Sex-Linked Disorders

Why some disorders are linked to sex

Humans usually have two sex chromosomes: females are $XX$ and males are $XY$. These chromosomes determine biological sex, but they also carry other genes. When an allele controlling a characteristic lies on a sex chromosome, its inheritance is described as sex-linked.

The GCSE examples are usually recessive disorders caused by alleles on the X chromosome, such as haemophilia and red–green colour blindness. The X chromosome is larger than the Y chromosome, so many genes on the X have no matching version on the Y.

Why X-linked recessive disorders are more common in males

Suppose $X^H$ carries a normal dominant allele and $X^h$ carries the recessive allele for haemophilia.

A female has two X chromosomes. A female with genotype $X^H X^h$ usually does not have the disorder because the dominant normal allele masks the recessive allele. She is a carrier, however, and can pass $X^h$ to a child. A female normally has the disorder only if she inherits two recessive alleles, giving $X^hX^h$.

A male has only one X chromosome. A male with genotype $X^hY$ has no corresponding allele on the Y chromosome to mask $X^h$, so he has the disorder. This is why an X-linked recessive disorder is more likely to be expressed in males. It is more precise to say that the male has only one copy of this X-linked gene than to describe him as homozygous recessive.

Following the chromosomes through a cross

Consider an unaffected carrier mother, $X^H X^h$, and an unaffected father, $X^H Y$. The mother's eggs carry either $X^H$ or $X^h$. The father's sperm carry either $X^H$ or $Y$.

The four equally likely combinations are:

• $X^H X^H$: an unaffected daughter who is not a carrier
• $X^H X^h$: an unaffected carrier daughter
• $X^H Y$: an unaffected son
• $X^hY$: an affected son

Therefore, the probability of an affected child is $1/4$, or 25%. Among sons only, one of the two possible male outcomes is affected, so the probability is $1/2$, or 50%. These percentages answer different questions: “25% of all children” is not the same as “50% of sons”. Each conception is a new independent event, so previous children do not alter the next child's probability.

The direction of inheritance matters

A son receives his X chromosome from his mother and his Y chromosome from his father. He therefore cannot inherit an X-linked allele directly from his father.

A daughter receives one X chromosome from each parent. Consequently, every daughter of a father with an X-linked allele receives that allele from him. Whether she is merely a carrier or has the disorder depends on the X chromosome inherited from her mother. For a daughter to have a typical X-linked recessive disorder, she must receive the recessive allele from both parents; her father must therefore have the disorder and her mother must at least carry the allele.

This gives useful pedigree clues. An affected son may have unaffected parents if his mother is a carrier. An affected father cannot transmit the disorder allele directly to a son, whereas his daughters all inherit that X-linked allele. A Punnett square then tests the possible genotypes and turns them into ratios, fractions or percentages.

Core pattern

• Sex-linked alleles are carried on a sex chromosome; GCSE crosses usually involve recessive alleles on the X chromosome.
• Females are $XX$ and males are $XY$.
• Because the Y usually has no matching allele, one recessive allele on a male's X is expressed.

Genotypes to recall

Using $H$ for the normal allele and $h$ for an X-linked recessive disorder:

• $X^H X^H$: unaffected female
• $X^H X^h$: unaffected carrier female
• $X^h X^h$: affected female
• $X^H Y$: unaffected male
• $X^hY$: affected male

Inheritance rules

• Sons receive their X from their mother and Y from their father.
• Daughters receive one X from each parent.
• There is no direct father-to-son transmission of an X-linked allele.
• Every daughter receives her father's X chromosome.

Crosses and probability

Write the parental genotypes, list their possible gametes, complete the Punnett square and identify both sex and phenotype. In a carrier-mother × unaffected-father cross, 25% of all offspring are predicted to be affected sons, equivalent to 50% of sons. Each birth is independent.