Leading Edge Review Cell Timescales of Genetic and Epigenetic Inheritance Oliver J Rando and Kevin J. Verstrepen epartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605 USA 2FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA ment of Molecular and Microbial Systems, K.U. Leuven, Faculty of Applied Bioscience and Engineering Kasteelpark Arenberg 22, B-3001 Leuven (Heverlee), Belgium dence: oliver. rando@umassmed edu(oJ. R), kverstrepen@cgr. harvard. edu(KJ v) DO10.1016/ce.2007.01.023 According to classical evolutionary theory, phenotypic variation originates from random mu- tations that are independent of selective pressure. However, recent findings suggest that organisms have evolved mechanisms to influence the timing or genomic location of herta ble variability. Hypervariable contingency loci and epigenetic switches increase the variabl ity of specific phenotypes; error-prone DNA replicases produce bursts of variability in times of stress. Interestingly, these mechanisms seem to tune the variability of a given phenotype to match the variability of the acting selective pressure. Although these observations do not undermine Darwin's theory, they suggest that selection and variability are less independent than once thought 1942). By contrast, other phenotypes exhibit unusually In 1943, by plating a number of independent bacterial rapid variation due to underlying hypervariable sequences cultures onto lawns of infectious phages, Salvador Luria in the genome(Srikhanta et aL, 2005; van der Woude and er phenotypes exhibit rapid varia- contained a widely variable number of phage-resistant on despite no underlying genotypic change; these pheno- mutants(Luria and Delbruck, 1943). Hence, they argued, types belong to the class of " epigenetically"heritable these mutants must have been generated prior to the phenotypes (for a review, see Jablonka and Lamb, 1995) phage infection and not in response to the infection, These and many other examples demonstrate that pheno- that would likely produce a comparable number of mu- typic stability spans many orders of magnitude beyond the tants in each culture. The apparent independence of va range expected from classic genetic mutation studies, iation and selection confirmed a comerstone of the classic with some phenotypes varying rapidly while others are Neo-Darwinist theory of evolution. In contrast to Darwin's unusually stable(Figure 1) original theory, the Neo-Darwinist theory firmly rejects Like phenotypic changes, changes in the selective pres Lamarck's idea that organisms pass on characteristics ure acting upon organisms also occur over an exception hey develop during their lives (Weismann, 1893).The ally broad timescale. Some changes, such as temperature Neo-Darwinian idea that evolution is driven by purely ran- changes and periods of famine, may occur within an dom germline mutations followed by independent natural organism s life span (one generation). Geological changes, selection on the progeny has become a widely accepted on the other hand, span several thousands or even millions dogma in biology. of biological generations. The ability of organisms to The resulting focus on mutation as the mechanism for change phenotypes to cope with changing environments henotypic variation has led to detailed during their lifetime is known as"plasticity. " For geological mutation rates. In addition, genotype-to-phenotype map- timescales, phenotypic change mostly occurs by se ping became one of the major focuses of the molecular quence evolution, and the ability to effect this change is biology revolution. Many studies have defined the stability called"evolvability. However, environments(and thus which is generally measured as the rate of change of the selection) change over timescales intermediate to these genotype per cellular generation, of various phenotypes. two. For example, predator-prey cycles, cyclical climate Notably, this massive research effort has identified pheno- changes such as El Nino, and battles between infectious types whose stability differs significantly from typical phe microbes and their host s immune system may all act on typic stabilities (Figure 1). For example, certain pheno- timescales greater than one generation but shorter than types are inherently less sensitive to mutation, and this geological timescales of thousands of generations sensitivity of a phenotype to genetic mutation is often re- This Review addresses the timescales, over which her- ferred to as"robustness "or"canalization"(addington itable biological phenotypes vary, and gathers examples ce128,655668. February23,2007@2007 Elsevier Inc.655Leading Edge Review Timescales of Genetic and Epigenetic Inheritance Oliver J. Rando1, * and Kevin J. Verstrepen2,3, * 1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA 2FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA 3Department of Molecular and Microbial Systems, K.U.Leuven, Faculty of Applied Bioscience and Engineering, Kasteelpark Arenberg 22, B-3001 Leuven (Heverlee), Belgium *Correspondence: oliver.rando@umassmed.edu (O.J.R.), kverstrepen@cgr.harvard.edu (K.J.V.) DOI 10.1016/j.cell.2007.01.023 According to classical evolutionary theory, phenotypic variation originates from random mu￾tations that are independent of selective pressure. However, recent findings suggest that organisms have evolved mechanisms to influence the timing or genomic location of herita￾ble variability. Hypervariable contingency loci and epigenetic switches increase the variabil￾ity of specific phenotypes; error-prone DNA replicases produce bursts of variability in times of stress. Interestingly, these mechanisms seem to tune the variability of a given phenotype to match the variability of the acting selective pressure. Although these observations do not undermine Darwin’s theory, they suggest that selection and variability are less independent than once thought. Introduction In 1943, by plating a number of independent bacterial cultures onto lawns of infectious phages, Salvador Luria and Max Delbru¨ ck showed that each bacterial population contained a widely variable number of phage-resistant mutants (Luria and Delbru¨ ck, 1943). Hence, they argued, these mutants must have been generated prior to the phage infection and not in response to the infection, as that would likely produce a comparable number of mu￾tants in each culture. The apparent independence of var￾iation and selection confirmed a cornerstone of the classic Neo-Darwinist theory of evolution. In contrast to Darwin’s original theory, the Neo-Darwinist theory firmly rejects Lamarck’s idea that organisms pass on characteristics they develop during their lives (Weismann, 1893). The Neo-Darwinian idea that evolution is driven by purely ran￾dom germline mutations followed by independent natural selection on the progeny has become a widely accepted dogma in biology. The resulting focus on mutation as the mechanism for phenotypic variation has led to detailed measurements of mutation rates. In addition, genotype-to-phenotype map￾ping became one of the major focuses of the molecular biology revolution. Many studies have defined the stability, which is generally measured as the rate of change of the phenotype per cellular generation, of various phenotypes. Notably, this massive research effort has identified pheno￾types whose stability differs significantly from typical phe￾notypic stabilities (Figure 1). For example, certain pheno￾types are inherently less sensitive to mutation, and this insensitivity of a phenotype to genetic mutation is often re￾ferred to as ‘‘robustness’’ or ‘‘canalization’’ (Waddington, 1942). By contrast, other phenotypes exhibit unusually rapid variation due to underlying hypervariable sequences in the genome (Srikhanta et al., 2005; van der Woude and Baumler, 2004). Still other phenotypes exhibit rapid varia￾tion despite no underlying genotypic change; these pheno￾types belong to the class of ‘‘epigenetically’’ heritable phenotypes (for a review, see Jablonka and Lamb, 1995). These and many other examples demonstrate that pheno￾typic stability spans many orders of magnitude beyond the range expected from classic genetic mutation studies, with some phenotypes varying rapidly while others are unusually stable (Figure 1). Like phenotypic changes, changes in the selective pres￾sure acting upon organisms also occur over an exception￾ally broad timescale. Some changes, such as temperature changes and periods of famine, may occur within an organism’s life span (one generation). Geological changes, on the other hand, span several thousands or even millions of biological generations. The ability of organisms to change phenotypes to cope with changing environments during their lifetime is known as ‘‘plasticity.’’ For geological timescales, phenotypic change mostly occurs by se￾quence evolution, and the ability to effect this change is called ‘‘evolvability.’’ However, environments (and thus selection) change over timescales intermediate to these two. For example, predator-prey cycles, cyclical climate changes such as El Nin˜ o, and battles between infectious microbes and their host’s immune system may all act on timescales greater than one generation but shorter than geological timescales of thousands of generations. This Review addresses the timescales, over which her￾itable biological phenotypes vary, and gathers examples Cell 128, 655–668, February 23, 2007 ª2007 Elsevier Inc. 655