Transgenerational Genetic Effects of the Paternal Y Chromosome on Daughters‘ Phenotypes

Abstract

Aims: Recent evidence suggests that transgenerational genetic effects contribute to phenotypic variation in complex traits. To test for the general occurrence of these effects and to estimate their strength, we took advantage of chromosome substitution strains (CSSs) of mice where the Y chromosome of the host strain has been replaced with the Y chromosome of the donor strain. Daughters of these CSS-Y males and host strain females are genetically identical and should be phenotypically indistinguishable in the absence of transgenerational genetic effects of the fathers‘ Y chromosome on daughters‘ phenotypes. Materials & methods: Assay results for a broad panel of physiological traits and behaviors were compared for genetically identical daughters of CSS-Y males and host strain females from the B6-Chr^A/J and B6-Chr^PWD panels of CSSs. In addition, behavioral traits including specific tests for anxiety-related behaviors were tested in daughters of B6-Chr¹²⁹ and 129-Chr^B6 CSS-Y males. Results: Across a panel of 41 multigenic traits assayed in the B6-Chr^A/J panel of CSSs females and 21 multigenic traits in the B6-Chr^PWD panel females, the frequency and strength for transgenerational genetic effects were remarkably similar to those for conventional inheritance of substituted chromosomes. In addition, we found strong evidence that the Y chromosome from the 129 inbred strain significantly reduced anxiety levels among daughters of B6-Chr¹²⁹ CSS-Y males. Conclusion: We found that transgenerational genetic effects rival conventional genetic effects in frequency and strength, we 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, and we propose that transgenerational genetic effects contribute to ‘missing heritability‘.

KEYWORDS::

• chromosome substitution strains
• epigenetics
• missing heritability
• transgenerational effects
• Y chromosome

Acknowledgements

We thank David Altshuler and Gary Churchill for discussions that stimulated this work, Toshihiko Shiroishi and Toyoyuki Takada for providing access to their B6-Chr^MSM database, and Gemma Casadesus for advice and guidance with the behavior tests.

Financial & competing interests disclosure

The NIH NCRR grant RR12305 supported this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The NIH NCRR grant RR12305 supported this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.