28th February 2024

Non-mendelian inheritance

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.

Trinucleotide repeats and anticipation

Anticipation is a phenomenon seen with some autosomal dominant conditions whereby the condition affects the younger generation at an earlier age with increased severity. This often occurs in diseases caused by trinucleotide repeats, such as Huntington’s disease, myotonic dystrophy, spinocerebellar ataxia and Fragile X syndrome.

The inherently unstable nature of the trinucleotide repeat allows expansion to occur during meiosis, which has been linked to increased severity of the condition between generations.

Multifactorial inheritance

Multifactorial inheritance is a catch-all term whereby a condition appears to be influenced by multiple genetic loci. This is commonly associated with many common conditions with multiple predisposing factors like cancer, cardiac conditions, asthma, and mental illness.

The liability threshold theory has been proposed to explain multifactorial inheritance. Genetic and environmental factors must be combined before the phenotype is expressed.

Large Scale population studies can be used to study and estimate the risk of recurrence within a family, but environmental factors prevent the generalisation of such results. Studies between monozygotic and dizygotic twins have been utilised to study various traits and allow the heritability of various conditions to be estimated.

References

• Jorde, L. B., Carey, J. C., & Bamshad, M. J. (2016). Chapter 12: Multifactorial Inheritance and Common Diseases. In Medical Genetics (5th ed.). United States: Elsevier.
• Mensink, K. A., & Highsmith, W. E. (2009). Chapter 5 – Basic Concepts in Human Molecular Genetics. In W. B. Coleman & G. J. Tsongalis (Eds.), Molecular Pathology (pp. 89–107). San Diego: Academic Press.
• Turnpenny, P. D., & Ellard, S. (2017). Patterns of inheritance. In Emery’s Elements of Medical Genetics. China: Elsevier.