Lack of evidence supporting transgenerational effects of non-transmitted paternal alleles on the murine transcriptome
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eLife assessment
This important article presents the results of a large screen for non-genetic transgenerational effects that may influence gene expression and other phenotypes in mice. An extraordinary amount of mouse breeding, phenotyping, and RNA sequencing data provide compelling evidence that, for the phenotypes and genomic regions interrogated in these mouse strains, non-genetic transgenerational effects of appreciable magnitude are likely to be extremely rare. This paper will be of broad interest to geneticists and of particular interest to those studying epigenetic inheritance.
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Abstract
Transgenerational genetic effects are defined as the effects of untransmitted parental alleles on the phenotype of their offspring. Well-known transgenerational genetic effects, in humans and other mammals, are the effects of a parental genotype on the nurturing ability of the parents, coined “genetic nurture”. However, there exist examples of transgenerational genetic effects in model organisms that are independent of nurturing effects and support the epigenetic transmission of a memory of the parental genotype possibly mediated by small RNA species. To test whether such transgenerational epigenetic effects might exist in mammals, we generated 833 isogenic C57BL/6J (B6) mice that differed only by the presence in the genome of their sire of one copy of four A/J chromosomes (MMU 15, 17, 19 or X). We measured 25 anatomical traits and performed RNA-Seq on five distinct tissues (heart, liver, pituitary, whole embryo, and placenta). There was no evidence of a significant effect from untransmitted A/J sire chromosome alleles, whether on anatomical traits or gene expression level. We observed an effect on Mid1 expression levels in multiple tissues, but this was shown to be due to a de novo mutation that occurred in one of the sire lines. We conclude that transgenerational epigenetic memory of non-transmitted paternal alleles - if it exists - is uncommon in mice and likely other mammals.
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eLife assessment
This important article presents the results of a large screen for non-genetic transgenerational effects that may influence gene expression and other phenotypes in mice. An extraordinary amount of mouse breeding, phenotyping, and RNA sequencing data provide compelling evidence that, for the phenotypes and genomic regions interrogated in these mouse strains, non-genetic transgenerational effects of appreciable magnitude are likely to be extremely rare. This paper will be of broad interest to geneticists and of particular interest to those studying epigenetic inheritance.
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Reviewer #1 (Public Review):
Summary:
This paper explores the contribution of transgenerational effects to phenotypic variation in twenty-five phenotypes and transcript variation in the heart, liver, pituitary, whole embryo, and placenta. The authors use a powerful design, exploiting the use of consomics, and argue that there are no observable changes attributable to the differences in the parental origin of the four chromosomes they examine.
Strengths:
It's good to see a use for consomics. This is a powerful and useful design to address the problem they are tackling.Weaknesses:
The difficulty faced by the authors is that they have interrogated only a small portion of the genome, using bulk RNA sequencing and a set of correlated phenotypes, thus restricting the conclusions they can draw from the absence of significant findings. -
Reviewer #2 (Public Review):
Summary:
In this study, Gularte-Merida et al investigate the occurrence of transgenerational effects of non-transmitted parental alleles outside of the well-described effect of "genetic nurture." To achieve this they employed consomic male mice to generate an N2 and N3 population, allowing for the observation of effects due to non-transmitted paternal alleles while controlling for maternal care by using isogenic B6 dams. The authors conduct RNAseq, qPCR validation, and anatomical phenotyping measures to investigate the presence of non-genetic nurture TGE. The author's findings challenge the frequency of non-genetic nurture TGE, a meaningful contribution to the field. Overall, this is an ambitious study with important negative data. The authors are to be commended on this. This greatly strengthens the …
Reviewer #2 (Public Review):
Summary:
In this study, Gularte-Merida et al investigate the occurrence of transgenerational effects of non-transmitted parental alleles outside of the well-described effect of "genetic nurture." To achieve this they employed consomic male mice to generate an N2 and N3 population, allowing for the observation of effects due to non-transmitted paternal alleles while controlling for maternal care by using isogenic B6 dams. The authors conduct RNAseq, qPCR validation, and anatomical phenotyping measures to investigate the presence of non-genetic nurture TGE. The author's findings challenge the frequency of non-genetic nurture TGE, a meaningful contribution to the field. Overall, this is an ambitious study with important negative data. The authors are to be commended on this. This greatly strengthens the negative findings within the paper.
The paper, however, is written extremely technically, with little detail, and is not currently suitable for the lay audience. The authors need to greatly increase the clarity of the writing and data presentation.
Strengths:
Elegant experimental design using consomic mouse populations.
The use of a second replication cohort using the same genetic founders as the first study.
Weaknesses:
While much of the explanation of the methods is understandable by geneticists, the paper has implications outside of the genetics field. Overall, I suggest expanding the explanation and language for non-geneticists. This will allow the paper to reach a wider audience.
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Reviewer #3 (Public Review):
Summary:
Gularte-Mérida and colleagues took advantage of the existence of so-called consomic strains in the mouse, which result from the substitution of one of their chromosomes by that of another strain, to ask through appropriate crosses whether information carried by this substitution chromosome impacts progeny that do not inherit it. With one exception, the authors did not detect any significant effect for any of the four non-transmitted chromosomes tested. Given these results, the authors conclude that such effects, if they exist, must be extremely rare in the mouse.
Strengths:
This is a very convincing and impressive study, with effects assessed in almost 2500 mice. The negative results obtained should put to rest once and for all the notion that intergenerational, let alone transgenerational, non-DNA …
Reviewer #3 (Public Review):
Summary:
Gularte-Mérida and colleagues took advantage of the existence of so-called consomic strains in the mouse, which result from the substitution of one of their chromosomes by that of another strain, to ask through appropriate crosses whether information carried by this substitution chromosome impacts progeny that do not inherit it. With one exception, the authors did not detect any significant effect for any of the four non-transmitted chromosomes tested. Given these results, the authors conclude that such effects, if they exist, must be extremely rare in the mouse.
Strengths:
This is a very convincing and impressive study, with effects assessed in almost 2500 mice. The negative results obtained should put to rest once and for all the notion that intergenerational, let alone transgenerational, non-DNA sequence-based inheritance via the male germline could be substantial in the mouse.
Weaknesses:
The terminology used (epigenetics, nurture-independent TGE, etc. ) is somewhat confusing and unnecessary.
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