Pierre Baduel

Eriko Sasaki
email: sasaki.eriko.997@m.kyushu-u.ac.jp

The genetic basis of epigenetic variation and its consequences for adaptation

Recent population genomic studies in plants have shed new light on natural epigenetic variation by identifying the key genetic determinants, " trans modifiers," which influence epigenetic states genome-wide, and their interplay with environmental factors. Here we review this progress by focusing on the epigenetic control of transposition and life-cycle transitions, highlighting the ecological consequences of this genetic architecture and their evolutionary significance. This knowledge provides an opportunity to address a long-standing question about the establishment of environment-associated epigenetic variation and its relevance in adaptation.

Introduction

Epigenetic mechanisms, which rely on non-DNA-sequence-encoded features, can play a significant role in transcriptional control [START_REF] Pikaard | Epigenetic regulation in plants[END_REF] . As such, epigenetic marks, including DNA methylation, which occurs in three sequence contexts in plants (CG, CHG, and CHH, where H represents A, T, or C), histone modifications, and small RNAs, are essential for transposable element (TE) silencing. Through stable transmission or faithful reconstruction, the epigenetic state of TEs can be maintained via sexual reproduction over generations, presumably because of its importance in maintaining genome integrity [START_REF] Zhang | Dynamics and function of DNA methylation in plants[END_REF] . Part of this transgenerational stability is hard-wired through positive feedback loops between epigenetic marks, such as those observed between methylation of lysine 9 of histone H3 (H3K9me) and CHG methylation (mCHG), or between CHH methylation (mCHH) and small RNAs via RNA-directed DNA methylation (RdDM) [START_REF] Zhang | Dynamics and function of DNA methylation in plants[END_REF][START_REF] To | Local and global crosstalk among heterochromatin marks drives DNA methylome patterning in Arabidopsis[END_REF] .

Nonetheless, heritable epigenetic variation, particularly in the level of DNA methylation over TE sequences, is widely observed in natural populations along climates [START_REF] Richards | Natural epigenetic variation in plant species: a view from the field[END_REF][START_REF] Schmitz | Patterns of population epigenomic diversity[END_REF][START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF] , prompting questions about their origin, functional consequences, and potential evolutionary roles [START_REF] Richards | Natural epigenetic variation in plant species: a view from the field[END_REF][START_REF] Charlesworth | The sources of adaptive variation[END_REF] . When experimentally induced, evidence has shown that epigenetic variation in the form of either moderate or full loss of DNA methylation, notably over TEs, can be inherited over multiple generations, independently of any DNA sequence polymorphisms (i.e. truly epiallelic), and with phenotypic consequences [START_REF] Cortijo | Mapping the epigenetic basis of complex traits[END_REF][START_REF] Reinders | Compromised stability of DNA methylation and transposon immobilization in mosaic Arabidopsis epigenomes[END_REF][START_REF] Lyons | Extensive de novo activity stabilizes epigenetic inheritance of CG methylation in Arabidopsis transposons[END_REF] . However, in genetically diverged natural populations, its entanglement with DNA sequence polymorphisms makes it significantly harder to distinguish truly epiallelic from genetically determined epigenetic variation [START_REF] Richards | Natural epigenetic variation in plant species: a view from the field[END_REF][START_REF] Baduel | The epiallelic potential of transposable elements and its evolutionary significance in plants[END_REF][START_REF] Richards | Inherited epigenetic variation--revisiting soft inheritance[END_REF] .

On par with its importance in animal development, epigenetic regulation also plays a crucial role in adjusting plant life-cycle traits, from germination to reproduction, to seasonal environmental changes [START_REF] Whittaker | The FLC Locus: A Platform for Discoveries in Epigenetics and Adaptation[END_REF][START_REF] Iwasaki | Parental and Environmental Control of Seed Dormancy in Arabidopsis thaliana[END_REF] . In this context, plants often rely on facultative histone marks, such as the Polycomb-deposited H3K27me3, that, in contrast to the meiotically stable marks described above, are dynamically modulated during development and are effectively reprogrammed during embryogenesis [START_REF] Whittaker | The FLC Locus: A Platform for Discoveries in Epigenetics and Adaptation[END_REF][START_REF] Iwasaki | Parental and Environmental Control of Seed Dormancy in Arabidopsis thaliana[END_REF] . While this system is typically not transgenerationally heritable, natural variation in the regulation of these epigenetic states has been reported to play an adaptive role by adjusting life cycles to natural conditions [START_REF] Whittaker | The FLC Locus: A Platform for Discoveries in Epigenetics and Adaptation[END_REF] .

Recent population genomic and epigenomic studies, in particular the large-scale datasets of the 1001 Genomes and Epigenomes projects in Arabidopsis thaliana , have unveiled some of the environmental and genetic determinants of both stable and transient natural epigenetic variations [START_REF] Schmitz | Patterns of population epigenomic diversity[END_REF][START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF]Genomes Consortium: 1,135 Genomes Reveal the Global Pattern of Polymorphism in Arabidopsis thaliana[END_REF] . Notably, the identification of functionally important natural variation at well-known epigenetic regulators ( trans modifiers) has opened new perspectives on the origin and, therefore, the ecological significance of epigenetic variations [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF]Genomes Consortium: 1,135 Genomes Reveal the Global Pattern of Polymorphism in Arabidopsis thaliana[END_REF][START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF] . By focusing on recent evidence on the adaptive impact of TE mobilization and life-cycle transitions obtained primarily in the model plant species, A. thaliana, this review aims at exploring the evolutionary significance of this genetic architecture underlying the epigenome in nature.

The genetic determinants shaping the epigenome in nature

Analysis of genome-wide DNA methylation data over 1,000 A. thaliana strains revealed a wide range of epigenetic variation, both in the levels and the distribution of DNA methylation, and recent genome-wide association studies (GWAS) have shed new light on their genetic determinants [START_REF] Schmitz | Patterns of population epigenomic diversity[END_REF][START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF][START_REF] Galanti | Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense[END_REF] . Epigenetic variation is mostly explained by local TE insertion polymorphisms (i.e., cis -genetic effects), as the typically heavily methylated states of TE sequences can spread upon insertion to nearby, previously unmethylated regions [START_REF] Hollister | Epigenetic silencing of transposable elements: a trade-off between reduced transposition and deleterious effects on neighboring gene expression[END_REF][START_REF] Quadrana | The Arabidopsis thaliana mobilome and its impact at the species level[END_REF] . In addition, the accumulation of mutations in TE sequences can also alter their methylation levels [START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF][START_REF] Hüther | MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant whole-genome bisulfite sequencing data[END_REF][START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF] . In contrast, trans modifiers, generated by allelic variants of key epigenetic regulators that can affect epigenetic landscapes genome-wide, have been found to play an important role in modulating DNA methylation levels over TE sequences genome-wide and both in heterochromatic and in euchromatic regions (Figure 1). Allelic variation at CHROMOMETHYLASE2 ( CMT2), NUCLEAR RNA POLYMERASE D1B ( NRPE1), ARGONAUTE1 ( AGO1 ), and AGO9 was found associated with changes in mCHH levels, and CMT3, MICRORNA823A ( MIR823A) , JUMONJI26 ( JMJ26), as well as alleles containing MULTICOPY SUPPRESSOR OF IRA1 (MSI1) and REPRESSOR OF SILENCING3 (ROS3) with changes in mCHG [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF][START_REF] Hüther | MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant whole-genome bisulfite sequencing data[END_REF][START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] (Table 1). Moreover, some rare alleles of VARIANT IN METHYLATION 1 ( VIM1 ) and HISTONE DEACETYLASE6 ( HDA6 ) have been identified in earlier studies to modulate CG-methylation (mCG) [START_REF] Woo | VIM1, a methylcytosine-binding protein required for centromeric heterochromatinization[END_REF][START_REF] Tessadori | Phytochrome B and histone deacetylase 6 control light-induced chromatin compaction in Arabidopsis thaliana[END_REF] . Such genetic architecture is not unique to A. thaliana, and contributions of trans modifiers have been reported in other Brassicaceae species as well [START_REF] Galanti | Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense[END_REF] .

Whereas each trans modifier substantially changes DNA methylation levels, their various combinations can generate a wide range of epigenetic variations in natural populations. While strains carrying multiple mCHG-decreasing alleles show additively reduced genome-wide mCHG levels, strains carrying both mCHH-and mCHG-decreasing alleles show entirely reduced asymmetric methylation levels. Given the partial interdependency between mCHH and mCHG pathways, the loss of both pathways results in a wide range of morphological and developmental defects [START_REF] Cao | Locus-specific control of asymmetric and CpNpG methylation by the DRM and CMT3 methyltransferase genes[END_REF] . Presumably because of this pleiotropy, there are very few natural loss-of-function mutants of epigenetic regulators [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF] , and the control of DNA methylation levels vary instead in a complex quantitative manner in nature, thus high statistical power is required in GWA approaches based on large sample sizes to identify trans modifiers. Further exploration of natural epigenetic trans modifiers beyond A. thaliana and Brassicaceae will contribute to enriching our understanding of the evolutionary history of this genetic architecture. CMT2a, b AT4G19020 mCHH Chromomethylase 2; Alternative CMT2a is a natural CMT2 overexpressor. [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF][START_REF] Hüther | MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant whole-genome bisulfite sequencing data[END_REF][START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF] AGO1 AT1G48410 mCHH Post-transcriptional gene silencing [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF] AGO9 AT5G21150 mCHH siRNA silencing [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF] JMJ26 AT1G11950 mCHG Putative histone H3K9 demethylase [START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] CMT3 AT1G69770 mCHG Chromomethylase 3 [START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] MIR823A AT3G13724 mCHG CMT3-targeting microRNA [START_REF] Hüther | MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant whole-genome bisulfite sequencing data[END_REF][START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] CMT2c AT4G19020 mCHG Chromomethylase 2 HDA6 AT5G63110 mCG Chromatin organization at the NOR [START_REF] Tessadori | Phytochrome B and histone deacetylase 6 control light-induced chromatin compaction in Arabidopsis thaliana[END_REF] Environmental clines of epigenetic variation

Strikingly, in natural settings, epigenetic variation often shows strong environmental correlations, leading many to hypothesize that it can be environmentally induced and/or contribute to local adaptation [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF][START_REF] Galanti | Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense[END_REF][START_REF] Foust | Genetic and epigenetic differences associated with environmental gradients in replicate populations of two salt marsh perennials[END_REF][START_REF] Keller | The multivariate association between genomewide DNA methylation and climate across the range of Arabidopsis thaliana[END_REF] . Indeed, statistical approaches that compare genetic and epigenetic phylogeny across individuals have found that some epigenetic variants are not associated with sequence variants [START_REF] Foust | Genetic and epigenetic differences associated with environmental gradients in replicate populations of two salt marsh perennials[END_REF] . Nonetheless, it is important to note that these genome-wide patterns, identified through comparisons of relatedness [START_REF] Foust | Genetic and epigenetic differences associated with environmental gradients in replicate populations of two salt marsh perennials[END_REF] , may not account for trans modifiers, which can have substantial effects on genome-wide epigenetic profiles. For example, mCG levels observed in gene bodies (i.e., gene body methylation) show a strong positive correlation with latitude in A. thaliana , and several trans modifiers including METHYLTRANSFERASE1 ( MET1 ), which is responsible for mCG maintenance, were found to share a similar population structure [START_REF] Kawakatsu | Epigenomic Diversity in a Global Collection of Arabidopsis thaliana Accessions[END_REF][START_REF] Dubin | DNA methylation in Arabidopsis has a genetic basis and shows evidence of local adaptation[END_REF][START_REF] Zhang | Natural variation in DNA methylation homeostasis and the emergence of epialleles[END_REF] . In addition, the geographical distribution of mCHH-decreasing NRPE1 alleles over RdDM-targeted TEs (referred to as NRPE1' [START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF] ) results in the longitudinal cline of mCHH levels, from Western to Eastern Europe. Conversely, mCHG-decreasing alleles show the opposite geographic patterns. These distributions of trans modifiers contribute to geographic and environmental clines of epigenetic variation, which given the allelic repulsion observed between mCHH-decreasing alleles of CMT2 and NRPE1' , are probably under some form of selective pressure [START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF] . While the ecological significance of these opposite patterns remains unclear, stabilizing selection is likely at work to maintain epigenetic homeostasis against deleterious genome-wide hypomethylation in CHH and CHG contexts [START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF][START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] , especially through the triggering of TE mobilization, whose dependence on genetic x environment interactions (GxE) is only starting to be fully apprehended [START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF][START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] .

The GxE of TE mobilization in nature

Indeed, many of the naturally variable trans modifiers described above have been found to be key parts of the regulatory network underlying the epigenetic control of TE mobilization [START_REF] Miura | Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis[END_REF][START_REF] Tsukahara | Bursts of retrotransposition reproduced in Arabidopsis[END_REF][START_REF] Quadrana | Transposition favors the generation of large effect mutations that may facilitate rapid adaption[END_REF] . However, knock-out experiments have clearly demonstrated that fully impairing their function does not always induce TE mobilization [START_REF] Miura | Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis[END_REF][START_REF] Tsukahara | Bursts of retrotransposition reproduced in Arabidopsis[END_REF][START_REF] Quadrana | Transposition favors the generation of large effect mutations that may facilitate rapid adaption[END_REF][START_REF] Ito | An siRNA pathway prevents transgenerational retrotransposition in plants subjected to stress[END_REF] . This is notably the case for the RdDM pathway, whose mutation only triggers transposition after exposure to environmental stress [START_REF] Ito | An siRNA pathway prevents transgenerational retrotransposition in plants subjected to stress[END_REF][START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF][START_REF] Thieme | Experimentally heat-induced transposition increases drought tolerance in Arabidopsis thaliana[END_REF] , thus emphasizing the importance of GxE interactions in the regulation of TE mobilization. Such a situation is particularly striking for the COPIA LTR-retroelement dubbed ONSEN ( ATCOPIA78 ), whose promoter contains binding sites for a number of heat-shock factors, notably some where binding was shown in vitro to be impaired by DNA methylation [START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] Such GxE regulations of TE mobilization may play a significant role in nature. Indeed, the NRPE1' alleles seemingly enhance the environmental sensitivity of TEs in nature [START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] . Furthermore, the effect of NRPE1' on transposition appears to be additive with that of multiple mCHG-decreasing alleles resulting in gradually increasing levels of TE mobilization [START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF][START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] . Rates of germline mutations, to which transposition represents a major contributor in natural populations [START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] , can themselves be a trait under natural selection [START_REF] Zhang | The mutation rate as an evolving trait[END_REF] , as illustrated by a recent vertebrate study [START_REF] Bergeron | Evolution of the germline mutation rate across vertebrates[END_REF] . Therefore, it is only reasonable to expect that, especially in large plant populations where the drift barrier is relatively low [START_REF] Lynch | Evolution of the mutation rate[END_REF] , natural selection can also act directly on the evolution of transposition rates. Supporting this hypothesis, and in line with Barbara McClintock's prediction that organisms may use TEs to adapt to challenging environments by altering TE mobility [START_REF] Mcclintock | The significance of responses of the genome to challenge[END_REF] , NRPE1' is found more frequently in extreme environments at the border of the ecological niche of A. thaliana [START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] . Indeed, although most of the mutations that TEs generate when they insert near or within genes are deleterious and efficiently purged by purifying selection [START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] , some can contribute to rapid adaptation [START_REF] Thieme | Experimentally heat-induced transposition increases drought tolerance in Arabidopsis thaliana[END_REF][START_REF] Van't Hof | The industrial melanism mutation in British peppered moths is a transposable element[END_REF] .

In extreme environments, transposition-enhancing alleles such as NRPE1' would be akin to the "mutator" alleles described in bacteria. These alleles are typically favored in harsh conditions as long as the advantage of increasing genetic diversity is greater than the cost of the higher mutation load [START_REF] Healey | Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance[END_REF][START_REF] Eshel | Clone-selection and optimal rates of mutation[END_REF][START_REF] Sniegowski | Evolution of high mutation rates in experimental populations of E. coli[END_REF][START_REF] Lynch | Genetic drift, selection and the evolution of the mutation rate[END_REF] . Yet, unlike these typically transient mutator alleles, multiple and relatively divergent NRPE1' alleles segregate at low frequency across the species range, indicative of a likely ancient origin. This long-term retention may be helped by the low population sizes at the borders of the species range which is a key parameter in the selection of trans modifiers of mutation rate (so called drift barrier [START_REF] Lynch | Evolution of the mutation rate[END_REF] ). Nonetheless, it is also enticing to speculate that, unlike classical mutator alleles, the environmentally-conditioned effect of alleles such as NRPE1' might mask the mutator phenotype unless exposed to stressful environments, where its increased transposition would be positively selected.

The GxE of epigenetically regulated life-cycle transitions

Epigenetic regulations of seasonal-environmental sensing play a central role in optimizing phenology in natural environments. Even though it may be an extreme case, the control of flowering time by FLOWERING LOCUS C ( FLC ), a MADS-box protein-coding gene that encodes a key suppressor of flowering [START_REF] Whittaker | The FLC Locus: A Platform for Discoveries in Epigenetics and Adaptation[END_REF] , illustrates the adaptive importance of such mechanisms. Early in the life cycle, FLC is highly expressed thus inhibiting flowering until plants experience prolonged winter-like conditions, known as vernalization. Inhibition of FLC during and after vernalization results from the cooperation of the H3K27me3 machinery and long noncoding RNAs [START_REF] Whittaker | The FLC Locus: A Platform for Discoveries in Epigenetics and Adaptation[END_REF][START_REF] Yang | Plant long non-coding RNAs: biologically relevant and mechanistically intriguing[END_REF] . Sequence variation at this locus can have a major impact on the epigenetic regulation of FLC , particularly when located within its first intron, which contains a long-noncoding RNA COLDAIR and a short element with two Sph/RY motifs that are essential for the H3K27me3-dependent silencing [START_REF] Yuan | A cis cold memory element and a trans epigenome reader mediate Polycomb silencing of FLC by vernalization in Arabidopsis[END_REF][START_REF] Li | Multiple FLC haplotypes defined by independent cis-regulatory variation underpin life history diversity in Arabidopsis thaliana[END_REF] . Moreover, the first intron of FLC is also a hot spot for TE insertions segregating in natural A. thaliana populations, where they are recurrently associated with early flowering and a shift to milder winter environments [START_REF] Quadrana | The Arabidopsis thaliana mobilome and its impact at the species level[END_REF][START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] , a pattern also observed in other Brassicaceae species [START_REF] Quadrana | The contribution of transposable elements to transcriptional novelty in plants: the affair[END_REF] . Interestingly, one such TE-containing allele has no impact on flowering time under standard growth conditions, but early flowering is induced upon heat shock because of the stress sensitivity of the ATCOPIA78 TE it contains [START_REF] Quadrana | Transposition favors the generation of large effect mutations that may facilitate rapid adaption[END_REF] . This example illustrates how transposition-induced genetic variation can bring an additional layer of epigenetic regulation to a locus, but also how such variants may link the epigenetic control of TEs to that of key developmental genes.

Seed dormancy is another critical life-history trait that prevents seed germination until environmental conditions become favorable. Natural variations in seed dormancy are partly associated with imprinted genes, whose expression in the endosperm is parentally-biased, and controlled by epigenetic marks, including H3K27me3, H3K9me2, and DNA methylation [START_REF] Iwasaki | Parental and Environmental Control of Seed Dormancy in Arabidopsis thaliana[END_REF] . Natural variation of DNA methylation has also been described at these genes to be associated with intraspecific variations in their imprinting and potentially critical ecological consequences [51] . While the genetic basis of epigenetic variation at imprinted genes remains unexplored, it would not be surprising if trans modifiers of DNA methylation over TEs and genes coregulate both ecologically significant imprinted genes and TE mobilization. Untangling how both components contribute to the selective pressure on the genetic architecture of epigenetic variation will be critical to understanding its evolutionary history.

Conclusions

Although epigenetic mechanisms can overrule DNA-sequence effects on transcriptional regulations, paradoxically, genetic variation is still the primary source of epigenetic variation in nature, thus providing a basis for selection to shape the epigenome within a traditional population genetics framework. By discussing the potential adaptive consequences of cis and trans modifiers of epigenetic states, we highlight how environmental clines of epigenetic variation are likely to result from selection acting on its genetic architecture (Fig. 1). On the other hand, the importance of epigenetic regulations over major developmental genes can potentially bias the selective pressures acting on trans modifiers of TE DNA methylation. Thus, it is not surprising that the epigenetic pathways involved in the regulation of development and those involved in TE control have gradually separated from the single ancestral Polycomb-based regulation over evolutionary times [52] . Yet, the generation by transposition of new TE-associated alleles, which may bring ecologically relevant transcriptional regulations to loci involved in life-cycle transitions, is likely constantly establishing new ties between the epigenetic control of TEs and that of major developmental phenotypes. Further understanding the evolutionary history of the genetic architecture underpinning the epigenome in Brassicaceae and beyond will be key to fully apprehend the complex ecological significance of epigenetic variation in nature.

Figures Figure 1. A molecular model of epigenetic contributions to environmental adaptation.

The schematic representation shows possible epigenetic architecture underpinning phenotypic variation. Three genetically and epigenetically divergent strains are represented: one that diverges from the top strain by cis allelic variation near a protein-coding gene, and the other by an allelic variant (allele X') of a trans modifier leading to reduced DNA methylation over TEs genome-wide (Low TE DNA methylation strain). Upon environmental change from A to B, the expression of the gene is activated, except in the presence of the cis modifier, and transposition is triggered in the low TE DNA methylation strain generating new cis variants. Altogether the genetic and GxE determinants of epigenetic variation lead to phenotypic and further genetic variation across the strains, some of which may be adaptive and maintained by natural selection in the pool of future generations. Studying recent TE mobilization in over 1000 genomes of A. thaliana collected across the globe, the authors identified both genetic and environmental determinants of transposition in nature and its contribution to local adaptation. These results revealed that TE mobilization is a major, yet finely modulated, generator of genetic variation which may be key in the demise or rescue of native populations in times of climate crises. While bisulfite sequencing has become a standard method for DNA methylation analysis, the identification of differentially methylated genome regions from large-scale data sets is still challenging. In this study, the authors have developed a pipeline that utilizes unsupervised methods and demonstrated its performance using the 1001 epigenome dataset. Notably, the GWAS results for mCHG and mCHH complement the findings of previous GWAS studies conducted by [START_REF] Sasaki | Common alleles of CMT2 and NRPE1 are major determinants of CHH methylation variation in Arabidopsis thaliana[END_REF][START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] .

22. Sasaki E, Gunis J, Reichardt-Gomez I, Nizhynska V, Nordborg M: Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes . PLoS Genet 2022, 18 :e1010345.

Using the epigenome data of A. thaliana natural populations, the authors have identified five trans modifiers that regulate genome-wide CHG methylation profiles. Combinations of these modifiers, which include the CHG-decreasing and CHH-decreasing alleles, explained a wide range of epigenome variations and showed their potential contribution to natural variation in TE mobilization described in [START_REF] Baduel | Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana[END_REF] .

36.

  A component of chromatin assembly factor (CAF-1) responsible for proper heterochromatin formation; (ROS3: a DNA demethylase)[START_REF] Hüther | MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant whole-genome bisulfite sequencing data[END_REF][START_REF] Sasaki | Conditional GWAS of non-CG transposon methylation in Arabidopsis thaliana reveals major polymorphisms in five genes[END_REF] VIM1 AT1G57820 mCG Modulating mCG in cooperation with MET1[START_REF] Woo | VIM1, a methylcytosine-binding protein required for centromeric heterochromatinization[END_REF]

17 .

 17 Galanti D, Ramos-Cruz D, Nunn A, Rodríguez-Arévalo I, Scheepens JF, Becker C, Bossdorf O: Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense . PLoS Genet 2022, 18 :e1010452The study explored the genetic basis of epigenomes in natural populations of Thalispi arvense and also environmental factors influencing their formation. Similar to A. thaliana , DNA methylation variations of T. arvense showed geographic clines, and several trans modifiers of DNA methylation were identified in all mCG, mCHH, and mCHG contexts. 20. Hüther P, Hagmann J, Nunn A, Kakoulidou I, Pisupati R, Langenberger D, Weigel D, Johannes F, Schultheiss SJ, Becker C: MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant whole-genome bisulfite sequencing data. Quantitative Plant Biology 2022, 3 :e19.

Fig 1

 1 Fig 1

Table 1 . Reported key trans modifiers of DNA methylation in A. thaliana

 1

	trans modifiers	Gene ID	Target	Annotation	Reference
	NRPE1' AT2G40030 mCHH The largest subunit of RNA polymerase V in	[6,21,26]
			RdDM

Natural epigenetic polymorphisms lead to intraspecific variation in Arabidopsis gene imprinting

  51. Pignatta D, Erdmann RM, Scheer E, Picard CL, Bell GW, Gehring M: . Elife 2014, 3 :e03198. 52. Déléris A, Berger F, Duharcourt S: Role of Polycomb in the control of transposable elements . Trends Genet 2021, 37 :882-889. The authors investigated mCG-dependent mCHH and mCHG establishment processes, on both TE and genic regions, by molecular genetic approaches in A. thaliana . The study showed local and genome-wide feedback systems to reprogram DNA methylation patterns.

	Annotated references from the past two years
	3. To TK, Yamasaki C, Oda S, Tominaga S, Kobayashi A, Tarutani Y, Kakutani T: Local and
	global crosstalk among heterochromatin marks drives DNA methylome patterning in
	Arabidopsis . Nat Commun 2022, 13:861.

11. Baduel P, Leduque B, Ignace A, Gy I, Gil J, Loudet O, Colot V, Quadrana L: Genetic and environmental modulation of transposition shapes the evolutionary potential of Arabidopsis thaliana . Genome Biol 2021, 22 :1-26.

  Thieme M, Brêchet A, Bourgeois Y, Keller B, Bucher E, Roulin AC: Experimentally heat-induced transposition increases drought tolerance in Arabidopsis thaliana. New Phytol 2022, doi:10.1111/nph.18322. This study experimentally showed the potential contribution of heat-responsive ONSEN transposon mobility to local adaptation in A. thaliana by heat shock and chemical controls of DNA methylation and siRNA.

Acknowledgments

We are grateful to Vincent Colot and Magnus Nordborg for their critical reading, valuable feedback, and suggestions on the manuscript. This review was supported by Japan Society for the Promotion of Science (20K22671 and 21H02538, to ES) and a research fellowship grant from Toyota Riken (2021, to ES).


for creating visualizations are quickly becom-25 ing more and more accessible. In addition, the visual 26 literacy of the general public has been increasing due 27 to the pervasiveness of visualizations in everyday life. 28 As the appetite for decision making tools grows, so 29 does the need to convey error, confidence, missing, or 30 conflicting data visually.

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However, practices around uncertainty visualiza-32 tion remain domain-specific, rooted in convention, 33 and in many instances, absent entirely. Part of the rea-34 son for this may be a lack of established guidelines 35 for navigating difficult choices of when uncertainty 36 should be added, how to visualize uncertainty, and 37 how to evaluate its effectiveness. Unsurprisingly, the 38 inclusion of uncertainty into visualizations has been 39 decried as a major challenge to visualization, and may 40 play a role in other current communication challenges, 41 like how to promote clear communication of

6

  Nadia Boukhelifa , Universit e Paris-Saclay, INRAE, AgroParisTech, F-91120, Palaiseau, France 7 Chris R. Johnson , University of Utah, Salt Lake City, UT, 84112, USA 8 Kristin Potter, National Renewable Energy Lab, Golden, CO, 80401, USA 9 Uncertainty is an important aspect to data understanding. Without awareness of 10 the variability, error, or reliability of a dataset, the ability to make decisions on that 11 data is limited. However, practices around uncertainty visualization remain domain-12 specific, rooted in convention, and in many instances, absent entirely. Part of the 13 reason for this may be a lack of established guidelines for navigating difficult 14 choices of when uncertainty should be added, how to visualize uncertainty, and how 15 to evaluate its effectiveness. Unsurprisingly, the inclusion of uncertainty into 16 visualizations is a major challenge to visualization. As work concerned with 17 uncertainty visualization grows, it has become clear that simple visual additions of 18 uncertainty information to traditional visualization methods do not appropriately 19 convey the meaning of the uncertainty, pose many perceptual challenges, and, in 20 the worst case, can lead a viewer to a completely wrong understanding of the data. 21 These challenges are the driving motivator for this special issue.Q1 22 V isualization has become a core component of 23 any decision or risk analysis pipeline, and tools 24

42

  experimental effects despite incentives for research-43 ers to overemphasize small effects, or how to explain 44 model workings and predictions in a way that is inter-45 pretable. As work concerned with uncertainty visuali-46 zation grows, it has become clear that simple visual 47 additions of uncertainty information to traditional 48 visualization methods do not appropriately convey the 49 meaning of the uncertainty, pose many perceptual 50 challenges, and, in the worst case, can lead a viewer 51 to a completely wrong understanding of the data.

52

  Numerous studies point to challenges people have in53 interpreting uncertainty-both conceptually and in 54 visual presentation. Visualizing uncertainty may be 55 perceived as conflicting with other goals of visualiza-56 tion authors, like conveying credible information. 57 There is no single definition of uncertainty, since 58 the term umbrellas things like confidence levels, distri-59 butions, and missing or erroneous data, among others, 60 and little by way of guidance to help visualization 61 authors understand how different sources of uncer-62 tainty manifest in different scientific domains 63 and may warrant different visual approaches. Finally, 64 large and heterogeneous datasets pose challenges 65 based on their size and the need to assimilate data 66 from multiple sources, all with uncertainty of different 67 type and scale.

  Types of Uncertainty 73 Uncertainty comes in many forms, mathematical 74 measures and conceptual ideas. We group these 75 potentially disparate ideas into the term uncertainty, 76 both for ease but also lack of understanding. Can we 77 develop a taxonomy of uncertainty types to help 78 define categories of uncertainty types that may be 79 treated in a similar fashion?80 Big Data Problems 81 The large scale of the data we are seeing today is just 82 going to grow. Many of the techniques to handle this 83 data use summarizations, sampling, or clustering, all 84 of which introduce uncertainties in and of themselves, 85 on top of the uncertainties within the data originally.Applications review process of the 10 submissions, we 174 accepted five papers for this special issue. In the arti-175 cle by Jin, Koesten, and M€ oller, A1 the authors present

	164	68 the different parties involved (e.g., between uncer-CHALLENGES TO UNCERTAINTY	change the perceived salience of uncertainty relative	116
	165	69 tainty modelers and decision makers)? How can we VISUALIZATION	to text presentations?	117
	166 167 168 169 170 171 172 Q2 173	P r o o f design uncertainty visualizations that take into 70 Representation and Modeling Understanding User Differences account the various sources of uncertainty in the data 71 Challenges as well as at the cognitive and relational levels? What Risk interpretation changes from person to person, as does statistical literacy. The visual inclusion of uncer-Depending on the situation, conveying uncertainty are the triggers and barriers for revealing and commu-72 91 to be developed and what are the most appropriate tainty may result in differential effects across users of different risk profiles or ability levels. What do we know about the impacts of user characteristics and can we define guidelines for designing for specific audiences? Perception There are mechanisms within the human visual sys-tem that can decode things like mean value estimates from scatter plots without explicit depiction, raising the question of when explicit representations of uncertainty like intervals are needed over displays of raw data. How can we better understand the percep-tual system's strengths and leverage those for visuali-zation of uncertainty? Social Challenges Ethical Risks and Incentives nicating uncertainty in a collaborative context? PAPERS IN THE SPECIAL ISSUE Through the formal IEEE Computer Graphics and P r o o f	118 119 120 137 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136
	I E E E 92 uncertainty quantification techniques and statistical 93 methods? 94 Propagation 95 Uncertainty arises in all stages of the decision making 96 pipeline, from data gathering and generation, through 97 visual presentation. Is there a way to better under-98 stand these uncertainties and provide guidelines to 99 how these different stages of uncertainty effect 100 understanding and decisions? Are there types of 101 uncertainty that are less impactful and thus need less 102 attention, or are there strong uncertainties in common 103 algorithms that may suggest better algorithms or at 104 the very least more attention by the community? 105 Comprehension Challenges 106 Challenges to Decision Making and Risk I E E E	may not add value for users or decision-makers, may conflict with the visualization author's incentives, or may have other ethical implications. What are com-mon uncertainty communication scenarios, where incentives and ethics may collide, what types of atti-tudes and rationales are at play in these scenarios, and can we define a normative way that a visualization researcher should respond? What can we conclude about the ethical ramifications of not including uncertainty? Collaboration Decision making is often a collaborative process that involves different types and levels of expertise. Collab-oration can help reduce uncertainty, but can also gen-erate new uncertainties due to compounded cognitive and relational factors. For example, uncertainty such as measurement error may be taken into account by a	138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154
		107	Analysis		modeling expert using a quantitative form, but the	155
		108	Though decision making under uncertainty and risk	same uncertainty can be translated to a qualitative	156
		109	are well studied fields unto themselves, the unique	form (e.g., confidence in a decision) at a later stage of	157
		00 2023 2	Published by the IEEE Computer Society	IEEE Computer Graphics and Applications

0272-1716 ß 2023 IEEE Digital Object Identifier 10.1109/MCG.2023.3302172 86 In addition, data fusion and assimilation pose a chal-87 lenge for uncertainty understanding since sources, 88 types, and meanings of uncertainties may change 89 between combined datasets. How can we handle 90 these challenges? What kind of new algorithms need 110 characteristics of decision making and analysis from 111 visualizations raise questions that remain unanswered 112 in those bodies of literature. For example, visualiza-113 tions are often accompanied by text; should uncer-114 tainty be visualized for users to properly integrate it 115 with text information? How does a visual channel 158 analysis by a decision maker who uses that model. 159 How can we make sure human understanding of 160 uncertainty in one stage (e.g., at modeling stage) is 161 properly translated to adequate forms of uncertainty 162 at later stages of analysis? How can we reduce the 163 cost of the coordination and synchronization between 176 different interface designs of sliders to support deci-177 sion-making problems with three criteria. They present

an exploration of the design space through an itera-


Fabien Bottini

Penser

Penser la loyauté en droit Mélanges en l'honneur de Christine Youego

  La prévention et la répression des manquements au devoir de probité comme conséquence du devoir de loyauté des décideurs publics au respect de la Constitution La Bible nous a prévenu : « nul ne peut servir deux maîtres (…) Dieu et Mammon », la divinité de l'argent. Or, cette injonction semble avoir survécu à la déchristianisation du monde constatée par Monseigneur Dupanloup, dans les années 1840. Car elle subsiste de nos jours sous une forme laïcisée pour assurer la loyauté des décideurs publics aux devoirs de leur charge parmi lesquels figurent en premier lieu celui de respecter leurs obligations constitutionnelles. Ce lien entre devoir de loyauté et obligation de probité est implicitement mis en lumière par les serments que doivent prêter certaines autorités, comme les juges constitutionnels. Car Car ceux-ci renforcent la nécessité d'un État capable d'assurer la protection des intérêts fondamentaux de la Nation sur la durée. Alors que l'impératif était dans les années 1990 d'assurer le bon fonctionnement du marché, il devient pour l'avenir d'assurer son bon fonctionnement durable. S'il incombe dans cette perspective au Léviathan de réguler de façon performante ce marché, cela suppose que les autorités publiques soient à même d'organiser la lutte contre le dérèglement climatique et de renforcer la résilience face à ses effets d'une façon neutre et impartiale sur la durée. Ce qui ne peut être possible qu'à condition que les décideurs publics fassent preuve de loyauté dans l'exercice de leur office au regard de leur mission d'intérêt général et de prévenir ou réprimer efficacement les manquements au devoir de probité dont ils pourraient se rendre coupables. I. La prévention des manquements au devoir de probité

ceux-ci sont tenus de jurer de « bien et fidèlement remplir leurs fonctions et de les exercer en toute impartialité dans le respect de la Constitution ». Si l'équivalent n'existe pas pour le chef de l'État et le Président de chaque assemblée, une proposition de révision avait proposé en 2005 de leur faire jurer au moment de leur prise de fonction de « loyalement remplir » leur fonctions « avec dignité, simplicité, exactitude et fidélité aux valeurs fondamentales de notre République »1. En droit pénal, cette obligation de loyauté a même connu un regain d'influence, dans les années 1980-1990 dans le contexte lié à l'éclatement d'un certain nombre de scandales politico-financiers en France et à l'étranger au moment où l'effondrement de l'URSS rendait possible la construction d'un grand marché planétaire alors perçu comme la condition de la paix et de stabilité du monde pour le futur. Car ce projet supposait de renforcer la neutralité de l'action publique dans l'économie de façon à laisser-faire les hommes et laisser passer les marchandises. D'où la multiplication des conventions internationales sur la période faisant de la lutte contre la corruption une obligation pour les États 2 . Ce regain d'influence reste d'actualité de nos jours face aux périls sécuritaires et climatiques notamment.

1 PROPOSITION DE LOI CONSTITUTIONNELLE instaurant pour le Président de la République, pour le Président du Sénat et pour le Président de l'Assemblée nationale, une prestation de serment,, Doc. S. 2005-419 2 Sur cette question, v. A. BAVITOT, , PUAM, 2019, p. 24.

Beaucoup a été fait depuis le tournant des années 2010 pour prévenir les manquements au devoir de probité des décideurs publics grâce à l'essor des procédés déontologiques. Ceux-ci s'inspirent des idées de Jérémy Bentham pour mettre en capacité les intéressés de mesurer les implications concrètes des droits et obligations liés à l'exercice de leurs fonctions en amont de la réalisation de toute infraction. Ils se traduisent par l'énoncé de principes matériels formellement énoncés dans des chartes éthiques et qui se doublent de certaines interdictions fonctionnelles dont le respect est assuré grâce à de nouvelles autorités organiques. Evolution intervenues sous la pression du droit international ; propension naturelle des décideurs nationaux à se tailler un statut sur mesure protecteur de leur intérêt propre