Incorrect Centromere Splitting Causes Genetic Disorders

The importance of centromere lies in its specialty of holding the chromosome arms together. Imagine two threads of 2cm each aligned in a cross-shape. Suppose you wish to align them on a pin-up board. How would you align them? The answer is very simple. Just place a pin on the intersecting point of the two threads such that they resemble a cross. Once you pin the threads, they remain intact. Similarly, consider another example of a paper cut out in a cross shape. The four arms of the cross-connect each other through a central point.

During the cell division, the spindle fibers attach to the centromere via kinetochore. Centromere splitting leads to separation of the chromatids. The centromere is also known as a primary constriction. Any error in the centromere proves catastrophic for the cell. During mitosis, centromere assists in proper segregation of chromosomes. The cell undergoes a cyclical pattern to grow and divide. The somatic cell cycle divides into interphase and a mitosis phase. Meiosis occurs in the gametes. During metaphase, the centromeres help in attachment with the kinetochores. Hence chromosomes align themselves on the equatorial plane. It occurs during normal centromere splitting. Later on, during anaphase, the centromeres separate the sister chromatids, each forming individual daughter chromosomes. These events have chances of centromere misdivision. The term centromere misdivision describes a condition in which a centromere or a near centromere region fails to split properly. In humans, errors in centromere separation result in various disorders. The chromosome segregation gets affected depending on the types of errors such as non-disjunction, out of phase separation, premature splitting, centromere puffing, and Isochromosome formation.

Centromere separation in humans:

The cells undergo a typical cyclical pattern consisting of interphase and mitosis. The division phase or mitosis involves an important phase dependent on the centromere splitting or separation. This phase is known as anaphase. It involves splitting of the centromere to move the daughter chromatids towards the opposite poles. Certain factors play a crucial role in the splitting of the centromeres. The initiation of the centromere splitting first requires an anaphase-promoting complex. This complex involves an inhibitory chaperone known as securin. The APC/C cyclosome degrades three main factors such as securin, S and M cyclins. The degradation of securin releases a protease known as separase which in turn cleaves the cohesins. The cohesins bond the sister chromatids intact and allow non-homologous centromere coupling. However, the cleavage of the cohesin happens during anaphase. It further accelerates the centromere splitting and sister chromatid separation. The centromere splitting may be either horizontal or longitudinal (vertical). Normally the centromere divides longitudinally. However, the centromere splitting may accompany errors. A common error occurs when the centromere divides horizontally. Two isochromosomes arise due to incorrect centromere splitting. These isochromosomes have genetically identical arms. The isochromosomes may have duplication on one arm and deletion on the other arm.

Image: Isochromosomes

More about isochromosomes:

An incorrect centromere splitting gives rise to a kind of metacentric chromosomes known as isochromosomes. A product of incorrect Centromeric division is due to a complete absence of the centromere. Another product of an incorrect division involves a centromere ready to duplicate. Thus an Isochromosome consists of an identical long arm or short arm depending on the Centromeric division product. An Isochromosome involving a long arm of X chromosome leads to a structural abnormality associated with gonadal dysgenesis. Isochromosome studies relate to the horizontal misdivision of the centromere. Misdivision occurs either in the maternal or a paternal chromosome. It is also known as centromeric fission. This type of horizontal splitting gives rise to i(Ap) and i(Aq) arms of the chromosome. The letter “i” indicates an Isochromosome. A U-type exchange results in a loop formation. This structure forms during mitosis and meiosis. Mosaicism arises due to a subsequent mitotic loss of an Isochromosome.

Two main types of isochromosomes reported so far include monocentric or dicentric chromosome. Monocentric Isochromosome consists of one centromere. A dicentric centromere consists of two centromeres. Some of the references mention the occurrence of the misdivisions in the pericentric regions consisting of homologous sequence sites. The early anaphase involves breakage and fusion of the sister chromatids with a U-type strand exchange. There is a repair mechanism for a double strand break. Fusion of the sister chromatids containing centromere repair a double-strand break.

Type of isochromosome	Condition
i(5p)	Refractory cytopenia pulmonary atresia
i(8p)	Mosaicism
i(18p); i(18q)	Mosaic tetrasomy
Robertsonion isochromosome	Down’s syndrome
i(17q)	Neoplasia
i(Xq)	Turner’s syndrome
i(11q), i(17q), i(21q)	AML
i(7q), i(9q), i(17q)	ALL
i(9q), i(17q), i(22q)	CML
i(X)(q13), i(17q), i(21q)	MDS
I(1q), i(16p), i(7q), i(18q), i(9q)	Recurrent isochromosomes in lymphoproliferative disorder.

Table: Types of isochromosomes and the conditions associated with the same.

Centromere separation and non-disjunction:

Failure of separation of chromosomes during anaphase leads to non-disjunction. It leads to an improper separation of the chromosome. Non-disjunction leads to an imbalance of chromosomes. It happens during mitosis or meiosis. Non-disjunction gives rise to conditions known as monosomy, trisomy or mosaicism. Pericentric exchanges contribute to non-disjunction. Premature separation of the sister chromatids arises due to degradation of the centromere. Non-disjunction in the first meiotic division arises due to a reduced exchange near a centromere. Non-disjunction in the second meiotic division arises as a result of an increased exchange near the centromere. In a tetrad, non-disjunction associates with the distance between the centromere and closest exchange.

Premature centromere division:

Non-disjunction arises due to premature centromere division. It occurs due to the absence of pairing proteins such as INCENPs (inner centromere proteins) or CLIPs (chromatid linkage protein). It may lead to failure of chromatid pairing and chromosome alignment. Premature centromere division is an age-dependent phenomenon and is more common in females. It arises mostly in the X chromosomes.

Out of phase centromere separation:

It involves centromere spreading and common in tumor cells. The chances of aberrations are very high. Out of phase separation involves very early or very late separating centromeres. The Centromeric division in human mitotic chromosomes is non-random. It occurs in a genetically controlled way. The timing of separation depends on the timing of the repetitive DNA replication. Pericentric heterochromatin mainly consists of such DNA. Out of phase separation of the centromere arises maximally in the X chromosome. Out of phase centromere separation in X chromosome results in pregnancy complications, repeated abortions, Klinefelter syndrome, and Ataxia telangiectasia. A few inactive centromeres result into myelomas and dicentrics.

Centromere puffing:

It involves a localized swelling of a Centromeric region. Centromere puffing is nothing but an excessive DNA replication in the centromere region. When centromere puffing occurs in an acrocentric chromosome, it increases the risk of Robert’s syndrome. Centromere puffing is common in acute myelogenous leukemia, acute non-lymphocytic leukemia, non-lymphocytic leukemia, and acute lymphocytic leukemia.

Robert’s syndrome accompanies deformities in the body, prenatal growth retardation, limb malformation, and craniofacial abnormalities. Hence, centromere misdivision and premature centromere splitting result in centromere instability syndromes.

References:
[1] Essentials Of Human Genetics Fifth Edition,  Manu L. Kothari, Lopa A. Mehta
[2] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[3] Mechanisms of Environmental Mutagenesis-Carcinogenesis, A. Kappas
[4] The Principles of Clinical Cytogenetics, Steven L. Gersen, Martha B. Keagle
[5] Centromeres and Kinetochores: Discovering the Molecular Mechanisms,  Ben E. Black

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