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Lack of Evidence Supporting Transgenerational Effects of Non-Transmitted Paternal Alleles on the Murine Transcriptome

Core Concepts
Transgenerational genetic effects, if they exist at all, are extremely rare in mammals under naturally occurring genetic variation and are unlikely to contribute significantly to phenotypic variance.
The study aimed to test the hypothesis of transgenerational genetic effects (TGE) via the paternal lineage in mice. The researchers generated 833 isogenic C57BL/6J (B6) mice that differed only by the presence of one copy of four A/J chromosomes (MMU 15, 17, 19 or X) in the genome of their sire. They measured 25 anatomical traits and performed RNA-Seq on five distinct tissues (heart, liver, pituitary, whole embryo, and placenta) to assess the effect of the non-transmitted paternal A/J chromosomes. The key findings are: There was no evidence of a significant effect from untransmitted A/J sire chromosome alleles, whether on anatomical traits or gene expression level. The initial suggestion of differential expression of three genes (Mid1, Crem, and Gm26448) was not replicated in subsequent validation experiments. The differential expression of Mid1 in the B6.A-19 consomic-derived isogenic mice was found to be due to a duplication event at the pseudoautosomal region, rather than a TGE. The researchers conclude that transgenerational epigenetic memory of non-transmitted paternal alleles, if it exists, is uncommon in mice and likely other mammals.
There was suggestive evidence (p = 0.0025) for a 6.7% reduction in heart weight in the B6.A-17 N2 consomic-derived line relative to B6.C purebred mice.

Deeper Inquiries

What other mechanisms, besides transgenerational genetic effects, could potentially contribute to phenotypic variation across generations in mammals?

In addition to transgenerational genetic effects, other mechanisms that could contribute to phenotypic variation across generations in mammals include epigenetic inheritance, environmental influences, and stochastic events. Epigenetic inheritance involves the transmission of molecular marks on DNA or histones that can alter gene expression without changing the underlying DNA sequence. These epigenetic marks can be influenced by environmental factors and can be passed on to subsequent generations, potentially impacting phenotypic traits. Environmental influences, such as diet, stress, and exposure to toxins, can also lead to changes in gene expression and phenotype that may persist across generations. Stochastic events, such as random mutations or genetic drift, can introduce variability in the genome that may contribute to phenotypic diversity over time.

How might the findings of this study be reconciled with previous reports of transgenerational effects in other model organisms, such as plants and invertebrates?

The findings of this study, which suggest that transgenerational genetic effects are uncommon in mice, can be reconciled with previous reports of transgenerational effects in other model organisms by considering the differences in genetic and environmental contexts between species. While some model organisms, such as plants and invertebrates, have demonstrated clear examples of transgenerational effects mediated by genetic or epigenetic mechanisms, the complexity of mammalian genomes and regulatory networks may result in different patterns of inheritance. Additionally, the specific genetic backgrounds and environmental conditions of the organisms studied can influence the manifestation of transgenerational effects. Therefore, the lack of evidence for transgenerational genetic effects in mice does not necessarily contradict previous findings in other model organisms, but rather highlights the need to consider species-specific factors in understanding the inheritance of phenotypic traits.

Could there be specific conditions or environmental factors that may be required to observe transgenerational genetic effects in mammals, which were not captured in this study?

Yes, there could be specific conditions or environmental factors that are necessary to observe transgenerational genetic effects in mammals, which may not have been captured in this study. For example, the timing of exposure to environmental stressors or the presence of specific dietary components during critical developmental windows could influence the transmission of epigenetic marks or the expression of non-transmitted alleles across generations. Additionally, interactions between genetic variants and environmental factors, known as gene-environment interactions, may play a role in determining the penetrance and expressivity of transgenerational effects. Furthermore, the presence of specific genetic modifiers or regulatory elements in the genome could modulate the transmission of non-transmitted paternal alleles or epigenetic marks. Therefore, future studies exploring the role of timing, environmental exposures, and genetic interactions in transgenerational inheritance in mammals may provide further insights into the conditions necessary for observing these effects.