[An algorithm that can analyse hundreds of millions of genetic
sequences has identified DNA-cutting genes and enzymes that are
extremely rare in nature.]
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SUNDAY SCIENCE: ‘TREASURE TROVE’ OF NEW CRISPR SYSTEMS HOLDS
PROMISE FOR GENOME EDITING  
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Sara Reardon
November 23, 2023
Nature [[link removed]]

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_ An algorithm that can analyse hundreds of millions of genetic
sequences has identified DNA-cutting genes and enzymes that are
extremely rare in nature. _

The CRISPR–Cas9 system (pictured) is used to find and cut specific
DNA sequences., Carlos Clarivan/Science Photo Library

 

CRISPR–Cas9 is best known as a laboratory tool for editing DNA, but
its natural function is as part of the immune system that helps
certain microorganisms to fight off viruses. Now, researchers have
used an algorithm to sort through millions of genomes to find new,
rare types of CRISPR system that could eventually be adapted into
genome-editing tools.

“We are just amazed at the diversity of CRISPR systems,” says Feng
Zhang, a biochemist at the Massachusetts Institute of Technology in
Cambridge and co-author of a 23 November paper in _Science _that
describes the systems1
[[link removed]].
“Doing this analysis kind of allows us to kill two birds with one
stone: both study biology and also potentially find useful things.”

Single-celled bacteria and archaea use CRISPR systems to defend
themselves against viruses known as bacteriophages. The systems
generally have two parts: ‘guide RNA’ molecules that recognize and
bind to phage DNA or RNA, and enzymes that cut or otherwise interfere
with the genetic material at the site indicated by the guide RNA.

Until now, researchers had identified six types of CRISPR system,
designated I–VI. These have different properties, including the type
of enzyme they use and how they recognize, bind to and cut RNA or DNA.
The CRISPR–Cas9 system commonly used for genetic engineering is
classed as type II, but the characteristics of other CRISPR types
could make them useful for other applications.

Similar sequences

To find diverse CRISPR systems in nature, Zhang, MIT bioengineer Han
Altae-Tran and their colleagues developed an algorithm called
FLSHclust, which analyses genetic sequences in public databases. These
databases contain hundreds of thousands of genomes from bacteria and
archaea, hundreds of millions of sequences that haven’t been linked
to a particular species and billions of genes that encode proteins.
FLSHclust found CRISPR-associated genes by looking for similarities
between genetic sequences and grouping them into about 500 million
clusters.

By looking at the predicted function of the clusters, the researchers
found around 130,000 genes associated in some way with CRISPR, 188 of
which had never been seen before, and tested several in the lab to
find out what they do. Their experiments reveal various strategies
that CRISPR systems use to attack bacteriophages, including unwinding
the DNA double helix, and cutting DNA in ways that allow genes to be
inserted or deleted. They also identified ‘anti-CRISPR’ fragments
of DNA that might help a phage to escape bacterial defences.

Among the new genes was the code for an entirely unknown CRISPR system
that targets RNA, which the team dubbed type VII. Co-author Eugene
Koonin, a biologist at the National Center for Biotechnology
Information in Bethesda, Maryland, says that it's increasingly hard to
find new CRISPR systems. Type VII — and any other types that
haven’t yet been identified — must be extremely rare in nature, he
adds. “It will probably take monumental efforts to find the next
type.”

It’s hard to know whether certain types of CRISPR system are rare
because they are not generally useful to microorganisms or whether
they are specifically adapted to an organism that lives in a
particular environment, says Christine Pourcel, a microbiologist at
Paris-Saclay University. She adds that because the genetic databases
used in the study include fragments of genomes that aren’t linked to
specific organisms, it will be difficult to study the roles of some of
the new systems.

Impressive haul

The algorithm itself is a major advance, in that it will allow
researchers to look for other types of protein across species, says
Chris Brown, a biochemist at the University of Otago in Dunedin, New
Zealand. “I’m impressed with what they could do,” he says.

“It’s a treasure trove for biochemists,” agrees Lennart Randau,
a microbiologist at the University of Marburg in Germany. The next
step, he says, will be to work out the mechanisms through which the
enzymes and systems work, and how they could be adapted for biological
engineering. Brown says that some CRISPR proteins chop up DNA at
random and are useless for engineering. But they are so precise at
detecting DNA or RNA sequences that they might make good diagnostic or
research tools.

It’s too soon to say whether type VII CRISPR systems or any of the
other genes identified by FLSHclust will be helpful for genetic
engineering, says Altae-Tran, but they have some properties that could
be useful. Type VII, for instance, involves only a very few genes that
could easily fit in a viral vector and be delivered into cells. By
contrast, some of the other systems the team found contain very long
guide RNAs, potentially allowing them to target particular genetic
sequences with unprecedented accuracy.

_doi: [link removed]

References

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Altae-Tran, H. _et al._ _Science_ 382, eadi1910 (2023).

_SARA REARDON:  I'm a freelance journalist covering biomedical,
environmental and social science from beautiful Bozeman, Montana. I've
previously  worked as a staff reporter at Nature, New
Scientist and Science. _

_​In my previous life, I studied mouse sperm and retinas. Realizing
that I could never limit my interests to one field of science, I
switched to science journalism -- a field that thrills me every
day. _

_I've reported from five continents and all over the United States. My
favorite stories involve the myriad ways in which science intersects
with society, particularly through law, ethics, and culture. I also
make short films about science and health-related issues affecting my
local community._

_Follow me on Twitter [[link removed]] to
see my latest work and drop me a message
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or tips! _

_NATURE is a weekly international journal publishing the finest
peer-reviewed research in all fields of science and technology on the
basis of its originality, importance, interdisciplinary interest,
timeliness, accessibility, elegance and surprising
conclusions. Nature also provides rapid, authoritative, insightful
and arresting news and interpretation of topical and coming trends
affecting science, scientists and the wider public._

_Nature's mission statement_

_First, to serve scientists through prompt publication of significant
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significance for knowledge, culture and daily life.
Nature's original mission statement
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published for the first time on 11 November 1869._

_About the Editors_

_Like the other Nature titles, Nature has no external editorial
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HOW THE T. REX BUILT UP THAT BONE-CRUSHING BITE
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JEANNE TIMMONS
An analysis of nine species of tyrannosaurs documented the
evolutionary forces that led to the dinosaur’s reign.
New York Times
November 10, 2023

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* CRISPR
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* DNA
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* enzymes
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* RNA
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