Atlas maps gene exercise, accessibility in creating mind | Spectrum
Mutation Map: Gene expression and DNA accessibility profiles of cells in the developing cerebral cortex can help scientists assess the effects of rare non-coding mutations in autism.
DR. J. Andersen / Pasca Laboratory at Stanford University
A new atlas profiles gene expression and DNA accessibility in individual cells in the developing human cerebral cortex during mid-pregnancy, the time when many of the genes associated with autism are active. The resource could help researchers better understand the molecular basis of cortical development and unravel the effects of rare mutations between genes associated with autism.
“Although we know quite a lot about the early stages of brain development, and we know quite a bit about the middle stages of brain development, the stages of middle and late pregnancy are still largely mysterious,” said co-head Sergiu Pasca, associate professor of psychiatry and behavioral science at Stanford University in California. “Our main goal here was to try to record the cell diversity during the transition between the states in this key stage of pregnancy with single-cell dissolution.”
To create the atlas, the researchers used 16 to 24 week old prenatal tissue from the cerebral cortex and sequenced the RNA from 57,868 cells to reveal all of the active genes in each cell. They also discovered regions of chromatin – the convoluted complexes of DNA and protein that make up chromosomes – that were accessible to enzymes in 31,304 cells.
The joint analysis of data from cells in both data sets resulted in 185 genes whose expression level could be predicted from the accessibility patterns of chromatin: the more accessible an area, the more likely the genes will be expressed there. The genes tended to cluster near putative enhancers or regulatory DNA sequences that are believed to increase gene transcription. That tendency suggests that these genes may help determine the future of immature cells in the developing cortex, the researchers say.
The researchers used their atlas to examine the role of spontaneous, or “de novo” mutations found between genes in some people with autism. They analyzed more than 200,000 such “non-coding” mutations found in the entire genome sequences of 1,902 autistic children or their non-autistic siblings, but not their parents. (The data comes from the Simons Simplex Collection, which is funded by the Simons Foundation, Spectrum’s parent organization.)
They trained a deep learning model called BPNet to predict how the spontaneous mutations disrupt chromatin accessibility profiles for different cell types in the developing brain.
Overall, children with autism have more de novo non-coding mutations than controls, as the study shows. These variants often disrupted the DNA binding sites of transcription factors such as NRF1, which regulates the expression of a subunit found in some receptors for gamma-aminobutyric acid (GABA), a chemical messenger associated with autism and other neuropsychiatric disorders .
“No one has ever looked at brain development like this,” says Lucia Peixoto, an uninitiated assistant professor of biomedical sciences at Washington State University Spokane.
Previous studies have struggled to determine the importance of non-coding mutations in autism, in part because they did not effectively prioritize areas of the genome that might be relevant to autism. The new atlas allows scientists to focus their analysis on regions that are involved in “a process important to autism like brain development,” she says. “It’s like having a magnifying glass.”
By linking these mutations to regulatory regions that control gene expression in the developing brain, the atlas enables researchers to assess the functional importance of non-coding mutations. The work was published in Cell in August.
“In some cases it’s very clear how [mutations are] Cause disease because they meet a very important protein or a very important amino acid in a protein, ”says Pasca. But when mutations are in non-coding regions, “we somehow leave it in the dark whether or not they have a physiological effect. Information about whether the regions in which these mutations are located are active or involved in neural development forces gives us additional clues as to whether they may be involved in cortical development and the pathogenesis of diseases. “
In the future, researchers plan to use CRISPR engineering to create cell lines that carry some of these mutations and test their effects in cortical organoids – miniature models of the cerebral cortex in the laboratory.
Quote this article: https://doi.org/10.53053/TOKB3054