Somatic Mutation

Context: The ‘Somatic Mosaicism across Human Tissues’ (SMaHT) Network is exploring somatic mutation’s significance, promoting insights into human biology and disease management through research.

Biological Terms 

Term	Meaning
Genome	The entire set of genetic material in an organism. It includes both the coding sequences (genes) and non-coding regions of DNA.
Human Genome	The complete set of genetic material (DNA) present in a human cell. It contains all the instructions necessary for the growth, development, functioning, and maintenance of a human being.
Deoxyribonucleic Acid (DNA)	The molecule that carries genetic information in cells. It consists of a double-stranded helical structure made up of nucleotide units.
Chromosomes	Thread-like structures made of DNA and proteins found in the nucleus of cells. They carry genetic information in the form of genes. In humans, there are 23 pairs of chromosomes (46 individual chromosomes), with one chromosome from each pair inherited from each parent.
Somatic Cells	Cells in the body other than sperm and egg cells (which are called germ cells). In humans, somatic cells are diploid, meaning they contain two sets of chromosomes, one inherited from each parent. DNA mutations in somatic cells can affect an individual, but they cannot be passed on to their offspring.
Germ Cells	Cells that give rise to the reproductive cells of sexually reproducing organisms – known as gametes – through a process called gametogenesis. In animals, the reproductive male gametes are sperm cells and the female gametes the oocytes.
Proofreading	The process by which enzymes detect and correct errors (mutations) that occur during DNA replication, ensuring the accuracy of DNA copying.
Turnover	Turnover is the replacement of old cells with new ones.
Mutation	A change in the DNA sequence of a gene or chromosome. Example: Single nucleotide changes (point mutations), deletions, insertions.
Somatic Genetic Mutation	A mutation that occurs in the DNA of somatic cells (body cells) after birth. These mutations are not passed on to offspring. Example: Skin cells acquiring mutations due to UV radiation exposure.
Driver Mutation	A mutation that provides a growth advantage to a cell, often contributing to the development of diseases like cancer.
Genetic Variants	Differences in the DNA sequence among individuals of the same species. These can include single nucleotide polymorphisms (SNPs) or larger structural variations.
Immune Cells	Cells of the immune system that defend the body against pathogens. Examples include B cells and T cells.
Genetic diseases	Disorders caused by mutations in an individual’s DNA. Example: Cystic fibrosis caused by mutations in the CFTR gene.
Mutation Signatures	Distinctive patterns of genetic variations associated with specific types of cancer or genetic diseases.
Microfluidics	A technology that manipulates small amounts of fluids at a microscopic scale.
Cancer	A group of diseases characterized by uncontrolled cell growth and division.
Somatic Mosaicism	The presence of different genetic variants in different cells of the same individual.

Somatic Genetic Mutations

• When cells divide, the DNA is copied with extremely high accuracy because of the proteins that proofread and correct errors in the DNA. 
• But despite this mechanism, various studies have estimated that there is still an error rate of 0.64-0.78 mutations per billion base pairs per division.
• Repeated copy-pasting of these cells results in more somatic genetic mutations, the older an individual is and the higher the turnover of the tissue.
• These conditions are not inherited from parents but are a result of new genetic variations in somatic cells.

Cause of Concern 

• Genetic Diseases:
  • Many genetic diseases arise from somatic genetic variants that occur during development, leading to various genetic diseases. 
  • Severity and distribution of the disease depends on how early or late during development the corresponding mutation occurred.
• Cancer Development: 
  • Somatic genetic mutations can lead to the development of cancers and can also be accelerated by cancer. 
  • These mutations are often responsible for the formation of tumors through driver mutations.

Need of Understanding these Mutations 

• Early Diagnosis: 
  • The relationship between somatic changes and cancer underscores the importance of understanding these mutations for early detection, diagnosis, and prognosis.
  • Understanding the timing and impact of these mutations during development is crucial for comprehending the severity and distribution of genetic disorders.
• A Positive Change: Somatic changes can be beneficial in a genetic disease by changing a deleterious change to a normal one, a phenomenon known as revertant mosaicism. For example, around 10% of cases of Wiskott-Aldrich syndrome, a rare genetic immunodeficiency, have been found to have revertant mosaicism, as a result alleviating the severity of the disease in many individuals.
• Immunity Building:
  • Somatic genetic variants play a vital role in the immune system’s ability to generate diverse antibodies.
  • Immune cells like B and T cells undergo significant somatic changes to produce a wide array of proteins that recognize and bind to pathogens. 
  • This diversity is critical for effective immune responses, and studying these variants can provide insights into immune-related disorders.

Global Example 

Somatic Mosaicism across Human Tissues’ (SMaHT) Network

• The U.S. National Institutes of Health has launched a programme focused on understanding the breadth of somatic mosaicism and the biological and clinical significance of such somatic events in humans.
• This network aims to catalyse study in the field by discovering somatic variants, developing tools and resources with which to study them, and improving ability to analyse, interpret, and organise them in different biological and clinical contexts.