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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A review on human chromosomes

An Introduction to chromosomes:

The ability of the chromosomes in getting stained reveals the true nature of the chromosome (derived from the Greek work word. The word chroma indicates color). These stainable bodies appear like threads under a microscope. They contain the genetic material, mainly the DNA coiled around the proteins. Human chromosomes are visible with when the cell is undergoing mitotic or meiotic cell division. There are total 46 chromosomes in each human cell.

·    Autosomes: There are total 44 autosomes or 22 pairs. Each pair consists of homologous chromosomes. In a pair, one chromosome comes from the father and the other chromosome comes from the mother.

·        Sex Chromosomes: There are two different types of sex chromosomes, X and Y respectively.

The average size of the human metaphase chromosome is 5 millimeters. Chromosomes tightly coil and get condensed during metaphase. Chromosomes appear in different shapes during each phase of the cell cycle. They appear thread-like during interphase. During metaphase, chromosomes look like rod-shaped. They look like V, J or rod-shaped during anaphase. Von Hartz coined the term chromosome. The scientists who first discovered the structure of chromosomes were Schleiden, Virchow, and Bütschli. Walter Sutton and Theodor Boveri independently developed the chromosome theory of inheritance in 1902.

An interphase nucleus contains strands of a material called chromatin. There are two regions in the chromatin, mainly coiled and extended regions.

·    Heterochromatin: It is the dark staining area of the chromatin. There are two types of heterochromatin. Constitutive heterochromatin contains repetitive sequences. It is present near the centromere. Constitutive heterochromatin never expresses itself. There is one more type of heterochromatin, known as facultative heterochromatin, which expresses itself.

·        Euchromatin: It is the light staining area of the chromatin.

The chief constituent of chromatin is DNA, the blueprint of life. At the time of cell division, chromatin strands coil into compact structures, so that they easily fit into the cell nucleus. Chromosomes appear as thick rods only during the cell division. They uncoil and form chromatin at the end of cell division.

Image: Human chromosomes revealed through karyotyping

Structure of the chromosome:

Metaphase chromosome appears clearly under the microscope. Following are the principal point to be discussed:

·        Chromatids: Each metaphase chromosome consists of two symmetrical halves parallel to each other. They are called chromatids. These chromatids are present in the form of chromonema during prophase. There are two types of chromatids mainly, sister and non-sister chromatids. Two chromatids are present on a single chromosome. Thus they are called sister chromatids. The concept of dyad describes a pair of sister chromatids. These structures join with the help of a centromere.  Non-sister chromatids are either of the two chromatids of a chromosome pair.

·        Centromere: A centromere is a light staining constricted area to which both the chromatids are attached. A centromere divides the chromatids into short and long arms respectively. The short arm is known as “p” arm. The long arm is known as “q” arm. Centromere produces a primary constriction. It is the position of the centromere. It is different for different chromosomes. Secondary constriction is also known as nucleolar organizer region. It is involved in the formation of the nucleolus. Human centromere consists of several hundred kilobases of repetitive DNA. Centromeres are the sites where spindle fibers are attached. Thus, centromere helps in the movement of the chromosome.

·     Satellite: A satellite is a region that is attached to the chromosome by a thread of chromatin. It is present at the distal region of the arm of the chromosome.

·        Telomere: A special DNA-protein complex is present at the ends of the chromosomes. This complex is known as a telomere, with tandem repeats of TTAGGG-3’ sequences between 3-20 kilobases in length. Telomeres are not genes since they do not code for any functional molecule. Telomeres provide structural stability to the chromosomes by sealing their ends. Telomeres protect the chromosomes from damage. They also protect the chromosome from fusing into a ring or binding to other DNA.

Classification of chromosomes:

1.     Classification based on the position of the centromere:  

·     Metacentric: The two arms are almost equal in their lengths. The location of the centromere is at the center of the chromosome.

·   Submetacentric: The two arms of the submetacentric chromosomes are unequal in length. The location of the centromere is slightly away from the center.

·   Acrocentric: One arm of an acrocentric chromosome is short. Whereas, the other arm is long.

·      Telocentric: A telocentric chromosome has only one arm.

2.     Standard classification: It is also known as Denver classification. It classifies chromosomes into seven groups, depending on the length of the chromosomes.

·  Group A: This group consists of pairs of chromosomes 1, 2 and 3. Chromosome 1 is the largest human chromosome. It represents 8% of the total DNA content.  Chromosome 2 is the second one. The third chromosome represents 6.5 % of the total DNA content.

·       Group B: This group consists of pairs of chromosome 4 and 5.

·    Group C: This group consists of pairs of chromosome 6, 7, 8, 9, 10, 11 and 12.

·        Group D: This group consists of pairs of chromosomes 13, 14 and 15.

·        Group E: This group consists of pairs of chromosomes 16, 17 and 18.

·        Group F: This group consists of pairs of chromosomes 19 and 20.

·        Group G: This group consists of pairs of chromosomes 21 and 22.

·  Sex Chromosomes: There are two types of sex chromosomes. X chromosome and Y chromosome are called sex chromosomes.

3.     Paris nomenclature: According to this method, the long and short arms of the chromosomes have specific regions that get stained. These regions are further stained using banding techniques. Such techniques may not only help to identify specific chromosomes, but also find out the location within the chromosome. Banding techniques may help to detect minor structural abnormalities.

What is sex chromatin?

The nucleus in the interphase is in the resting phase. An interphase nucleus shows a dark stain chromatin mass attached on one side of the nuclear membrane. Sex chromatin is also known as the Barr body. It is observed only in females. However, the chromatin determination using the Barr body is not as accurate as the Karyotyping technique.

What are chromosomal aberrations?

Chromosomal mutations or aberrations are variation in the normal chromosome structure or chromosome number.

A deletion is a chromosomal mutation in which a part of a chromosome is missing. Chromosomal breaks result in deletions. Sometimes an entire chromosome may get deleted. Duplication may lead to doubling of a chromosomal segment. Excision of a chromosomal segment follows reinsertion leading to an inversion. A translocation is a chromosomal mutation in which a chromosome segment gets positioned in a different location in the genome.

Chromosome Analysis:

Chromosome analysis indicates a proper diagnosis of many clinical conditions. It is a microscopic analysis of chromosomes in the dividing cells. Chromosomal analysis can detect chromosome number and structure.

Uses of chromosome analysis are as follows:

·        Detection of congenital malformations, mental retardation, and repeated abortions.

·        Prenatal diagnosis

·        Diagnosis of malignancies

Karyotyping:

Karyotyping is a test to evaluate the number and the structure of the chromosomes. In this procedure, the metaphase chromosomes are obtained and photographed. The procedure of karyotyping is specialized. Peripheral blood lymphocytes, bone marrow cells or amniotic fluid samples are collected and analyzed for chromosomes. A photo-micrograph reveals chromosomes scattered randomly. These chromosomes are arranged into groups, using the software. A karyotype can be sued to detect chromosomal abnormalities.

Chromosome Banding:

Analysis of chromosome becomes precise with the help of banding techniques. There are four types of banding techniques such as G-banding, Q-banding, R-banding, and C-banding. A unique pattern of light and dark bands are obtained using the G-banding technique.

Fluorescence in-situ hybridization (FISH):

FISH is a new diagnostic technique that involves a single-stranded probe annealing to its complementary sequence. FISH can be used to detect minute chromosomal aberrations, malignancies, and study of chromosomes.

References:
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter

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