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Mouse Study Offers Insights into Epigenetic Inheritance across Generations

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A study appearing in the August issue of the journal Epigenomics hints that some epigenetic patterns can be passed down across generations in mice.

Researchers from Case Western Reserve University studied dozens of traits in the offspring of male mice that had their own Y chromosomes replaced with Y chromosomes from donor strains. Even though female mice don't inherit these sex chromosomes from their fathers, the team reported, female mice fathered by these Y chromosome-substituted males often showed traits that differed from genetically identical mice — a pattern that they attributed to epigenetic inheritance associated with the Y chromosome.

"We found that transgenerational genetic effects rival conventional effects in frequency and strength," senior author Joseph Nadeau, a Case Western School of Medicine genetics chair, and his co-authors wrote.

Based on these findings in mice, they suggest that "some phenotypic variation found in conventional studies of complex traits are attributable in part to the action of genetic variants in previous generations."

The team was specifically interested in exploring situations in which genetic variants in one generation affect offspring in subsequent generations without directly passing on the original genetic variant itself.

To explore this sort of transgenerational epigenetic inheritance, the team used chromosome substitution mouse strains, generated by popping Y chromosomes from donor mice into inbred male mice from different genetic backgrounds.

The researchers bred these so-called chromosome substitution strain mice with female mice from the same host strain as the males, female offspring of the mice were genetically identical to inbred mice in this host strain. They then compared behavioral and phenotypic traits in the offspring with those of the parental host strains.

For instance, when they looked at 41 traits (22 behavioral traits, 12 blood-related traits, and seven heart related traits) in one mouse strain background, the researchers found that more than a third of the traits differed in female offspring of chromosome-substituted fathers compared with other host mice sharing the same genetic profiles.

The effects — which researchers suspect stem from transgenerational epigenetic signals introduced by the transplanted Y chromosome — showed similar effect sizes to the effects detected in the offspring of mice with substituted X or autosomal chromosomes.

The researchers also conducted follow-up studies, which included specific tests for anxiety-related behaviors — in carefully controlled environmental settings. In these studies, they saw shifts in mouse anxiety levels that appear to be a consequence of similar epigenetic effects — but only in one of the two genetic backgrounds tested.

In that study, female offspring in the B6 genetic background showed anxiety differences compared to other B6 mice when their fathers had received a Y chromosome from another strain background called 129. On the other hand, female offspring from the 129 strain background did not show changes in anxiety compared to other 129 mice when their fathers received a Y chromosome substitution from B6 mice.

Based on these findings, the team speculated that the Y chromosome from 129 mice flipped an epigenetic switch in B6 mouse fathers that was inherited by their female offspring leading to decreased anxiety related behavior.

"By controlling the influence of potentially confounding genetic, social, and environmental factors, we found striking evidence for frequent and strong phenotypic changes in daughters that are attributable in a transgenerational genetic manner to the paternal Y chromosome," they explained.

Those involved in the study noted that more research is needed to understand how such epigenetic inheritance occurs — and to explore the extent of this inheritance. But, they argued, if similar patterns hold in humans, it's possible that transgenerational epigenetic inheritance explains some of the so-called "missing heritability" associated with complex diseases and traits.

"We propose that trangenerational genetic effects contribute to 'missing heritability,'" they wrote. "The present study together with related reports suggest that heritable epigenetic effects are as common and as strong as genetic variants whose phenotypic effects are inherited in the conventional manner."

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