregulation of genes and overexpression of proteins, or loss of tumor
suppressor genes.
Furthermore, certain consistent chromosomal abnormalities can turn
normal cells into a leukemic cell such as the translocation of a gene,
resulting in its inappropriate expression.
DNA damage during spermatogenesis
During the mitotic and meiotic cell divisions of mammalian gametogenesis, DNA repair is effective at removing DNA damages. However, in spermatogenesis the ability to repair DNA damages decreases substantially in the latter part of the process as haploid spermatids undergo major nuclear chromatin remodeling into highly compacted sperm nuclei. As reviewed by Marchetti et al., the last few weeks of sperm development before fertilization
are highly susceptible to the accumulation of sperm DNA damage. Such
sperm DNA damage can be transmitted unrepaired into the egg where it is
subject to removal by the maternal repair machinery. However, errors in
maternal DNA repair of sperm DNA damage can result in zygotes with chromosomal structural aberrations.
Melphalan is a bifunctional alkylating agent frequently used in chemotherapy.
Meiotic inter-strand DNA damages caused by melphalan can escape
paternal repair and cause chromosomal aberrations in the zygote by
maternal misrepair. Thus both pre- and post-fertilization DNA repair appear to be important in avoiding chromosome abnormalities and assuring the genome integrity of the conceptus.
Detection
Depending on the information one wants to obtain, different techniques and samples are needed.
- For the prenatal diagnosis of a foetus, amniocentesis, chorionic villus sampling or circulating foetal cells would be collected and analysed in order to detect possible chromosomal abnormalities.
- For the preimplantational diagnosis of an embryo, a blastocyst biopsy would be performed.
- For a lymphoma or leukemia screening the technique used would be a bone marrow biopsy.
