Sex linkage

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Sex linked describes the sex-specific reading patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, X-linked dominant and Y-linked. The inheritance and presentation of all three differ depending on the sex of both the parent and the child. This makes them characteristically different from autosomal dominance and recessiveness.

Contents

Background on Sex Determination and Human Sex Chromosomes

In humans (and mammals in general), biological sex is determined by genetics; however this is not the case for all animals, with the biological sex of some reptiles being environmentally determined, and the sex of some worms being dependent on location. [1]

22 of the 23 pairs of human chromosomes are autosomal (not involved in sex determination), while the 23rd pair of human chromosomes are the sex chromosomes. The possession of two X-chromosomes defines a biological female, while the possession o f one X and one Y chromosome defines a biological male. [2] The two sex chromosomes differ in size and gene content, and unlike the sets of autosomal chromosomes, are not homologous. The X-chromosome contains an estimated 1400 genes, most of which are involved in tissue development and the development of human disorders. [3] [4] The Y-chromosome is host to the SRY gene, which is involved in the development of several male sex characteristics, while the identified functions of many of the remaining approximately 200 genes on the Y-chromosome are associated with human disease. [5] Sex linkage thus refers to the association of a trait encoded by one of the genes on these sex chromosomes. There are many more X-linked conditions than Y-linked conditions.

Sex linked Patterns of Inheritance

In X-linked recessive inheritance, a son born to a carrier mother and an unaffected father has a 50% chance of being affected, while a daughter has a 50% chance of being a carrier, however a fraction of carriers may display a milder (or even full) form of the condition due to a phenomenon known as skewed X-inactivation, in which the normal process of inactivating half of the female body's X chromosomes preferably targets a certain parent's X chromosome (the father's in this case). If the father is affected, the son will not be affected, as he does not inherit the father's X chromosome, but the daughter will always be a carrier (and may occasionally present with symptoms due to aforementioned skewed X-inactivation).

In X-linked dominant inheritance, a son or daughter born to an affected mother and an unaffected father both have a 50% chance of being affected (though a few X-linked dominant conditions are embryonic lethal for the son, making them appear to only occur in females). If the father is affected, the son will always be unaffected, but the daughter will always be affected. A Y-linked condition will only be inherited from father to son and will always affect every generation.

The inheritance patterns are different in animals that use sex-determination systems other than XY. In the ZW sex-determination system used by birds, the mammalian pattern is reversed, since the male is the homogametic sex (ZZ) and the female is heterogametic (ZW).

In classical genetics, a mating experiment called a reciprocal cross is performed to test if an animal's trait is sex-linked.

(A) X dominant affected father.svg (B) X dominant affected mother.svg (C) X recessive carrier mother.svg
Illustration of some X-linked heredity outcomes (A) the affected father has one X-linked dominant allele, the mother is homozygous for the recessive allele: only daughters (all) will be affected. (B) the affected mother is heterozygous with one copy of the X-linked dominant allele: both daughters and sons will have 50% probability to be affected. (C) the heterozygous mother is called "carrier" because she has one copy of the recessive allele: sons will have 50% probability to be affected, 50% of unaffected daughters will become carriers like their mother. [6]

X-linked dominant inheritance

X-linked dominant traits can affect females as much as males X-linked dominant (affected mother).svg
X-linked dominant traits can affect females as much as males

X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. In this case, someone who expresses an X-linked dominant allele will exhibit the disorder and be considered affected.[ citation needed ] The pattern of inheritance is sometimes called criss-cross inheritance. [7]

X-linked dominant traits do not necessarily affect males more than females (unlike X-linked recessive traits). The exact pattern of inheritance varies, depending on whether the father or the mother has the trait of interest. All fathers that are affected by an X-linked dominant disorder will have affected daughters but not affected sons. However, if the mother is also affected then sons will have a chance of being affected, depending on whether a dominant or recessive X chromosome is passed on. When the son is affected, the mother will always be affected. Some X-linked dominant conditions are embryonic lethal in males, making them appear to only occur in females. [8]

Genetics

As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked inheritance is determined by the sex of the parent carrying a specific gene and can often seem complex. This is due to the fact that, typically, females have two copies of the X-chromosome, while males have only one copy. The difference between dominant and recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.[ citation needed ]

X-linked dominant disorders tend to affect females more often because they tend to be developmentally fatal in males. This is because males have only one copy of X-chromosome while females have two copies.[ citation needed ]

Inheritance

In X-linked dominant inheritance, when the mother alone is the carrier of a mutated, or defective gene associated with a disease or disorder; she herself will have the disorder. Her children will inherit the disorder as follows:

When the father alone is the carrier of a defective gene associated with a disease or disorder, he too will have the disorder. His children will inherit the disorder as follows:

If both parents were carriers of a defective gene associated with a disease or disorder, they would both have the disorder. Their children would inherit the disorder as follows:

In such a case, where both parents carry and thus are affected by an X-linked dominant disorder, the chance of a daughter receiving two copies of the X chromosome with the defective gene is 50%, since daughters receive one copy of the X chromosome from both parents. Were this to occur with an X-linked dominant disorder, that daughter would likely experience a more severe form.

Some X-linked dominant conditions such as Aicardi syndrome are fatal to boys; therefore only girls with these conditions survive, or boys with Klinefelter's syndrome (and hence have more than one X chromosome).

A few scholars have suggested discontinuing the use of the terms dominant and recessive when referring to X-linked inheritance, stating that the highly variable penetrance of X-linked traits in females as a result of mechanisms such as skewed X-inactivation or somatic mosaicism is difficult to reconcile with standard definitions of dominance and recessiveness. [9]

X-linked dominant diseases

X-linked recessive inheritance

In X-linked recessive inheritance, males can only inherit the trait from the mother X-linked recessive (2).svg
In X-linked recessive inheritance, males can only inherit the trait from the mother

X-linked recessive inheritance is coded by the recessive version of a gene. The mutation of a gene on the X chromosome causes the phenotype to be always present in the male because they have only one X chromosome. The phenotype only occurs in a female if she is homozygous for the mutation. A female with one copy of the mutated gene is considered a carrier.

A carrier female with only one copy of the mutated gene does not often express the diseased phenotype, although X-chromosome inactivation (or skewed X-inactivation), which is common in the female population, may lead to different levels of expression. [15] There are characteristic patterns for X-linked recessive inheritance. [16] As each parent contributes one sex chromosome to their offspring, sons cannot receive the X-linked trait from affected fathers, who provide only a Y chromosome. Consequently, affected males must inherit the mutated X chromosome from their mothers. X-linked recessive traits are more common in males as they only have one X chromosome, they need only one mutated X chromosome to be affected. In contrast, females have two X chromosomes and must inherit two mutated recessive X alleles, one from each parent, to be affected. X-linked recessive phenotypes tend to skip generations. [17] A grandfather will not affect the son but could affect the grandson by passing the mutated X chromosome to his daughter who is, therefore, the carrier.

Y-linked

Sex-linked traits in other animals

It is important to distinguish between sex-linked characters, which are controlled by genes on sex chromosomes, and two other categories. [21]

Sex-influenced traits

Sex-influenced or sex-conditioned traits are phenotypes affected by whether they appear in a male or female body. [22] Even in a homozygous dominant or recessive female the condition may not be expressed fully. Example: baldness in humans.

Sex-limited traits

These are characters only expressed in one sex. They may be caused by genes on either autosomal or sex chromosomes. [22] Examples: female sterility in Drosophila; and many polymorphic characters in insects, especially in relation to mimicry. Closely linked genes on autosomes called "supergenes" are often responsible for the latter. [23] [24] [25]

Genetic diseases

An X-linked genetic disease is a disease inherited through a genetic defect on the X chromosome. In human cells, there is a pair of non-matching sex chromosomes, labelled X and Y. Females carry two X chromosomes, whereas males have one X and one Y chromosome. A disease or trait determined by a gene on the X chromosome demonstrates X-linked inheritance, which can be divided into dominant and recessive patterns.

The first X-linked genetic disorder described on paper was by John Dalton in 1794, then later in 1910, following Thomas Hunt Morgan's experiment, more about the sex-linked inheritance was understood. In 1961, Mary Lyon proposed the hypothesis of random X-chromosome inactivation providing the fundamental for understanding the mechanism of X-linked inheritance.

There is currently an estimation of 867 X-linked genes identified, with over 533 diseases related to X-linked genes. Common X-linked genetic diseases include Red-green colour blindness, which affects an individual's ability to see red or green images; X-linked agammaglobulinemia, resulting in a deficiency of immunity; Duchenne Muscular Dystrophy, causing muscle weakness and immobility; Hemophilia A, leading to blood clotting deficiency. X-linked recessive diseases are more frequently encountered than dominant ones and predominantly affect males, with Red-green colour blindness having the highest prevalence among all.

Genetic screening including carrier screening, prenatal screening and newborn screening could be done on individuals for early detection of genetic defects. As there are many X-linked genetic diseases, the pathology and mechanism of each varies significantly, there is no clear-cut diagnosis and treatment for all diseases. Methods of diagnosis range from blood tests to genetic tests, while treatments range from specific medications to blood infusion.

The incidence of X-linked recessive conditions in females is the square of that in males: for example, if 1 in 20 males in a human population are red–green color blind, then 1 in 400 females in the population are expected to be color-blind (1/20)*(1/20). Examples include:

There are fewer X-linked dominant conditions than X-linked recessive, because dominance in X-linkage requires the condition to present in females with only a fraction of the reduction in gene expression of autosomal dominance, since roughly half (or as many as 90% in some cases) of a particular parent's X chromosomes are inactivated in females.[ citation needed ] Examples include:

Red-green colour blindness

Red-green colour blindness is a type of colour vision deficiency (CVD) caused by a mutation in X-linked genes, affecting cone cells responsible for absorbing red or green light.

The perception of red and green light is attributed to the Long (L) wavelength cones and Medium (M) wavelength cones respectively. [26] In Red-green colour blindness, mutations take place on the OPN1LW and OPN1MW genes [27] coding for the photopigments in the cones. In milder cases, those affected exhibit reduced sensitivity to red or green light, as a result of hybridisation of the genes, [27] shifting the response of one cone towards that of the other. [26] In the more extreme conditions, there is a deletion or replacement of the respective coding genes, [28] resulting in the absence of L or M cones photopigments and thus losing the ability to differentiate between red or green light completely.

X-linked agammaglobulinemia

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder that impairs the body’s ability to produce antibodies, which are proteins protecting us from disease-causing antigens, resulting in severe bacterial infections. [29]

XLA is associated with a mutation in the Bruton's tyrosine kinase (BTK) gene on the X chromosome, [30] which is responsible for producing BTK, an enzyme regulating B cells development. [30] B cells are a type of white blood cells essential in the production of antibodies, when at an early stage, called pre-B cells, they rely on expansion and survival signals involving BTK to mature. [31]

In affected individuals, their BTK genes have an amino acid substitution mutation, [30] altering the amino acid sequence and the structure of BTK making it faulty. Therefore, they have a normal pre-B cell counts but cannot develop mature B cells, resulting in antibody deficiency.

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a severe neuromuscular disease causing progressive weakness and damage of muscle tissues, [32] leading to mobility loss and difficulties in daily activities. In a later stage of DMD, as respiratory and cardiac muscles start to degenerate, affected individuals are likely to develop complications such as respiratory failure, cardiomyopathy and heart failure. [32]

DMD arises from a mutation, likely to be the deletion of the exons, [33] [34] a nucleotide sequence in the DMD gene that codes for dystrophin. Dystrophin is a protein responsible for strengthening and stabilising muscle fibres. [35] With the loss of the dystrophin complex, the muscle cells would no longer be protected and therefore result in progressive damage or degeneration.

Haemophilia A

Haemophilia A is a blood clotting disease caused by a genetic defect in clotting factor VIII. It causes significant susceptibility to both internal and external bleeding. Individuals having more severe haemophilia can experience more frequent and intense bleeding.

Severe haemophilia A affects most patients. Patients with mild haemophilia often do not experience heavy bleeding except for surgeries and significant trauma. [36]

Screening for Genetic Disorders

Carrier screening

Carrier screening aims to screen for recessive diseases. Targets of carrier screening typically do not show any symptoms but rather might have a family history of the disease or are in a stage of family planning. Carrier screening is done by performing a blood test on the individual, to identify the specific allele. [37]

Prenatal screening

Prenatal screening is offered to females during pregnancy, it involves both maternal blood tests and ultrasound to check for possible defect genes in developing fetus. [38] The screening result only confirms a possibility of genetic disease, so parents would be prepared psychologically, or could consider the option of pregnancy termination.

Newborn screening

The heel prick test is commonly used. A few drops of blood would be collected with a cotton paper from the heel of a newborn that is less than a week old, [39] samples would then be analysed for a variety of disorders.

History

Red-green colour blindness was the first X-linked genetic disorder described on paper, in 1794 by John Dalton, who is affected by the disorder himself. [40] However, it was not until later that the inheritance pattern and genetics were worked out. The X-chromosome was discovered in 1890 by Hermann Henking, [41] then in 1910, Thomas Hunt Morgan discovered an X-linked mutation on a Drosophila, [42] who then conducted experiments and observations to understand the X-linked inheritance.

In 1961, Mary Lyon proposed that one of the two X chromosomes in female mammalian cells would experience random inactivation (see X-chromosome inactivation) in the early embryonic stage. [43] According to her hypothesis, both males and females should have one single X chromosome that is active. This provided an enhancement for understanding the fundamental mechanisms of X-linked inheritance.

See also

References

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  2. ↑ Gilbert, Scott F (2000). "Chromosomal Sex Determination in Mammals". Archived from [ohttps://www.ncbi.nlm.nih.gov/books/nbk9967/ the original] on 23 January 2025.{{cite journal}}: Cite journal requires |journal= (help)
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