Quantitative epigenetics through epigenomic perturbation of isogenic lines - PubMed (original) (raw)
Quantitative epigenetics through epigenomic perturbation of isogenic lines
Frank Johannes et al. Genetics. 2011 May.
Abstract
Interindividual differences in chromatin states at a locus (epialleles) can result in gene expression changes that are sometimes transmitted across generations. In this way, they can contribute to heritable phenotypic variation in natural and experimental populations independent of DNA sequence. Recent molecular evidence shows that epialleles often display high levels of transgenerational instability. This property gives rise to a dynamic dimension in phenotypic inheritance. To be able to incorporate these non-Mendelian features into quantitative genetic models, it is necessary to study the induction and the transgenerational behavior of epialleles in controlled settings. Here we outline a general experimental approach for achieving this using crosses of epigenomically perturbed isogenic lines in mammalian and plant species. We develop a theoretical description of such crosses and model the relationship between epiallelic instability, recombination, parent-of-origin effects, as well as transgressive segregation and their joint impact on phenotypic variation across generations. In the limiting case of fully stable epialleles our approach reduces to the classical theory of experimental line crosses and thus illustrates a fundamental continuity between genetic and epigenetic inheritance. We consider data from a panel of Arabidopsis epigenetic recombinant inbred lines and explore estimates of the number of quantitative trait loci for plant height that resulted from a manipulation of DNA methylation levels in one of the two isogenic founder strains.
Figures
Figure 1.—
Construction of epigenetic recombinant inbred lines (epiRIL): (A) Induction of epigenomic perturbation by means of a mutation in genes involved in chromatin control, followed by selfing (plants) or sibling mating (mammals) of conditional intercross (_F_2 | C.C) or backcross (BC | C.C) progeny. It is assumed that the parental strains have nearly identical DNA sequences (shaded horizontal bars) but different epigenomic profiles (white, gray, and black triangles). The exceptions are rare de novo sequence changes (not shown for simplicity) resulting from compromised chromatin states in the mutant parent (_P_2 | c.c). (B) Same crossing scheme as above but using environmental manipulations in place of mutations to invoke the initial perturbation.
Figure 2.—
Epigenomic structure of the parental strains and epiallelic reversion: (A) As a result of the perturbation the wt (_P_1|C.C) and the mutant (_P_2|c.c) parents will differ in their diploid chromatin states (epigenotypes) at N loci. The mutant (_P_2|c.c) parent will have a proportion τ of phenotypically increasing epigenotypes (Ω.Ω and Ω˜.Ω˜) as well as a proportion (1 − τ) of decreasing epigenotypes (ω.ω and ω˜.ω˜), with s and (1 − s) of these being either stable or unstable, respectively (see text). (B) Unstable epialleles (Ω˜,ω˜) induced in the mutant parent have the capacity to revert to wt states over time according to some function, γ(t). This reversion can be perfect or imperfect. We quantify epialleles in the parental generation by setting Ω=Ω˜=12 and ω=ω˜=−12. Starting at t = 0 (the _F_2|C.C or BC|C.C generation) the state values of reversible epialleles begin to change.
Figure 3.—
Transgenerational dynamics of epigenetic variation. We show the dynamic behavior of epigenetic variation in the case of additivity (A), complete dominance of mutant epialleles (B), and complete dominance of wt epialleles (C). Throughout we show the Mendelian inheritance case with linkage (r− = 0.44, s = 1 and τ = 0, solid black line) and with no linkage (r− = 0.5, s = 1 and τ = 0, dashed black line). For each mode of action we consider four key phenomena: inheritance of unstable epialleles (A–C, I): s = 0, τ = 0, and variable reversion function with rate parameter β evaluated at equal increments over the range 0.1 (top line) to 0.5 (bottom line); _x_-axis plots generation time and _y_-axis gives the epigenetic variance, σ2(η, t). Mixed inheritance of stable and unstable epialleles (A–C, II): τ = 0, fixed reversion function with β = 0.2, and variable s evaluated at equal increments over the range 0 (bottom line) to 0.9 (top line); _x_-axis and _y_-axis defined as above. Effects of imperfect epigenomic resetting (A–C, III): Parameter settings were chosen as in (A–C, I) but reversion was assumed to be imperfect with transitions to epiallelic states that are twice the initial wt state (dark gray solid lines) or intermediate between wt and mutant (light gray solid lines); _x_-axis and _y_-axis defined as above. Realized transgression potentials (A–C, IV): s = 0.5, fixed reversion function with β = 0.2, and variable τ evaluated in equal increments over the range 0 (bottom line) to 0.35 (top line); the _x_-axis plots generation time and the _y_-axis gives the fold change in epigenetic variance relative to the between-parental variance, σ2(η,t)[σP2(y)−σε2]−1.
Figure 4.—
Estimates of the number of QTL. Plotted are estimates of number of QTL (N) against the transgression potential parameter τ. Parameters were set according to the shade coding shown in the figure. Confidence intervals (95%) were calculated using 1000 nonparametric bootstrap samples (Appendix B). The black solid vertical line marks the expected maximum detectable N in a backcross-derived RIL, which is approximately 6 (see Appendix B).
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