Several molecular mechanisms canproduce heritable epigenetic mutations
For natural selection to act on pure epigenetic variation in away that results in adaptation, this variation needs to beheritable. Several mechanisms can produce heritable epige-netic variation. One extensively studied example of epigeneticinheritance is paramutation, where the combination of twoalleles permits a heritable change in gene expression. Here,one of the alleles associated with a transcriptionally silentgene causes the silencing of a gene associated with the otherallele. Initially found in maize more than 50 years ago ,paramutations have been found across a wide range of plantspecies  and in mice . The functional basis of paramu-tations is not clear, but chromatin modiﬁcations and smallnon-coding RNA may play a role .Small RNAs are another mechanism for transmitting non-genetic information between generations. Recent studies in
have demonstrated that RNA interference (RNAi)can maintain epigenetic changes over multiple generations.Worms were injected with a double-stranded RNA targeting agene via RNAi. Following this, gene silencing persisted inpopulations indeﬁnitely and in the absence of the initialstimulus . In a second study, a piwi-interacting RNAinduced gene silencing over at least 24 generations . Inboth cases, a particular Argonaute protein is required tomaintain silencing , and a number of chromatin factorswere identiﬁed in the second study. For a recent review of theroles thatsmall RNAs can play intransgenerational epigeneticinheritance, see Castel and Martienssen .Another mechanism that has been implied in transgenera-tional epigenetic inheritance is methylation, even though it isnot known how a particular subset of methylation marks arepreserved during meiosis instead of being ‘‘reset’’ along withtheothers.Inrats,asingle doseofafungicide (Vinclozolin,anandrogen antagonist) given to pregnant females has beenfound to decrease male fertility for at least four generations[5, 17], and the epigenetic mechanism responsible for trans-mitting the effect is thought to be methylation patterns. Asecond study showed that in mice, susceptibility to testiculartumors can been found in offspring of a carrier of a null allele
, and tumor susceptibility persisted for at leastthree generations even when
had been restored by backcrossing. Since
is thought to encode part of acytidine deaminase, the authors suggested that the epigeneticeffects from the lack of the deaminase persisted and causedtumors over several generations . For reviews on transge-nerational epigenetic inheritance, see [1, 2, 18].In all of these cases, it is the epigenetic state itself that ispassed from one generation to the next, not the genetic blue-print of how to set up a particular methylation pattern orchromatin conﬁguration. In cases where this epigenetic stateis independent of underlying genetic variation, it correspondsto ‘‘pure epigenetic variation’’
Richards . Of coursenot all epigenetic changes are heritable, the somatic epige-netic changes involved in cell differentiation being a case inpoint. Neither are all changes to DNA methylation, chromatinstate or small interfering RNA in the germline heritable. Whilethe proportion of heritable changes in epigenetic states isunknown,asistheproportionofheritableepigeneticvariationthat contributes to pure epigenetic variation, the examplesabove show that at least some epigenetic changes can bepassed from one generation to the next even in the absenceof underlying genetic changes. For the case studies involvingRNAi, there is no limit on the function of target genes that canbe silenced, and there is a dedicated molecular machinery forepigenetic inheritance. Here we ask: what can natural selec-tion do with this mechanism?
Epigenetic mutations and evolution:Theoretical approaches
Recent studies have explored different ways to incorporate non-geneticinheritance,includingepigeneticmarks,parentaleffects,ecological inheritance, and cultural inheritance, into evolution-ary theory [8,11,19–21]. In general, these studiescategorize non-geneticinheritancebymechanism,andexamplesofmechanismsinclude epigenetic modiﬁcation and other aspects of the ‘‘inter-pretive machinery’’ of a genome, ecological modiﬁcations, andbetween-generationlearning.Bydoingthis,particularmolecularmechanisms can be explicitly incorporated into adaptive theory.For example, Geoghegan and Spencer  extend previousmodels on phenotypic plasticity by Kirkpatrick and Lande to integrate epigenetically encoded plastic responses into popu-lation-epigeneticmodelsofselection,andﬁndthatepiallelescanmaintain phenotypic variation in a changing environment, evenin the absence of genetic variation. A second approach, taken by BondurianskyandDay[8,20],usesthePriceequationtopartitionthe contributions of non-genetic and genetic inheritance duringevolution. This approach highlighted the potential for complexinteractions between genetic alleles and epialleles such as epi-alleles impeding the ﬁxation of beneﬁcial genetic alleles.Here we use a model that differs in approach and appli-cability from previous work discussed above in several ways.Models by Pal and Miklos and Pal consider non-genetic inher-itance as part of an environmentally induced plastic response[22, 23], whereas we consider epigenetic variation that isindependent of genetic variation, also called ‘‘pure epigeneticvariation’’ . Second, models by Bonduriansky and Day [8,20] and Geoghegan and Spencer  investigate the contri-bution of non-genetic inheritance in the absence of geneticvariation, or in the case of a single variable epigenetic locusand a single variable genetic locus [8, 20, 21]. In contrast, ourmodel investigates how pure epigenetic inheritance affectsadaptive walks where population ﬁtness increases by thesequential substitution of beneﬁcial variants in a population,andwheremutationscanarisedenovoatmultiplegeneticandepigenetic loci. This allows us to investigate how pure epige-netic variation can speed up or slow down evolutionary tra-jectories on a variety of ﬁtness landscapes.
Natural selection on epigenetic mutations:The effect of mutation rate
Individuals in a population differ in ﬁtness, that is they differ in their expected number of offspring. Because ﬁtter
F. D. Klironomos et al. Prospects & Overviews
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