Scientists have created a huge database revealing how half a million different mutations in DNA generate errors in proteins in humans. The researchers hope that the database can be used to develop new, personalized drugs that directly reverse the effects of mutations.
The human genome carries the instructions for At least 20,000 proteinswhich is considered necessary For almost all physiological processes. Each building block of protein – called an amino acid – is key to its function, so an exchange around amino acids can essentially break the protein apart. “Missense” mutations – changes in A DNA A sequence that replaces one amino acid with another Nearly 5,000 human proteins It is known to cause hereditary diseases, such as: Huntington’s disease and Cystic fibrosis.
However, in many cases, it is not entirely clear how these mutations affect the structure and function of proteins and thus cause disease. Without this understanding, it will be difficult to develop targeted treatments for genetic disorders without altering the genome itself, according to the authors of a new study published Jan. 8 in the journal. nature.
“Depending on what happens to the protein, if you were to design a drug to try to fix a disease, the approach would be very different depending on the individual mutation you are considering.” Anthony BeltranThe study’s lead author and a postdoctoral researcher at the Center for Genome Regulation in Spain told Live Science.
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To address this problem, Beltran and his colleagues created a large database that catalogs the effect of more than 500,000 missense mutations on the stability of 522 protein “domains,” that is, regions of proteins that are essential to their function. They called the database the human “domain,” and they built it by systematically mutating proteins in the laboratory. They then transferred the mutations into yeast cells and observed the effects.
In the new study, the team focused specifically on 621 missense mutations from the database that are already known to cause diseases in humans. They found that 60% of these mutations made the affected proteins less stable. Unstable proteins More susceptible to distortion or distortion; Like origami, proteins must be folded in a specific way to reach their intended shape. Misfolded proteins can accumulate inside cells, which may cause damage, or simply damage them be degraded in the body, making the cells unable to perform their functions.
For example, the hereditary form of cataracts – an eye disease that causes the lens of the eye to be obscured eye – Caused by mutations in genes Beta Crystalline Proteins, which normally maintain the transparency of the lens. In the new study, Beltran and his colleagues found that 72% of these mutations destabilize crystalline proteins, making them more likely to clump together and form cloudy areas in the lens.
Instead of causing instability, some missense mutations led to different changes in the proteins. For example, some mutations behind Rett syndromea rare neurodevelopmental disorder, prevents specific protein From binding to DNA. This process usually enables a protein to turn genes on and off in the cell brainBut in this syndrome, this goes awry.
Beltran admitted that although it is the first and largest database of its kind, it so far covers only 2.5% of known human proteins, so more work is needed to expand it. More research will also be needed to determine whether effects seen in isolated domains are also seen in full-sized proteins.
Beltran said the team’s ultimate goal is to build a useful database for predicting the effect of any mutation on protein stability. Such a tool could theoretically enable scientists to develop better drugs for genetic diseases that target defects in the proteins that cause these conditions.