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

© Copyright, 2018 All Rights Reserved.

Disorders of Incorrect Autosome Numbers

Autosomes are also known as non-sex chromosomes. A karyotype depicts the chromosomes arranged according to their sizes and centromere positions. The chromosomes are arranged into groups A to G and are known as autosomes. The sex chromosomes are named as X and Y respectively. A karyotype is a photomicrograph of chromosomes arranged in groups after the processing of the blood samples. Anomalies in chromosome structure or number may change the karyotype.

The review article discusses abnormalities associated with an abnormal number of autosomes. Abnormalities in chromosome number arise due to non-disjunction. The paired chromosomes do not separate properly. This usually happens during the metaphase of the cell division phase. Hence, it leads to abnormality in the chromosome number. This phenomenon is known as nondisjunction. It occurs either during mitosis or meiosis. There are many causes of non-disjunction. The main cause of nondisjunction is the advanced maternal age. The advancing age of the mother increases the risk of chromosomal abnormalities and nondisjunction in the zygote. There is a direct relation between suspended inactivity of the primary oocyte and the chromosomal abnormalities. Meiosis I in primary oocyte completes at the ovulation phase of the menstrual cycle. Primary oocyte remains suspended until the age of 45, after which it undergoes meiosis II. It happens as the age progresses further. As the mother’s age increases, there arises abnormality in spindle formation. Hence, it may predispose to non-disjunction. Another reason behind nondisjunction is the delayed fertilization after ovulation.

Nondisjunction is under complete genetic control. Other factors causing nondisjunction include radiation, smoking, alcoholism, excessive use of oral contraceptives, fertility drugs, pesticide exposure, and chemicals. More than 50% of spontaneous abortions arise due to either numerical or structural abnormalities in chromosomes. 1-2 % of congenital abnormalities and childhood disabilities arise due to chromosomal anomalies. The number of chromosomes helps to decide whether the cells are capable of becoming malignant. 

Image: Variations in chromosome numbers

Conditions associated with nondisjunction:

Monosomy (2N-1) is a condition in which one of the chromosomes in a pair is missing. Hence a chromosome is absent in this condition. A cell with a missing chromosome consists of 45 chromosomes instead of 46. This condition leads to monosomic disorders. During segregation stage, two chromosomes enter into a gamete, leaving the other gamete empty.

Trisomy is a condition in which the cells are diploid but contain an extra copy of the chromosome. The extra chromosome is homologous with the existing chromosome pair. Trisomy observed in autosomes is known as autosomal trisomy. Trisomy observed in sex chromosome is known as sex chromosomal trisomy. In rare cases, a phenomenon known as trisomic rescue occurs. Trisomic rescue is a condition in which trisomy occurs, but the cell loses the extra chromosome.

Polyploidy or an increase in a number of chromosomes is a condition seen in the somatic cells. The exact description of polyploidy involves an increase in the number of the haploid set of chromosomes in the cell leading to many whole sets of chromosomes. Examples include triploids, tetraploid, pentaploid, and hexaploids.

Mosaicism in autosomes is a result of nondisjunction. In this case, two or more different cell lines prevail. Thus, a chimeric tissue contains two or more genetically distinct cell types. The chromosomal constitution is different.

Incorrect centromere splitting may result into nondisjunction in anaphase. Thus, there leads to an improper separation of daughter chromosomes. Nondisjunction may also arise due to pericentromeric exchanges.

Nullisomy involves loss of a homologous chromosome pair during meiosis.

Abnormalities	Karyotype	Conditions associated with non-disjunction	Affected autosome number
Down’s syndrome (Trisomy 21)	47, XY 47, XX	Trisomy	21
Patau’s syndrome (Trisomy 13)	47, XY 47, XX	Trisomy	13
Edward’s syndrome (Trisomy 18)	47, XY 47, XX	Trisomy	18
Warkany’s syndrome (Trisomy 8)	47, XY 47, XX	Trisomy	8
Trisomy 14	47, XY 47, XX	Trisomy	14
Alfi’s syndrome (Monosomy 9)	45, XY 45, XX	Monosomy	9

Table: Abnormalities associated with an incorrect number of autosomes.

Down’s syndrome:

Trisomy 21 or Down’s syndrome is an abnormality due to trisomy of the 21^st chromosome. The chromosome 21 is an autosome. It belongs to the G group of chromosomes. These chromosomes are small, acrocentric with satellites them. Three copies of a 21^st chromosome are present. Hence, this condition is an example of trisomy. The incidence of Down’s syndrome is 1 in 700 live births and is affected by maternal age. A high number of males are affected. These individuals exhibit poor growth and developmental characteristics. They show mental retardation and poor I.Q. Heart disease and abnormal facial features are clearly visible in these patients. Mostly the trisomies, monosomies, and mosaicism lead to variations in chromosome numbers.

Trisomy 21 arises due to nondisjunction in the chromosome 21 during meiosis I in the mother. These individuals live only for sixteen to twenty years. Other reasons include Robertsonian translocation, isochromosomes, or ring chromosomes. An overexpression of gene portions on the 21^st chromosome causes half the percentage of Down's syndrome cases. Some other studies report the involvement of microRNAs too. Genetic counseling and prenatal diagnosis help to manage this condition.

Patau’s syndrome:

It is known as trisomy 13. The incidence rate is 1 in 5000 live births. There is physical and mental retardation in these children with a very less life expectancy. They may have a cleft lip or cleft palate. Such individuals are born with an extra finger or a malformed thumb. There is nondisjunction of the chromosome during meiosis. Trisomy 13 may not be inherited but arise due to spontaneous mutations. Alternatively, such cases occur due to the random events during the formation of gametes in the parents.

Edward’s syndrome:

It results due to spontaneous abortions. Mental retardation, heart defects, hearing disabilities, and abnormal tendons are peculiar features of the affected individual. An extra copy of the 18^th chromosome arises due to nondisjunction. The affected individuals exhibit microcephaly or small head, cleft lip or cleft palate, webbed toes, and abnormalities in fingers.

Warkany’s syndrome:

It is also known as trisomy 8 with or without mosaicism. It accompanies RECQL4 helicase disorder. These individuals are affected with telangiectasia, atrophies, and malignancies. Chronic myeloid leukemia with a bcr-abl fusion gene may also accompany trisomy 8.

Trisomy 14:

The condition results in an extra copy of the 14^th chromosome. It results in craniofacial malformations, microphthalmia, palpebral fissures, low set ears, and an abnormal cleft and palate. Trisomy 14 mosaics have hyperpigmentation, genital malformations, cryptorchidism, and asymmetric limbs.

Alfi’s syndrome:

It arises due to monosomy of the 9^th chromosome. It accompanies micro genitalia and microcephaly. It is also known as 9p deletion syndrome. It is a rare genetic disorder. It leads to mental retardation and physical defects.

Tetrasomy 12p syndrome:

It is known as Pallister-Killian syndrome. It is a rare multiple congenital anomaly with mosaicism. It is involved in an extra chromosome 12p (isochromosome). This condition leads to tetrasomy. A prenatal diagnostic technique such as chorionic villus sampling is efficient in detecting this condition.

References:
[1] Medical Genetics,  Lynn B. Jorde, John C. Carey
[2] Emery's Elements of Medical Genetics, Peter D Turnpenny, Sian Ellard
[3] Trisomy 8- Wikipedia
[4] Monosomy 9p- Wikipedia
[5] Tetrasomy 12p- Wikipedia

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