Ring Chromosomes Lead to Chromosomal Mosaics

Human growth and development starts right from the cellular stage. The basic blueprint of life or the genetic material lies inside the cellular nucleus. The genetic material consisting of the DNA-protein complex gets packed into the structures known as chromosomes. The chromosome studies mainly involve genetic analysis and other techniques to know more about complex processes regulated inside the cells. Karyotyping includes chromosome analysis. A software oriented karyotyping technique generates a photomicrograph of the chromosomes arranged in groups. Thus it is possible to study the structure and number of chromosomes for detecting the aberrations if any. Chromosomes vary in their structure and number. The structural or numerical aberrations could completely change the phenotype of the individual. An abnormal number of chromosomes result in trisomies, monosomies, and mosaicism. The structural abnormalities in the chromosomes lead to the chromosome breakage, deletions, inversions, duplications, isochromosomes, translocations, and ring chromosomes.

The structural chromosomal abnormalities such as ring chromosomes lead to mosaicism. Formation of the ring chromosomes is a relatively rare abnormality. A structurally abnormal chromosome forms a ring or a closed circle. This type of chromosome arises as a result of breaks near the chromosome tips or ends. The broken ends become sticky. They can fuse with each other. The cell loses the two distal fragments during the division phase. An abnormal exchange of sister chromatids occurs. The cell thus loses an entire chromosome leading to mosaicism. A ring chromosome is also known as an aberrant chromosome with no ends. Lilian Morgan discovered the ring chromosomes in 1926. The letter “r” indicates ring chromosomes in humans. The letter “R” indicates ring chromosomes in Drosophila. Chemical, physical or any other mutagen leads to the formation of ring chromosomes.

Image: Ring chromosomes

The process of ring formation:

High resolution molecular karyotyping or array CGH helps to study ring chromosomes. A break occurring on each arm of the chromosome leaves two sticky ends on the central portion that stick to each other forming a ring. The formation of a ring chromosome deletes the two distal fragments. The ring chromosomes are unstable during the mitosis. Ring breakage leads to the formation of larger and smaller rings. The breaks near the telomere results into loss of the distal regions. The formation of the ring chromosome changes the gene order. Formation of the autosomal ring chromosomes occurs due to breakage in autosomes (non-sex chromosomes). If the rings exhibit no loss of the genetic material, then the individuals show the normal phenotype. Hence, the two main factors such as the chromosomes involved in a ring formation (autosomes or sex chromosomes) and the extent of gene loss decide the phenotype of the individual. The way of breakage and re-joining of the sister chromatids decides ring formation. Absence of sister chromatid exchange during the prophase also results in a ring formation. However, the two ring chromatids separate at anaphase. It results in the formation of equal sized rings. Dicentric rings arise due to crossing over. Formation of a dicentric ring results in the ring instability. Hence the formation of deletions, duplications and interlocking rings occur.

The number of crossovers also affects the ring structure. A single crossover gives rise to two centromeres in the dicentric ring. Unbalanced ring chromosomes form during the telophase if the two centromeres move towards the opposite poles in anaphase. A lot of genetic material is deleted or duplicated. Sometimes the sub-telomeric regions remain intact while there is a loss of the telomere. Sometimes the ring gets disappeared completely. All such structural abnormalities arise in the autosomes.

Events occurring in the cells	Types of ring chromosomes formed
Even number SCEs	Interlocked rings
Odd number SCEs	Double sized continuous ring
SCEs with chromosomal breaks	Simple ring structure or an interlocked ring
Non-homologous end joining	Interlocked rings or single rings
Single crossover	Dicentric ring
Unstable dicentric ring	Interlocked rings

Table 1: Events occurring in cells leading to the formation of ring chromosomes.

Breakage fusion bridge cycle:

It arises due to sister chromatid exchanges. It first leads to the formation of a bridge followed by breakage or non-disjunction. The broken ends fuse to form a normal ring structure. The anaphase involves breakage and pulling of the dicentric chromosome towards both the poles. Then the broken ends fuse. Again during the next anaphase, the dicentric ring undergoes breakage and fusion. The cycle goes on. However, after the bridge formation, there are chances of breakage. The bridge breaks between the chromosome and the spindle attachment. Breakage of the bridge leads to cellular apoptosis. It may also allow more and more fusion of broken ends leading to the formation of novel ring structures. Thus, the breakage fusion bridge cycle constantly keeps producing such rings with amplified genes.

Sex chromosome rings:

Like autosomes, the sex chromosomes also involve themselves in a ring formation. Cases of ring X and ring Y exist. The deletion of genes present on the Y chromosomes due to rings determines the phenotype of the individual. Y chromosomes may form dicentric rings with unequal sizes.

Rings and mosaicism:

A mosaic or a chimera consists of two or more genetically distinct cell types or different genetic or chromosomal constitution. Often a karyotype with the ring chromosome(s) represents a dynamic mosaic. Such mosaics exhibit ring syndrome. Although ring chromosomes mostly lead to mosaicism, all mosaic cases not necessarily associate with ring chromosomes. Other causes of mosaicism include monosomies, trisomies or any other condition. Turner syndrome individuals with ring chromosomes have a complete absence of an X chromosome or presence of a ring X chromosome. Mosaicism accompanying ring chromosomes arise due to the presence of a ring chromosome with an abnormal number of chromosomes. For example, trisomy 8 is a condition with 47, XX, r(8). Hence, the formation of a ring chromosome affects the chromosome number.

There is a loss of the acentric fragments due to fusion or a breakpoint in the euchromatin. It affects the short and long arms of the chromosomes. In some cases, telomere fusion leaves the euchromatin untouched. It leads to mitotic abnormality. Centromere fission results into a rare U-type exchange. The difficulties in analyzing ring chromosomes include low-grade mosaicism cases.

Karyotype of the individuals having ring chromosomes	Condition	Explanation
45, XO 46, X, r(X)	Turner syndrome	Mosaicism may be present
46, XX, r(14) 46, XY, r(14) 45, XY, r(14) 46, XY, dic r(14)	Ring chromosome 14 syndrome	Mosaicism present Leads to intellectual disability
46, XY, r(20) 46, XX, r(20)	Ring chromosome 20 syndrome	Mosaicism present
47, XY, r(1) 46, XY, r(1) 46, XX, r(1)	Ring chromosome 1 syndrome	Mosaicism present Supernumerary rings form
47, XX, r(8)	Trisomy 8	Cancerous condition

Table 2: Ring chromosomes and the conditions associated with the same.

Supernumerary ring chromosomes and mosaicism:

A supernumerary chromosome is a small chromosome with a centromere seen in a mosaic state. Congenital ring chromosomes involve supernumerary chromosomes. In mosaics or non-mosaics, the supernumerary chromosomes occur together with two normal homologs. It results in trisomies. Cancerous conditions involve ring chromosomes with mosaicism. Different types of cancers and tumors exhibit large supernumerary chromosomes. Some cells show the presence of the ring chromosomes. The other cells get dropped during the development. Few rings consist of genetically active material from the p and q arms. This type of ring chromosomes results in developmental problems, learning and speech problems. Some of the rings consist of inactive material from the long arm or material around the centromere. These rings may be harmless.

References:
[1] Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes, Huntington F Willard
[2] The Principles of Clinical Cytogenetics, Steven L. Gersen, Martha B. Keagle
[3] Cytogenetics: Plants, Animals, Humans, J. Schulz-Schaeffer
[4] The AGT Cytogenetics Laboratory Manual, Marilyn S. Arsham, Margaret J. Barch, Helen J. Lawce
[5] Human Chromosomes: Structure, Behavior, Effects, Eeva Therman

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