Numerical Abnormalities of Sex Chromosomes

Chromosomes are of two main types such as autosomes and sex chromosomes. Karyotyping is a cytogenetic technique used to detect an abnormal number of chromosomes. A photomicrograph of chromosomes reveals the actual status of the individual. An abnormal number of autosomes leads to monosomies and trisomies. An abnormal number of sex chromosomes lead to respective conditions. Thus, representation of a karyotype depends on the number of chromosomes. Various conditions arise due to an abnormal number of X and Y chromosomes. Mosaicism may also arise due to an abnormal number of sex chromosomes. Conditions such as trisomies, monosomies, and mosaicism arise due to numerical abnormalities.

Turner syndrome:

The karyotype of a turner female is 45, XO. In this syndrome, an X chromosome is missing. It is a condition associated with monosomy. Repeated spontaneous abortions arise due to monosomies. Clinical features of turner females include the webbed neck, small breast size, heart defects, rudimentary ovaries, and slight mental retardation. Infertility is very high in these females. Secondary sexual characteristics are underdeveloped. Hence they undergo Estrogen replacement therapy. Aneuploidy is common in such individuals. It leads to an extra copy or a missed chromosome leading to an unbalanced chromosome complement. Thus, their genomic complement is 45, XO or 45 X.

A majority of 45, X embryos die before birth. Some of the genes are involved in controlling characteristics other than sexual characteristics. A gene involved in bone development in turner females is known as SHOX gene. A copy of this gene is not present in the affected individuals. Hence, turner females exhibit short stature and skeletal abnormalities.

Image 1: Karyotype revealing Turner's syndrome (45, XO)

Klinefelter syndrome:

This syndrome affects males. The karyotype of Klinefelter’s syndrome is 47, XXY. It occurs in 1 per 1000 newborn males. If not detected earlier the affected individual and his family members may not even know about the condition. The body of a Klinefelter male may slightly appear like that of a female with wide hips, breasts, small testis and poor growth of the beard. Secondary sexual characteristics in Klinefelter individuals are underdeveloped accompanying mosaicism. These individuals exhibit the presence of a Barr body. They have to undergo a hormone treatment such as testosterone therapy. An egg or a sperm cell may gain an extra X chromosome due to non-disjunction. Mother’s age may be responsible for the non-disjunction. Pregnancy above 35 years of age imposes a great risk of developing this syndrome in the embryo. Mosaic Klinefelter syndrome arises due to an extra X chromosome in some cells and a normal XY complement in other cells. Klinefelter boys have very low energy, low self-esteem, shyness, and problems in reading and writing. In their later years of life, such individuals also experience erectile dysfunction and low sex drive.

                          Image 2: Karyotype revealing Klinefelter's syndrome (47, XXY)

47, XXX females (Triple X syndrome):

It happens with 0.1 % cases of females. They are phenotypically normal with less or moderate I.Q. and reproductive life. Trisomy X is diagnosed using chromosome analysis (karyotyping). It reveals an extra copy of the X chromosome. FISH may help to detect the condition in detail.

47, XYY Males:

These males exhibit the presence of two Y chromosomes. They are phenotypically normal. However, they are abnormally tall and show slight mental retardation. Such individuals show emotional immaturity. Presence of an additional Y chromosome is due to non-disjunction in meiosis II during spermatogenesis. This syndrome is also known as Jacob’s syndrome or YY syndrome. Chromosomal analysis may help to detect this problem. Jacob’s syndrome arises due to an error in cell division in the sperm before conception.

48, XXXX syndrome:

This condition is also known as Tetrasomy X or a quadruple X syndrome which is an extremely rare disorder in the females. It arises due to aneuploidy or defects in the meiosis. The homologous chromosomes fail to separate in forming sperms or eggs. Karyotyping and FISH help to detect this condition.

48, XXXY syndrome:

It is a variant of Klinefelter syndrome accompanying hypotonia and hypogonadism. Random errors in cell division are common in this case. This condition may not be necessarily inherited.

48, XXYY syndrome:

The affected males experience infertility, deep vein thrombosis, learning disabilities, and underdeveloped reproductive system. Testosterone is not adequately synthesized.

49, XXXXY syndrome:

They are males with completely undeveloped or absent sperms. They exhibit hypogonadism with micropenis and cryptorchidism. It is an extremely rare condition.

49, XXXXX syndrome:

It is known as Pentasomy X and associated with developmental delays, physical and mental abnormalities. The phenotype is that of a female with an abnormal number of X chromosomes. Problems in parental reproductive cells give rise to pentasomy X.

Gonadal dysgenesis:

It is of two main types such as XY and XX gonadal dysgenesis. The XY gonadal dysgenesis is known as Swyer syndrome and characterized by hypogonadism. A person’s phenotype is that of a female. However, there is no puberty. They show the presence of streak gonads. Internal male organs are not well developed. XX gonadal dysgenesis is a kind of female hypogonadism. However, XX gonadal dysgenesis affects both males and females. They show poor growth of secondary sexual characteristics and low Estrogen levels. Some references report mutations in mitochondrial tRNA synthetase. Perrault syndrome accompanies this syndrome along with deafness.

XX Male syndrome:

The genotype of a female is normal. However, the phenotype is like a male. This condition arises due to unequal crossing over between an X and Y chromosome during meiosis. The X chromosome consists of SRY gene from the father’s Y chromosome. It is also known as De la Chapelle syndrome.

References:
[1] Vogel and Motulsky's Human Genetics, Friedrich Vogel, Gunter Vogel, Arno G. 
[2] Gardner and Sutherland's Chromosome Abnormalities and Genetic Counseling
By R.J. McKinlay Gardner, David Amor

© Copyright, 2018 All Rights Reserved.

The X and Y Chromosomes

The scientists discovered the sex chromosome for the first time while studying the insects. In the year 1950, Clarence McClung, Nettie Stevens, and Edmund Wilson worked on the insect sex chromosomes. They discovered certain accessory chromosomes in the grasshoppers. These accessory chromosomes determined the sex of the insects. They also determined the presence of an even number of chromosomes in the Orthoptera females and the odd number of chromosomes in the males. The Orthoptera females had an extra copy of a chromosome (meaning, two copies of an accessory chromosome). Thus they named it as X chromosome. Each of the egg consisted of X chromosomes. However, half of the sperms had X chromosomes. The remaining half of the sperms did not have X chromosomes. Those sperms had some other type of accessory chromosome. Later on, the scientists named it as Y chromosome. Insects having two X chromosomes got identified as females. Those having X and Y chromosomes got identified as males.

Another study involved common mealworms. The scientists found a partner chromosome for X. Stevens called it the Y chromosome. It was smaller in size consisting of a lesser number of genes. Similarly, human sex chromosomes also got identified.

Image: Human karyotype (showing X and Y chromosomes)

The human X chromosome:

The human cells possess two kinds of sex chromosomes. The X chromosome consists of 155 million base pairs and occurs in each cell. The homogametic sexes consist of two copies of this chromosome (females). The heterogametic sex (males) consists of one copy of this chromosome. During the early embryonic stage in females, one of the two X chromosomes gets inactivated. The process of X-inactivation plays a crucial role in avoiding the occurrence of lethality. The process usually depends on the X-controlling element and the XIST gene (X-inactivation specific transcript. It gets transcribed into a large RNA molecule. It, later on, does not undergo translation. Instead, it coats the X chromosome and makes it inactive. Hence, the genes on the X chromosome get silenced. Although, the females possess two X chromosomes, one of them occurs in a silenced state. The process is known as Lyonization.

The active X chromosome achieves its state randomly. Meaning, the X chromosome derived from any of the parents achieves an active state. The active chromosome gets derived either from the maternal or the paternal cells. Some of the genes situated at the end of the X chromosome do not get covered by the X-inactivation process. These genes are present in the pseudoautosomal regions. They purposely get skipped from the process of X-inactivation since they play a crucial role in the normal developmental process. Also, if all the genes on one of the X chromosome get inactivated for the entire life, it would be useless to keep such a chromosome in the cell. Thus, the X-inactivation of one X chromosome does not include all the genes on that particular X chromosome.

The human Y chromosome:

It is very short in size. It consists of 59 million base pairs of DNA. The genes occurring in the Y chromosome play a crucial role in sex determination. The inheritance of the Y chromosome depends on the father to son transmission.  It is also known as the holandric mode of inheritance. The mutant genes get transmitted from father to the son. Hence, it follows a male to male transmission pattern. It does not involve dominance or recessiveness. The transmission pattern is straightforward. The affected father has all his sons affected. The genes present on the Y chromosome are known as Y-linked genes. Although we know only a few genes on the Y chromosome, every gene encodes for a particular product. For example, SRY region of the Y chromosome is also known as sex region determining factor. It is a testis-determining factor. It is adjacent to the pseudo-autosomal region. It plays a crucial role in normal male development. These regions only exhibit a capacity of recombination. Not all genes on the Y chromosome undergo genetic recombination.

Sex chromosomal disorders in humans:

Certain conditions arise due to an abnormality in the sex chromosome number or the structure. Numerical abnormalities arise due to trisomies, monosomies, and mosaicism. The structural abnormalities arise due to deletions, translocations, inversions, and duplications. The disorders associated with the X chromosome involve different features as compared with the disorders associated with the Y chromosome. The former ones are known as X-linked disorders. The latter ones are known as Y-linked disorders. Their patterns of inheritance also differ. The X-linked inheritance follows dominance or recessive types. The Y-linked inheritance does not follow any such types. 

X-linked dominant inheritance	X-linked recessive inheritance
The expression of the trait depends only on the presence of one copy of the mutated gene on the X chromosome.	The expression of the trait depends on the presence of two copies of the mutated genes on the X chromosome.
Affects both males and females.	Highly affects males.
Examples include Fragile X syndrome, Rett syndrome, Alport’s syndrome, and X-linked hypophosphatemia.	Examples include Duchenne muscular dystrophy, hemophilia, and color blindness.
Y-linked inheritance
It gets transmitted through the Y chromosome. It mainly affects the males. Examples include abnormal testicular development, gonadal dysgenesis, and retinitis pigmentosa.

                                     Table: Sex-linked inheritance in humans

The Z and W chromosomes in birds:

They show the presence of Z and W chromosomes. The W chromosomes determine the femininity of the bird. Hence, females are known as heteromorphic sexes in the birds. They show the presence of one Z and one W chromosome. 

References:

[1] Chromosomes: Organization and Function, Adrian T. Sumner
[2] Medical genetics, G.P. Pal

© Copyright, 2018 All Rights Reserved.