Genome Diversity in the Brain Revealed

Every cell in the body have the same DNA. But, the brain cells have changes in their DNA that make each neuron different. One such variation called long interspersed nuclear elements, or L1s has been identified by researchers at the Salk Institute and their collaborators. Variation in L1s is present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Earlier studies have shown that L1s are small bits of DNA called ‘jumping genes’ that copy and paste themselves throughout the genome. But the researchers have found that L1s can also cause large deletions of entire genes. This variation can influence the expression of genes that are crucial for the developing brain.

The findings explain what makes us each unique and why even identical twins can be different from one other. The study is published in the journal Nature Neuroscience.

Lead author of the study, Rusty Gage, a professor in Salk's Laboratory of Genetics, said, "In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person."

"This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism," said Gage, who is also a holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases.

Gage’s team discovered L1s as a mechanism of genome diversity in the brain in 2005. But, it was was until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations.

In 2013, using single-cell sequencing, the team showed that large chunks of DNA were inserted or deleted into the genomes of the cells. However, the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more likely to be altered, as well as whether jumping genes were related to the deletions.

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In the current study, Gage, with co-authors Jennifer Erwin and Apuã Paquola, and collaborators developed a method to better capture L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before.

The team used stem cells that are coaxed to differentiate into neurons in a dish and found that L1s are prone to DNA breaks. Specific enzymes that chew through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots.

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"The surprising part was that we thought all L1s could do insert into new places. But the fact that they're causing deletions means that they're affecting the genome in a more significant way," says Erwin, a staff scientist in Gage's group.

Gage said that diversity can be good for the brain--after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone--but that too much of it can cause disease.

Studies have shown evidence that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amount of L1 variations in their genomes.

In the current study, the researchers examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene's expression and subsequent maturation of neurons. The team plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.

Source-Medindia