The 98% mystery: Scientists just cracked the code on “junk DNA” linked to Alzheimer’s
When people picture DNA, they often imagine a set of genes that shape our physical traits, influence behavior, and
When people picture DNA, they often imagine a set of genes that shape our physical traits, influence behavior, and help keep our cells and organs functioning.
But genes make up only a small slice of our genetic code. Just around 2% of DNA contains our 20,000-odd genes. The other 98% has long been labelled the non-coding genome, or so-called ‘junk’ DNA. This larger portion includes many of the control switches that determine when genes turn on and how strongly they act.
Astrocytes and hidden DNA switches in the brain
Researchers from UNSW Sydney have now pinpointed DNA switches that help regulate astrocytes. Astrocytes are brain cells that support neurons, and they are known to be involved in Alzheimer’s disease.
In research published on December 18 in Nature Neuroscience, a team from UNSW’s School of Biotechnology & Biomolecular Sciences reported that they tested nearly 1000 possible switches in lab-grown human astrocytes. These switches are strings of DNA called enhancers. Enhancers can sit far from the genes they influence, sometimes separated by hundreds of thousands of DNA letters, which makes them difficult to investigate.
Testing nearly 1000 enhancers at once
To tackle that problem, the researchers combined CRISPRi with single-cell RNA sequencing. CRISPRi is a method that can switch off small stretches of DNA without cutting it. Single-cell RNA sequencing measures gene activity in individual cells. Together, the tools let the team examine the effects of nearly 1000 enhancers in a single large-scale test.
“We used CRISPRi to turn off potential enhancers in the astrocytes to see whether it changed gene expression,” says lead author Dr. Nicole Green.
“And if it did, then we knew we’d found a functional enhancer and could then figure out which gene — or genes — it controls. That’s what happened for about 150 of the potential enhancers we tested. And strikingly, a large fraction of these functional enhancers controlled genes implicated in Alzheimer’s disease.”
Cutting the list from 1000 candidates to about 150 confirmed switches greatly reduces the search area in the non-coding genome for genetic clues linked to Alzheimer’s disease.
“These findings suggest that similar studies in other brain cell types are needed to highlight the functional enhancers in the vast space of non-coding DNA”
Why “in-between” DNA matters for many diseases
Professor Irina Voineagu, who oversaw the study, says the results also provide a useful reference for interpreting other genetic research. The team’s findings create a catalogue of DNA regions that can help explain results from studies looking for disease-related genetic changes.
“When researchers look for genetic changes that explain diseases like hypertension, diabetes and also psychiatric and neurodegenerative disorders like Alzheimer’s disease — we often end up with changes not within genes so much, but in-between,” she says.
Her team directly tested those “in-between” stretches in human astrocytes and showed which enhancers truly control key brain genes.
“We’re not talking about therapies yet. But you can’t develop them unless you first understand the wiring diagram. That’s what this gives us — a deeper view into the circuitry of gene control in astrocytes.”
From gene switches to AI prediction models
Running nearly a thousand enhancer tests in the lab took painstaking effort. The researchers say this is the first time a CRISPRi enhancer screen of this size has been carried out in brain cells. Now that the groundwork has been done, the dataset can also be used to train computer models to predict which suspected enhancers are real gene switches, potentially saving years of lab work.
“This dataset can help computational biologists test how good their prediction models are at predicting enhancer function,” says Prof. Voineagu.
She adds that Google’s DeepMind team is already using the dataset to benchmark their recent deep learning model called AlphaGenome.
Potential tools for gene therapy and precision medicine
Because many enhancers are active only in specific cell types, targeting them could offer a way to fine-tune gene expression in astrocytes without changing neurons or other brain cells.
“While this is not close to being used in the clinic yet — and much work remains before these findings could lead to treatments — there is a clear precedent,” Prof. Voineagu says.
“The first gene editing drug approved for a blood disease — sickle cell anemia — targets a cell-type specific enhancer.”
Dr. Green says enhancer research could become an important part of precision medicine.
“This is something we want to look at more deeply: finding out which enhancers we can use to turn genes on or off in a single brain cell type, and in a very controlled way,” she says.
