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-Chr(129) 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-Chr(129) 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'.

Figure 1. Study design testing for the effects of the paternal Y chromosome on daughters’ phenotypes

(A) Generation of substitution strains for the Y chromosome. Males were backcrossed to the C57BL/6J host strain, with selection for males from at least 10 backcross generations to reconstitute the genetic background of the host strain [23,24]. (B) Genetic identity for daughters of CSS and host strain males. (C) Controlling for social effects. Male parents and siblings were removed at birth from home cages and then one from each of the two tests and two control females (total of four females) were housed together after weaning. CSS: Chromosome substitution strain.

Figure 2. ‘B6’ test versus B6 control females in the B6-Chr^A/J and B6-Chr^PWD chromosome substitution strain surveys

Results highlighted in light blue represent significant differences from C57BL/6J. ‘B6’ test and B6 control groups are boxed to highlight the primary contrast in this test. p < 0.05 after Bonferroni correction for multiple hypothesis testing [22,30]. (A) MPV (fL) for B6-Chr^A/J chromosome substitution strains (CSSs); (B) QT interval (ms) for B6-Chr^A/J CSSs; (C) total fatty acids (mg/dl) for B6-Chr^A/J CSSs; (D) startle reflex (response to airpuff) for B6-Chr^A/J CSSs; (E) plasma triglyceride (mg/dl) for B6-Chr^PWD CSSs; (F) BMD (g/cm²) for B6-Chr^PWD CSSs. BMD: Bone mineral density; MPV: Mean platelet volume.

Figure 3. Elevated plus maze and open field tests for anxiety-related behavior

(A) ‘129’ test and 129 control females, and (B) ‘B6’ test and B6 control females. In total, 16 independent tests were made, with four mice in each test (Figure 1C) and a total of 64 mice. For the elevated plus maze test, the percent of time spent in and entrances into the open rather than closed arms of the maze was measured, and for the open field test, the time spent in the center of the open field was measured. The y-axis shows the level (percentage) of particular traits that are provided for each data set along the x-axis. Data shown as mean ± SEM. ^*p < 0.05 after Bonferroni correction for multiple testing.