Genome-wide analysis of mice brains has found that maternally inherited genes are expressed preferentially in the developing brain, while the pattern shifts decisively in favor of paternal influence by adulthood.

The study, led by Catherine Dulac and Christopher Gregg at Harvard University and described in the journal Science, identified 1,300 genes active in the mouse brain that show some degree of parental bias, greatly expanding on the 45 previously known “imprinted genes” expressed in the brain. Fewer than 100 imprinted genes had been known to exist in the body, suggesting they may be far more common than previously thought.

The new work helps in understanding genomic imprinting, through which each parent is thought to contribute genes nudging offspring development in a direction most favorable, and least costly, to the ultimate transmission of that parent’s genetic material. It contributes to scientists’ growing understanding of a subtle tug-of-war between genes inherited from the mother and the father that shapes the development of their offspring early in life, and may provide lasting parental influence well after birth, even into adulthood.

“Our work shows that parental bias in gene expression is a major mode of genetic regulation in the brain,” said Dulac, the Higgins Professor of Molecular and Cellular Biology at Harvard and an investigator with the Howard Hughes Medical Institute. “Despite tantalizing reports, our understanding of the neural systems governed by imprinted genes has been very limited.”

In studies of the brains of 15-day-old mice embryos as well as adult mice, Dulac and her colleagues found that about a quarter of brain regions are hotspots for expression of imprinted genes. Many of these genes are expressed in brain areas associated with feeding, mating, pain sensation, social interactions, and motivated behavior.

The work builds on previous research by co-author David Haig, the George Putnam Professor of Organismic and Evolutionary Biology at Harvard. Haig’s analysis of rare genetic disorders has shown that certain maternal and paternal genes can clash well into childhood.

Other previous research had offered evidence of a genetic struggle for supremacy only during fetal development. In the womb, some genes of paternal origin have been shown to promote increased demands on mothers, leading to fetal overgrowth, while genes of maternal origin tend to have the opposite effect.

In the current study, Dulac and her colleagues found that 61 percent of imprinted genes in the fetal brain are maternal in origin, suggesting a major maternal influence over the brain development of offspring. By adulthood, the proportions are flipped. About 70 percent of imprinted genes in both the adult cortex and hypothalamus appear to derive from the father, suggesting a major paternal influence on the brain function of adult offspring.

This new work expands on the known timeline for the internal conflict between maternal and paternal genes. Maternal genes may predominate in fetal development, followed by a period of childhood where maternal and paternal genes tussle for control, followed by eventual bias in favor of paternal genes during adulthood.

The data also suggest a highly dynamic regulation of parental biases in gene expression during development and in the adult brain, which had not previously been anticipated, as the authors reported major differences in the parental influence exerted upon distinct brain regions.

In a second study published by Dulac and her colleagues in the same issue of Science, the authors report a preferential expression of the maternal versus paternal X chromosome in the cortex of females, demonstrating a maternal influence over the brain function of adult daughters through X-linked genes. This second study also uncovered the existence of sex-specific parental bias in gene expression that may shed new light into sex differences in brain function and disease susceptibility.

Dulac, Gregg, and Haig’s co-authors are Jiangwen Zhang, James Butler, and Brandon Weissbourd at Harvard, and Shujun Luo and Gary P. Schroth of Illumina Inc. of Hayward, Calif. The work was funded by the Klarman Family Foundation Grants Program in Eating Disorders Research, the Howard Hughes Medical Institute, the Human Frontier Science Program, and the Alberta Heritage Foundation for Medical Research.

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