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By cloning mouse neurons, TSRI scientists find brain cells with 100+ unique mutations

In a new study published in the journal Neuron, scientists from The Scripps Research Institute (TSRI) are the first to sequence the complete genomes of individual neurons and to produce live mice carrying neuronal genomes in all of their cells.

Use of the technique revealed surprising insights into these cells’ genomes – including the findings that each neuron contained an average of more than 100 mutations and that these neurons accumulated more mutations in genes they used frequently.

“Neuronal genomes have remained a mystery for a long time,” said TSRI Associate Professor Kristin Baldwin, senior author of the new study and member of the Dorris Neuroscience Center at TSRI. “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.”

Unique Mutations

Our individual genomes are inherited from our parents and make us unique in our behavior, appearance and susceptibility to disease. While new mutations in genomes of individual cells are known to cause cancer, only recently have researchers begun to appreciate how different the genomes within normal cells of the body may be. Several lines of research have suggested cells in the brain may be particularly unique – and prone to accumulating new mutations of various sorts, including “jumping” genes called transposons.

Many of these mutations may not be harmful – but collecting too many mutations, or having them build up in genes needed for a cell’s function, might lead to loss of neurons or incorrect brain wiring, which are suspected causes of diseases such as Alzheimer’s and autism.

“We need to know more about mutations in the brain and how they might impact cell function,” said TSRI Research Associate Jennifer Hazen, co-first author of the new study with Gregory Faust of the University of Virginia School of Medicine.

However, studying mutations in single neurons has presented a challenge: A single cell doesn’t contain enough genetic material for analysis, yet these mutations only exist in single cells. Unfortunately, current single-cell analysis approaches introduce new DNA errors and also destroy the only copy of the cell’s DNA in the process, making it impossible to go back and check to see if the mutations were really there. Scientists can’t generate copies of neurons because, unlike other cell types, neurons don’t divide in cell culture.

“There has been no easy way to get more copies of a neuron,” explained TSRI Research Assistant William Ferguson, a co-author of the paper.