Unlocking the brain’s secrets: scientists find over 100 unique mutations in brain cells

Your brain is made up of approximately 100 billion neurons. These are the cells that process information and pass along electrical and chemical signals to their other neuron buddies throughout the body to coordinate thoughts, movement, and many other functions. It’s no small task to create the intricate neuronal network that is the backbone of the central nervous system. If any of these neurons or a group of neurons acquire genetic mutations that alter their function, a lot can go wrong.

The genetic makeup of neurons is particularly interesting because it appears that each neuron has its own unique genome. That means 100 billion different genomes in a single cell type in the brain. Scientists suggest that this “individuality” could explain why monozygotic, or identical, twins have different personalities and susceptibilities to neurological disorders or mental illnesses and why humans develop brain diseases or cancer over time.

To understand what a genome of a cell looks like, you need to sequence its genetic material, or the DNA, that’s housed in a cell’s nucleus. Sequencing the genome of an individual cell is hard to do accurately with our current technology, so scientists have developed clever alternatives to get a front-row view into the workings of neuronal genomes.

Cloning mouse neurons reveals 100+ unique genetic mutations

One such method was published recently in the journal Neuron by a CIRM-funded team from The Scripps Research Institute (TSRI). Led by senior author and Associate Professor at TSRI, Kristen Baldwin, the team took on the challenge of cloning individual mouse neurons to unlock the secrets of neuronal genomes. (For those who aren’t familiar with the term, cloning is a process that produces new cells or organisms that harbor identical genetic information from the originating cell.)

What they found from their cloning experiment was surprising: each neuron they sequenced had an average of more than 100 unique genetic mutations, and these mutations tended to appear in genes that were heavily used by neurons, something that is uncommon in cell types of other organs that tend to protect their frequently used genes. Their findings could help unravel the mystery behind some of the causes for diseases like Alzheimer’s and autism.

In a TSRI news release, Kristen Baldwin explained:

Kristen Baldwin

Kristen Baldwin

“Neuronal genomes have remained a mystery for a long time. The findings in this study and the extensive validation of genome sequencing-based mutation discovery that this method permits, open the door to additional studies of brain mutations in aging and disease, which may help us understand or treat cognitive decline in aging, neurodegeneration and neurodevelopmental diseases such as autism.”

Making mice with neuronal genomes

To clone individual neurons, the team took the nucleus of a single neuron and transplanted it into a mouse egg cell that lacked its own nucleus. The egg developed and matured all while copying and passing on the genetic information of the original mouse neuron. The team generated cloned embryonic stem cell lines from these eggs and were able to expand the stem cell lines to generate millions of stem cells that contained the same genetic material.

TSRI Research Assistant Alberto Rodriguez uses a tiny straw-like micropipette to pick up red fluorescent neurons and transfer their genomes into an egg.

TSRI scientists extract the nuclei of neurons and transfer their genomes into an egg. (Image courtesy of TSRI)

They made several different cloned stem cell lines representing different neuronal genomes and sequenced these lines to identify unique genetic mutations. They also were able to generate cloned stem cell lines from the neurons of older mice, and thus were able to track the accumulation of genetic mutations over time. Even more impressive, they made living mice that contained the cloned genomes of individual neurons in all of their cells, proving that neuronal genomes are compatible with development.

The team did report that not all neurons could be developed into cloned stem cell lines for reasons that they couldn’t fully explain, but they decided to focus on studying the cloned stem cell lines that were successful.

What does this mean for humans?

Baldwin explained that what was most surprising about their study was “that every neuron we looked at was unique – carrying more than 100 DNA changes or mutations that were not present in other cells.”

The next steps for their research are to explore why this diversity among neuronal genomes exists and how this could contribute to neurological disease in humans.

Co-first authors Jennifer Hazen and Gregory Faust.

Co-first authors Jennifer Hazen and Gregory Faust.

Co-first author Jennifer Hazen explains, “We need to know more about mutations in the brain and how they might impact cell function.”

Also mentioned in the news release, the team plans “to study neuronal genomes of very old mice and those with neurological diseases. They hope this work will lead to new insights and therapeutic strategies for treating brain aging and neurologic diseases caused by neuronal mutations.”


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Key stem cell gene controlled from afar, Canadian scientists discover

Embryonic stem cells can, by definition, mature into any cell type in the body. They are able to maintain this state of so-called pluripotency with the help of a gene called Sox2. And now, researchers at the University of Toronto (U of T) have discovered the unseen force that controls it. These findings, reported in the latest issue of Genes & Development, offer much-needed understanding of the steps a cell must take as it grows up.

Mouse embryonic stem cells grown in a round colony of cells (A) and express Sox2 (B), shown in red. Sox2 control region (SCR)-deleted cells have lost the typical appearance of embryonic stem cells (C) and do not express Sox2 (D). [Credit: Jennifer Mitchell/University of Toronto]

Mouse embryonic stem cells grown in a round colony of cells (A) and express Sox2 (B), shown in red. Sox2 control region (SCR)-deleted cells have lost the typical appearance of embryonic stem cells (C) and do not express Sox2 (D). [Credit: Jennifer Mitchell/University of Toronto]

Led by U of T Professor Jennifer Mitchell, the research team were, for the first time, able to identify the specific molecular regulator that switched the Sox2 gene on and off at specific times during an embryonic cell’s lifetime. As Mitchell explained:

“We studied how the Sox2 gene is turned on in mice, and found the region of the genome that is needed to turn the gene on in embryonic stem cells. Like the gene itself, this region of the genome enables these stem cells to maintain their ability to become any type of cell.”

The team named this region the Sox2 control region, or SCR.

For the last decade scientists have been using knowledge gleaned from the Human Genome Project to map how and when genes are switched on and off. Interestingly, the regions that control the gene in question aren’t always located close by.

This was the case with Sox2, said Mitchell. Early on, researchers had argued that Sox2 was regulated from nearby. But in this study, the team found the SCR, which controls Sox2, to be located more than 100,000 DNA base pairs away. According to Mitchell, the process by which the SCR activates Sox2 is fascinating:

“To contact the gene, the DNA makes a loop that brings the SCR close to the gene itself only in embryonic stem cells… It is possible that the formation of the loop needed to make contact with the Sox2 gene is an important final step in the process by which researchers practicing regenerative medicine can generate pluripotent cells from adult cells.”

Indeed, despite a flurry of research breakthroughs and a promising number of clinical trials moving forward, there are still some fundamental aspects of stem cell biology that remain unknown. This discovery, argues Mitchell, is an important step towards reaching toward improving the way in which scientists manipulate stem cells to treat disease.