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February 24, 2017

Through Development, Some Brain Cells May Favor Mom’s Genes, or Dad’s

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    Many cells in the brain express two copies of each gene, one inherited from mom and one from dad. Others express just one copy. If the single copy happens to carry a genetic mutation, it may cause the cell to become sick. New research offers a previously undescribed form of autosomal, epigenetic allele-specific expression that can bias the expression of certain maternal or paternal genes. This form of bias may vary by cell type and developmental stage. [Christopher Gregg/University of Utah School of Medicine]

    If we look at a child’s face, we may feel moved to say that she has her mother’s eyes, or her father’s nose. But if we consider an individual cell, we’re less discriminating. Our usual baseline assumption is that each cell expresses maternal gene alleles and paternal gene alleles more or less equally. Yet this pattern is known to admit certain deviations, including those due to genomic imprinting or X-inactivation. Some deviations, however, may remain undiscovered. And these deviations may be due to unknown mechanisms.

    New kinds of bias in the expression of maternal and paternal alleles have been explored by scientists based at the University of Utah School of Medicine. These scientists, led by Christopher Gregg, Ph.D., an assistant professor of neurobiology and anatomy, invented a screen to measure the activity of specific genes from both parents.

    Using this screen, the scientists found that it is not uncommon for cells in the brain to preferentially activate one allele over the another. In at least one region of the newborn mouse brain, the new research shows, inequality seems to be the norm. About 85% of genes in the dorsal raphe nucleus, known for secreting the mood-controlling chemical serotonin, differentially activate their maternal and paternal gene copies. Ten days later in the juvenile brain, the landscape shifts, with both copies being activated equally for all but 10% of genes.

    The researchers added that in monkey and human brains, it's not unusual for individual neurons or specific types of neurons to silence genes from one parent or the other.

    Details of the work appeared February 23 in the journal Neuron in an article entitled “Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain.” The article describes how genomics, in situ hybridization, and mouse genetics strategies uncovered diverse allelic effects in the brain that are not caused by imprinting or genetic variation.

    “We found allelic effects that are developmental stage and cell type specific, that are prevalent in the neonatal brain, and that cause mosaics of monoallelic brain cells that differentially express wild-type and mutant alleles for heterozygous mutations,” wrote the article’s authors. “Finally, we show that diverse non-genetic allelic effects that impact mental illness risk genes exist in the macaque and human brain.”

    "This story has its roots in understanding why we reproduce sexually—normally, having two copies of a gene acts as a protect buffer in case one is defective," said Dr. Gregg. "Our findings suggest that periods when the healthy gene copy is turned off could be critical windows during which cells are particularly vulnerable to a mutation in the other copy."

    Often mutations causing mental illness are heterozygous, meaning that they impact just one gene copy, and the Gregg lab is now exploring whether the effects they uncovered could explain why the same gene can be associated with a wide range of mental illnesses, from autism to schizophrenia, and why different people experience variation in the severity of their symptoms or risk for disease. The study demonstrates that it is possible for some cells in the brain to predominately express a mutant copy of a gene while others don't.

    Scientists have known for decades that some specific classes of genes differentially activate their maternal and paternal copies in the brain; however, the study from Dr. Gregg's lab uncovered a new and vast landscape of effects in the brain that cause differences in the activation of maternal and paternal gene copies according to age, cell type, brain region, and tissue.

    The study also raises the possibility of yet undiscovered mechanisms for how cells decide which parent's genes to shut off. Currently, it's known that children can inherit epigenetic imprints on their genome from parents that communicate whether a gene should be expressed, and for females, each cell inactivates one X chromosome. Finding the mechanisms that cause the effects described in the Gregg lab's new study could lead to new therapeutic approaches that work by activating silent healthy gene copies in the brain.

    "The screens revealed a new landscape of effects on maternal and paternal gene copies in the brain that were not due to imprinting and not due to X-inactivation but took on all kinds of different forms," Dr. Gregg explained. "Some effects are age specific, some are stable after birth, some impact most brain cells, some are more cell specific, some involved antagonistic effects where the maternal gene would go up and the paternal gene would go down, while others took on a different pattern."

    Dr. Gregg and his team are now focused on understanding how differences in parental gene expression shape brain functions and disease risk. And while these investigators are specifically looking at brain cells and mental illness, the screen they developed, now available to the scientific community, could provide insights across many cell types.

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