28th February 2024

Epigenetics

Gene expression is a tightly controlled process, and many factors affect gene transcription. Epigenetics refers to the various factors that alter the expression of a gene. This process allows selective gene expression between different cell types, allowing the differentiation of cells.

X-inactivation

This process is predominantly seen in females, whereby the presence of 2 X chromosomes would result in lethal aneuploidy. Female cells compensate for this by inactivating one copy of the X-chromosome within its cells, ensuring only one X chromosome is actively involved in gene transcription. The inactivated X-chromosome can be seen as a Barr body. Therefore, females will naturally display mosaicism for the X chromosome as half of their somatic cells with an active maternal X chromosome, and the other half contains an active paternal X chromosome. The female’s children will not inherit the pattern of X-inactivation as both X chromosomes are active within gonadal tissues.

The impact of X-inactivation depends on the gene product:

Milder phenotype displayed – For example, heterozygous carriers of haemophilia will display deranged clotting time, but no clinical significance is seen.

The patchy distribution of normal and abnormal tissue throughout the body – For example, patchy skin pigmentation in incontinentia pigmenti in heterozygous females.

Genetic imprinting

Genetic imprinting is the process of silencing an allele from a particular parent, leaving only one active copy of the gene within all somatic cells. Imprinting occurs due to DNA methylation and histone modification to condense the affected allele, preventing the transcription of genes within that allele.

Classically, this is exemplified by Prader-Willi syndrome and Angelman syndrome. Both syndromes are caused by a deletion within the long arm of chromosome 15, and the phenotype displayed depends on the parent from which the mutation is inherited. Paternal inheritance of the deletion results in Prader-Willi syndrome, while maternal inheritance results in Angelman syndrome. This is due to genetic imprinting preventing any gene product from being produced.

Prader-Willi syndrome is typically characterised by short stature, obesity and learning difficulties. Severe learning difficulties and persistent happy affect with ataxia characterise Angelman syndrome.

Other conditions that are caused by genetic imprinting include Beckwith-Wiedemann syndrome and Russell-Silver syndrome; both conditions are caused by abnormal methylation of imprinted genes within the maternal and paternal chromosome 11, respectively, resulting in increased or decreased expression of insulin-like growth factor 2 (IGF2) respectively.