Mutations in Genes

Small harmless variations in genes lead to the production of proteins which are slightly different, causing subtle but observable disparity (or “traits”) between individuals such as eye color or skin tone. However, when the variation is deleterious and results in a protein that affects normal function and physiology, the consequence is sickness and disease.

Mistakes occur most often when the DNA molecule copies itself before cell division. On an average, the copying machinery makes 1 mistake every 100 million base copied (mutation rate of 1/100 million).Our DNA consists of 3 billion bases; approximately 30 mistakes are made every time the DNA is copied. Also, environmental and dietary toxins can negatively impact our genetics. Fortunately, only around 2% of the human DNA actually codes for proteins and most of the mutations occur in the non-coding region (i.e. no protein are produced from these regions of the DNA).

Disease causing mutations can affect either the production, or the function of a protein. Activation of genes to initiate protein production is controlled by two regulatory regions located at the start of the coding sequence termed “promoter” and “enhancer”. Mutations in these regions can cause genes to become super-active or inactive (“silenced”), making too much or too little protein products. On the other hand, mutations within a gene can lead to problems such as ‘constitutively active’ (meaning always turned-on) or non-functional proteins. Both forms of mutations can result in cancer, as excessive production of growth-driving proteins results in unchecked cell division forming tumors; inadequate production of growth-regulators also lead to loss of cell division safeguards, causing aberrant cells to proliferate.

To learn more on the topic of gene mutation and disease, please refer to the blog “Genetically Inherited Diseases” written by Gouri Mukerjee.

Genetic Mutations are Non-Reversible!

Changes in the genetic sequence of the DNA cannot be reversed. An event causing a base change from X -> Y will remain as a “Y” unless another mutation occurs to reverse it. Every time the mutated cell divides, it produces more ‘problem’ cells with the mutated gene. This is especially true in cancer where one mutated cell with the ability to grow indefinitely gives rise to a population of cells all carrying the same cancer-causing mutations.

Treatment for such a population of cancerous cell usually involves small chemical compounds (or drugs) to block the function of excessive or over-active proteins. The uncontrollably dividing cells also lead to higher mutation rates, meaning, that a drug that worked at the beginning may eventually lose efficacy due to additional mutations accumulated by the specific target protein. Then, cytotoxic methods have to be employed to kill the cancer cells, leading to detrimental collateral damages to normal cells near-by.

Epigenetics – Reversible Regulations

Epigenetics was first described by C. H. Waddington in 1942. He defined the term as the “physical nature of genes”; the idea that the physical arrangement of the DNA molecule in the nucleus exerts an additional control on gene activation, independent of the basic genetic sequences. Today, epigenetic is defined as “changes in a trait (observable disparity) that is inheritable but does not involve DNA mutation (or “sequential changes”)”. In simple terms, epigenetics can control genetics.

A mammalian nucleus is about six micrometer (6/100000 meter) while the DNA is about 2 meters long. DNA is compacted into chromosomes by interacting with “histones” (DNA organizing proteins) to fit into this tiny space (see Figure 1). This physical organization is central to the epigenetic regulation of gene expression. In general, tightly packed regions of DNA and histones will not be as active as loosely packed regions where the DNA is more accessible. If genes are books, then epigenetics is the librarian that organizes them. Books that are hidden cannot be borrowed; they need to be correctly placed on shelves for people to read.

Genetic sequence mutations cannot be reversed, unlike epigenetic mistakes that can be corrected. If a librarian continuously misplaces books onto the wrong shelf, the librarian can be taught (by “medication”) to reorganize the books for borrowing.

This reversibility has major implications for cancer therapeutics. Current cancer treatments do not fix the root of the problem: genetic mutations that grant a population of cells immortality. Cancer drugs either target the problem protein(s) or kill the mutant cells. For epigenetic alternations, the root of the problem can be corrected by attempting to reorganize the abnormal physical landscape of a gene to ‘allow’ or ‘forbid’ its expression.

Many types of cancer have epigenetic mutations. For example, in some breast cancer subtypes, aberrant DNA methylation (an epigenetic regulation) lead to inactivation of tumor suppressor genes. Currently, there are no sensitive and specific plasma or serum biomarkers for the early detection of breast cancer. DNA methylation changes, or other epigenetic alterations, might serve as a useful marker for early detection. Many new drugs are being developed to target epigenetic mechanisms that lead to abnormal DNA methylation. The vast therapeutic value of genetic sequencing and epigenetics in cancer treatment are just starting to be realized.

To learn more on Epigenetics and Cancer, please stay tuned for my upcoming blog on this topics.

What’s next?

If you would like to read more about genetics, continue reading this related blog post: “Can genetic advances improve chronic pain management?”.

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