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New single-cell sequencing technique can track subtle neurogenetic mutations spatially.

DNA sequences were once thought to be identical from cell to cell, but it’s increasingly understood that mutations can arise during brain development that affect only certain groups of brain cells. A technique developed at Boston Children’s Hospital allows these subtle mutation patterns to be traced and mapped spatially for the first time. This capability is a significant advance for genetics research and provides a new way to study both the normal brain and brain disorders such as epilepsy and autism.  The opensource study is published in the journal Neuron.

The technique uses deep, highly sensitive whole-genome sequencing of single neurons and a new technology that identifies inserted bits of DNA caused by retrotransposons, one of several kinds of so-called somatic mutations that can arise as the brain develops.

The technique picks up somatic mutations that affect just a fraction of the brain’s cells, in a mosaic pattern. It also allows lineage tracing, showing when during brain development the mutations arise and how they spread through brain tissue as the mutated cells grow, replicate and migrate, carrying the mutation with them.

The team state there is a lot of genetic diversity from one neuron to the other, and the current study gets at how somatic mutations are distributed in the brain.  Some mutations may occur on one side of the brain and not the other. Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.

The study examined brain tissue from a deceased 17-year-old who had been neurologically normal, sampling in more than 30 brain locations. It builds on work published by the lab in 2012, which developed methods to sequence the genomes of single neurons, and represents the first time single neurons have been sequenced in their entirety. The single-cell technique is better at detecting subtle mosaicism than usual DNA sequencing methods, which sequence many thousands or millions of cells mixed together and read out an average for the sample.

Somatic brain mutations, affecting just pockets of cells, can be harmful, and have been suggested as a possible cause of neurodevelopmental disorders such as autism, epilepsy or intellectual disability. But they also can be completely benign or have just a subtle effect.

The team state that the findings are intriguing because they suggest that every normal brain may in fact be a mosaic patchwork of focal somatic mutations, though in normal individuals most are likely silent or harmless. These same technologies can now be used to study the brains of people who died from unexplained neuropsychiatric diseases to determine whether somatic mutations may be the cause.

The team summise that the findings provide a proof-of-principle for a systematic way of studying how brain cells disperse and migrate during development, something that has not been possible to do before in humans.

Mirroring these findings, a study published by the lab in 2014 used single-neuron sequencing to detect copy number variants, another type of mutation affecting the number of copies of chromosomes or chromosome fragments. The study found that these mutations can occur in both normal and neurologically diseased brains.

Source:  Boston Children’s Hospital

Developmental Model of Mutation Events and Lineages in This Study.  L1#1 is illustrated as occurring inthe first trimester, though its exact timing is unknown.  MFG, middle frontal gyrus; VZ, ventricular zone; SVZ, subventricular zone; ISVZ, inner SVZ; OSVZ, outer SVZ; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone.  Cell Lineage Analysis in Human Brain Using Endogenous Retroelements.  Walsh et al 2015.
Developmental Model of Mutation Events and Lineages in This Study. L1#1 is illustrated as occurring inthe first trimester, though its exact timing is unknown. MFG, middle frontal gyrus; VZ, ventricular zone; SVZ, subventricular zone; ISVZ, inner SVZ; OSVZ, outer SVZ; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone. Cell Lineage Analysis in Human Brain Using Endogenous Retroelements. Walsh et al 2015.

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