Question

Briefly explain how epigenetic modifications might be responsible for the incomplete penetrance of some dominant alleles.  

Answer 1

ANSWER) Penetrance refers to the likelihood that a clinical condition will occur when a particular genotype is present. A condition is said to show incomplete penetrance when some individuals who carry the pathogenic variant express the associated trait while others do not.. In incomplete or reduced penetrance, some individuals will not express the trait even though they carry the allele. An example of an autosomal dominant condition showing incomplete penetrance is familial breast cancer due to mutations in the BRCA1 gene.

Epigenetic changes and penetrance

Epigenetic changes or modifications indicate the sum of heritable changes, such as DNA methylation, histone modification and miRNA expression as well as environmental and stochastic factors which can affect gene expression and reduced penetrance without changing the DNA sequence. Epigenetic variations have been suggested to have an important role in cellular senescence, tumorigenesis and in several diseases including type 2- diabetes, cardiovascular, autoimmune diseases, obesity and Alzheimer’s disease. A correlation between epigenetic DNA modifications and human life span had been  found that global and local-specific differences in DNA methylation in identical twins of different ages are influenced by environmental factors and lifestyle. Most studies demonstrated that aging is associated with a relaxation in epigenetic control, due to a decrease in global cystosine methylation mostly in transportable repetitive elements. Epigenetic modifications in the pathophysiology of neurodegenerative diseases with consequent transcriptional dysregulation might be an important marker of disease status and its progression. Epigenetic allele silencing may also play a role in malignant hyperthermia susceptibility. Epigenetic modification may also account for a specific disease phenotype in twins and in terms of an epigenotype as they are discordant for childhood leukaemia because they have discordant BRCA1 methylation status. A special case of imprinting is provided by X-inactivation, when a disease gene is X-linked. Shewed X-inactivation can cause variable penetrance of pathogenic mutations in female carriers e.g. the EBP gene (XP11.23) in X-linked dominant chondrodysplasia punctata. Genes can also affect one’s risk of obesity. However there are several epigenetic influences that alter the expression of our genes and ultimately our risk of becoming obese. Failure of epigenetic markers or imprinting can affect gene expression and cause extreme forms of obesity (e.g. Prader–willi syndrome).The disruption of genomic DNA methylation patterns was the first epigenetic abnormality to be described in human cancer. This imbalance involves the promoter CpG island hypermethylation of tumor-suppressor genes, causing transcriptional repression, and global genomic hypomethylation, leading to chromosomal instability and reactivation of endoparasitic sequences. The relationship between DNA methylation and histone modifications was initially described in the context of the inactivation of female X chromosomes and of the demonstration of strong interactions between the DNA methylation machinery and chromatin modifiers.The repression of tumor-suppressor genes by promoter hypermethylation was also found to be associated with a specific histone modification index.In human and mouse tumors, histone H4 undergoes a loss of monoacetylated and trimethylated lysines 16 and 20, respectively. Most importantly, these alterations occur within the context of the repetitive DNA sequences that also become hypomethylated in transformed cells. The global alterations of histone acetylation status suggest novel pathways by which histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) may play roles as tumor-suppressor genes or oncogenes.