Systematic mining of sequencing databases helps discover protein families and functional systems. This method has uncovered diverse CRISPR-Cas systems, especially programmable genome editing. However, conventional methods for sequence mining lag behind the fast-growing databases that currently contain billions of proteins, restricting the discovery of rare protein families and associations.
What is CRISPR Technology?
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a technology researchers use to modify the DNA of living organisms selectively. It was discovered in bacterial immune systems, which cut the DNA of invading viruses and has been repurposed as a gene editing tool.
CRISPR acts like genetic scissors which cut a target DNA sequence. It comprises two key parts: a CRISPR-associated (Cas) nuclease and a guide RNA sequence (gRNA). The Cas nuclease binds and cuts DNA while gRNA directs it to its target.
Treasure Trove of New CRISPR Systems
Recently, scientists have unearthed 188 rare CRISPR systems in bacterial genomes composed of thousands of individual systems. The study "Uncovering the functional diversity of rare CRISPR-Cas systems with deep terascale clustering" expands the known diversity of CRISPR systems in microorganisms, opening new avenues for precise gene editing with less "off-target" effects.
The new CRISPR systems were discovered by analyzing millions of genomes using an algorithm called fast locality-sensitive hashing-based clustering (FLSHclust). This novel algorithm is designed to hunt down genes related to CRISPR and works by efficiently grouping similar objects.
The research team used FLSHclust on three massive public datasets containing billions of DNA and protein sequences from bacteria. This allowed the experts to parse through data in a time frame that was short enough to recover results and make biological hypotheses. According to study lead author Soumya Kannan, FLSHclust accomplishes in weeks what existing algorithms would achieve in months.
Upon discovering new types of CRISPR, the team experiments with four systems to understand how they work. The systems they previously knew about came in six variants - types I through VI - which differ in size, the enzyme used, and the way they latch onto genetic material.
Of the four CRISPR clusters studied by the researchers, two were variants of type I CRISPR systems, and one was type IV. The experiment demonstrated that both kinds of I systems made small, precise cuts in DNA in human cells. Kannan and her colleagues think that type I systems have the potential to be less prone to making off-target, accidental cuts than CRISPR-Cas9, making them more useful for gene editing.
The final cluster was a new type of CRISPR, dubbed type VII. Like the other types, this cluster targets RNA, a biomolecule that plays an important role in protein synthesis. In theory, type VII systems can be useful for RNA editing.
The researchers claim that it is too soon to determine whether type VII CRISPR systems or any newly identified genes will benefit genetic engineering. In the future, the team plans to sift through more of the newfound systems to understand how their parts work.
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