Detailed explanation of common genetic variation types

At the cellular level, a gene is equivalent to a point on a chromosome, called a locus. At the molecular level, a site can also be divided into many basic units, called seats. A locus generally refers to a nucleotide pair, and sometimes a mutation may occur when one of the bases changes.

There are various ways to alter the DNA sequence of genes, and the impact of genetic mutations on health depends on their location and whether they alter the function of proteins. So what are the common types of genetic mutations?

Genetic variation is the genetic foundation of individualized medicine

The human genome contains approximately 3.16 billion base pairs, encoding approximately 30000 genes, with an average of one mutation per 500 to 1000 base pairs. If calculated at a 0.1% ratio, there are 3 million variations. Why is this 3 million variation the genetic basis of personalized medicine?

The 3 million variations in the human genome are closely related to the disease genome and drug genome. Simply put, genetic variations are closely related to precision medicine.

The disease genome involves genomic testing of both healthy and asymptomatic disease states, including genetic susceptibility genes, which can achieve accurate prediction and prevention.

The drug genome involves symptomatic disease states and chronic disease treatment, including genes related to drug efficacy/toxicity/resistance/monitoring/recurrence, which can achieve precise treatment.

What are the common types of genetic variations?

1. Single nucleotide polymorphism

Single nucleotide polymorphisms (SNP): Mutations in a single base at a specific location in the genome, typically occurring at a frequency greater than 5%. More than 90% of human mutations are caused by SNPs, which are the main cause of differences in drug metabolism and response in humans.

CYP2C9:430C>T (Arg144Cys)

2. Insertion deletion mutation

Insert deletion mutation (Indel): An insertion or deletion of a certain length of nucleotide at a certain position in the genome, collectively known as Indel.

Case introduction (see figure below):

ACE I/D:Intron16 287bp insertion rs1799752

3. missense mutation

Missense mutation is the change of a DNA base pair, resulting in the replacement of one amino acid by another in the protein encoded by the gene. The result of missense mutation can usually make the polypeptide chain lose its original function, and many protein abnormalities are caused by missense mutation.

The base A has changed to C, and the protein encoded for synthesis has changed

4. nonsense mutation

Similar to missense mutation, nonsense mutation is also a change of DNA base pair, which changes from one amino acid to another. However, this change of DNA sequence will lead to the early termination of cell translation peptide chain. This type of mutation leads to protein shortening, which may affect protein function or completely destroy protein function.

The change of base C to T leads to premature termination of amino acid synthesis and abnormal structural and functional changes in the protein

5. Code shift mutation

Code shift mutations occur when the insertion or deletion of DNA bases alters the reading frame of the gene. Simply put, it means that the code encoding amino acids is misplaced, which changes the type of amino acids encoded and synthesized, ultimately leading to changes in the structure and function of the protein. The resulting protein is usually non functional. Among them, insertion, deletion, and duplication can all be frameshift mutations.

Code shift mutation causes overall right shift

6. Microsatellites

Microsatellite, also known as short segment tandem repeat sequence, is a tandem repeat sequence composed of 2-6 nucleotides in the genome.

7. Microsatellite instability

Microsatellite instability (MSI): The phenomenon of microsatellite length change caused by the increase or decrease of one or more microsatellite repeat fragments. It is generally caused by changes in the activity of the DNA mismatch repair system (MMR) in the body.


8. Copy number variation

Copy number variation (CNV) refers to the deletion, insertion, inversion, and duplication of DNA fragments ranging from 1Kb to 3Mb in length in the genome, collectively known as copy number variation.

HER2 amplification

9. DNA methylation

DNA methylation: the most common epigenetic modification, the cytosine of two nucleotides of CG of DNA is added with methyl to form 5-methylcytosine, thus affecting gene expression.

MGMT promoter methylation