X-linked Genes

Humans have a pair of sex chromosomes in all of their cells, which can be XY (non-homologous, codes for male primary and secondary sex traits) or XX (homologous, codes for female primary and secondary sex traits). Although this is the basic division, there can be alterations in the chromosomes themselves or the number of chromosomes that alter the phenotypic expression of an XY or XX individual.

On top of this, the chromosomes can have (beneficial or) damaging mutations unrelated to sex characteristics. Because females have two copies of the X chromosome, they can escape some of the deleterious recessive mutations in an X chromosome if they have a healthy copy of the altered gene. However males, because they have only one copy of each chromosome (one X and one Y) will express any recessive traits in either chromosome. So, how can we know if our sons and brothers will suffer from an X-carried disease based on the family tree? Read on to find out!

• First, we will discuss what X-linked genes are.
• Then, we will identify the different types of X-linked genes.
• Next, we will look at different examples of X-linked genes.
• Finally, we will distinguish between X-linked and Y-linked genes.

X-linked Genes Genetics

So, what exactly are X-linked genes? X-linked genes are the genes present on the X chromosome. Pretty simple!

Let's do a deeper dive into the human genome to give X-linked genes some context. The human genome is made up of 23 pairs of chromosomes. Out of these 23 pairs, 22 pairs are called autosomal chromosomes, whereas the 23^rd pair is called the sex chromosome pair. In humans, there are two types of sex chromosomes, X and Y.

• A person who inherits two X chromosomes usually develops the anatomy of the female sex, and a person who inherits one X and one Y chromosome usually develops the anatomy associated with the male sex.

Here, we will mainly focus on X-linked genes and how they are expressed in males and females.

The characteristics and traits of the X-linked genes may be expressed differently in both males and females because females have twice the number of X chromosome copies than males. Males may be affected more by X-linked genes because they have a single copy of the X gene, while females carry two copies of that same copy.

For example, if a female has an altered gene on one of her two X chromosomes, she will usually not be completely affected, but will be a carrier of that alteration or disease-causing gene. However, if a male has an altered gene on his X chromosome, he will be affected by this mutation because he doesn't have another X chromosome with another copy of the gene.

We will further discuss the effects of X-linked genes, how they interact with each other, and what characteristics are expressed in both males and females.

Types of X-linked Genes

There are two types of inheritance patterns that are influenced by X-linked genes:

1. X-linked dominant inheritance

2. X-linked recessive inheritance

Let's discuss each one.

X-linked Dominant Inheritance

X-linked dominant traits are more common than X-linked recessive traits. This type of inheritance usually indicates that the person with this gene will express a disorder or genetic defect and is considered affected.

X-linked dominant inheritance can be lethal in some cases and may cause the person pregnant with a male child to have a miscarriage. Essentially speaking, the gene can be passed down to a female, but passing it down to a male will cause a miscarriage in most cases. Remember that in the case of X-linked dominant diseases, affected females can have a healthy copy of the gene, whilst affected males will only have the altered copy of the gene, and thus the altered gene product.

X-linked Dominant Inheritance in Females

Take the case of a mother with a dominant mutation in an X-linked gene that has a female baby with a healthy dad. In this case, the baby has a 50% chance of inheriting the altered gene copy from the mother, as she can inherit either of the mother's X chromosomes.

On the other hand, if it's the father that has a mutant X-linked dominant gene, the female baby has a 100% chance of inheriting the father's mutant X chromosome.

X-linked Dominant Inheritance in Males

If the same mother (the one with a dominant mutation in an X-linked gene) has a male baby with the healthy father, the baby has a 50% chance of inheriting the chromosome with the altered gene. This is because, as with the female baby, the baby will inherit only one of the mother's X chromosomes.

If it's the father that has a mutant X-linked dominant gene, the male baby has a 0% chance of suffering the disease, because he can only inherit the Y chromosome from his father.

Takeaways for X-linked Dominant Patterns

• No male-to-male transmission as it is an X-linked inheritance.

• Fathers will always pass down the mutated gene to all their daughters.

• Sons will have a 50-50 chance of inheriting the trait from the mother.

X-linked Recessive Inheritance

X-linked recessive disorders are also caused by a mutated gene present on the X chromosome, however, in X-linked recessive inheritance, the mutated gene is usually masked by a dominant allele and will only get expressed when there are two copies of the recessive allele, or the dominant allele is absent. This inheritance pattern is expressed in males more than in females because males only have one copy of the X chromosome.

X-linked Recessive Inheritance in Females

Since females have two copies of the X chromosome, the alleles need to be homozygous (there needs to be two copies of the same allele) for the trait or disease to be expressed. If the female has only one copy of the recessive X-linked gene, then she will be a carrier for the trait but will not express it. This is extremely rare, as it means that both of the parents must be carriers of the X-linked recessive gene.

Let's go back to the example above. If the mother is the carrier of an X-linked recessive trait but the father is completely healthy, it is impossible that the female baby expresses the trait or disease. There is, as before a 50% chance that she will inherit an altered copy of the gene from her mother, but the altered gene won't be expressed. The situation is the same if it's the father that has the altered copy of the gene. Only if both the mother and the father have the altered allele will the female baby express the trait or disease, and then only if she inherits the altered allele from the mother (50% chance).

X-linked Recessive Inheritance in Males

In the case of males, just one copy of the gene is enough for the trait to be expressed. Since males inherit the X chromosome from their mothers and not their fathers, the mutated X-linked gene can only be inherited from the mother. Meaning, there is no male-male transmission.

The chances of the son inheriting the gene from the mother are 50% if the mother is just a carrier for the trait. The son may either inherit the mutated gene or the normal gene from the mother. This is the reason X-linked recessive inheritance is more common in males than females, as just one copy is enough for the male baby to manifest the trait or disease.

Patterns of X-linked Recessive inheritance

• No male-to-male inheritance as the male inherits an X chromosome from the mother.

• Daughters will be carriers for this inheritance and will only express the trait if the gene is homozygous for the recessive allele.

• Sons will have a 50-50 chance of inheriting the gene from the mother.

Example of X-linked genes

To finish off, let's look at some examples of disorders that are associated with X-linked genes.

Fragile X Syndrome

Fragile X Syndrome is an X-linked dominant inheritance genetic disorder. It occurs in approximately 1 in 4,000 males and 1 in 8,000 females. Males are usually more severely affected by this disease than females.

This disorder is caused by a mutation in the FMR1 gene on the X chromosome. This gene is responsible for providing instructions that help make a protein called FMRP. FMRP plays a role in the development of synapses, specialized connections between nerve cells. Synapses help relay important information as they act as the site.

The hindrance in the development of this protein causes severe learning and cognitive impairment in those affected by this syndrome. Since it follows X-linked dominant inheritance patterns, only one allele is enough for this trait to be expressed!

Other symptoms include delayed development of speech, attention deficit disorder (ADD), physical features like a long and narrow face, large ears, flat feet etc. 1 out of 3 people with Fragile X syndrome may also be on the autism spectrum.

Hemophilia

Hemophilia is an X-linked recessive disorder characterized by prolonged bleeding in the event of an injury. When we get injured, our bodies have certain proteins called clotting factors that clot the blood to prevent excessive blood loss. A person with hemophilia does not have enough proteins to clot the blood. As a result, even a minor injury like a cut can prove fatal, as blood loss over a period of time can lead to several complications if proper medical assistance isn’t provided.

Hemophilia is an inherited genetic disorder. There is no male-to-male transmission since it is X-linked, meaning, the father can't pass this mutated gene to their sons. However, they can pass this gene to their daughters. In the case of females, if there is only one allele, they will be carriers. For the trait to be expressed, the female must be homozygous for this trait (have two alleles of hemophilia allele). Mothers can pass this allele to both their sons and daughters.

Difference between X-linked and Y-linked genes

We have discussed what X-linked genes are, but there are also Y-linked genes. You must be wondering what the difference between X-linked and Y-linked genes is. Below is a table highlighting the difference between the two.