Cel and males with more repeat copies in the Avpr1a promoter FLO1 show increased caretaking for their pups and increase pair bonding with partner females compared to individuals vith fewer repeats. This repeat variation could therefore allow for rapid evolution of behavioral traits that may be at-driven recombination of adaptive benefit in different environments. a second ex- ample of repeat-associated phenotypic plasticity that is seemingly not pathogenic was found by Fondon and Gar- ner(Fondon and Gamer, 2004). These authors demon- strate that repeat variability in the coding regions of the Alx-4(aristaless-like 4)and Runx-2(runt-related transcrip- tion factor) genes is associated with quantitative differ- ences in limb and skull morphology in dogs. Hence, these repeats may allow rapid evolution of morphological vari- ants on a conserved basic body plan that may provide an adaptive advantage as the selective environment changes Epigenetic Inheritance and Rapid Phenotype Another class of phenotypes vary at rates similar to, or often even higher than those typically generated by conti gency loci In most cases, this variation does not rely on mutations in the DNA sequence but rather relies on altena- tive, so-called"epigenetic"methods of inheritance. Like ontingency loci, epigenetically heritable traits typically exhibit a limited repertoire of phenotypes and interconvert (switch )more rapidly than do phenotypes that change by point mutation. Epigenetic switches can be grouped Figure 2. Recombination in Intragenic Repeats according to the mechanism of inheritance, as epigenet information is carried by substrates ranging from DNA ertain genes, such as the s cerevisiae FLo1 gene, contain tandem peats within their coding sequences. These repeats are highly unsta methylation pattens to the folding of prion proteins. ble and recombine at frequencies around 10- per(mitotic or meiotic) Methylation of dNa bases is one of the major mecha resulting in the net loss or gain If the repeat nisms of epigenetic inheritance and has been implicated nits are not a multiple of three nucleotides, recombination gives rise in phenotypic inheritance in unicellular organisms, in frameshifts, resulting in switching on and off of the gene. Most cell-state inheritance in multicellular organisms(during peats found within open reading frames, ho ree nucleotides long. In this case, recombination results in longer one organismal generation), and in transgenerational in- shorter alleles of the protein. The length variation can have func- heritance in multicellular organisms. For example al- tional consequences. In FLo1, for example, longer alleles confer floc- though some phase variation in bacteria is due to changes yeast cells to each other to fo in genomic sequence(above), other cases rely on epig netic inheritance of methylation patterns. One of the bes confer gradually weaker flocculation, with the very shortest alleles studied examples is found in control of the pyelonephri- resulting in completely tis-associated pili(pap)operon by DNA methylation(Her day et al., 2002). Here, the on and off states are distin- not only of amino acid sequence but also at the DNA level, guished by methylation of Lrp-binding sites found which suggests the possibility of a beneficial outcome to proximal and distal, respectively, to the papBA promoter some rapid repeat variation that offsets the disadvantages the switch from on to off occurs at 10-4 per generation, used by pathogenic repeat variation(Verstrepen et al., whereas the converse switch occurs at 10per gener 2005) ation. An interesting example of heritable methylation- An interesting example of repeat variation that could mediated phenotypic variation in multicellular organisms conceivably prove beneficial in a population is found in in the flowering plant Linaria vulgaris. Naturally occurring a tandem repeat region upstream of the vasopressin re variation in methylation of the Lcyc gene distinguishes ceptor gene Avpr1a, which is known to influence sociobe peloric"morphological mutants with radial floral symme- havioral traits in voles (Hammock and Young, 2005 ). The try from the wild-type variant with bilateral floral symmetry repeat locus is highly variable in populations, which sug-(Cubas et al., 1999). The accelerated phenotypic variation gests an elevated mutation rate compared to that of other due to this"epimutation"may be adaptive in the context genomic regions(though the per-generation rate of repe of the rapid timescale of plant-pollinator coevolution. variation was not directly measured). Phenotypically, Another classic example of epigenetic inheritance is the pansion of this repeat region increases promoter acti silencing of subtelomeric genes in microorganisms. Yeast 658 Cell 128, 655-668, February 23, 2007 @2007 Elsevier Indnot only of amino acid sequence but also at the DNA level, which suggests the possibility of a beneficial outcome to some rapid repeat variation that offsets the disadvantages caused by pathogenic repeat variation (Verstrepen et al., 2005). An interesting example of repeat variation that could conceivably prove beneficial in a population is found in a tandem repeat region upstream of the vasopressin re￾ceptor gene Avpr1a, which is known to influence sociobe￾havioral traits in voles (Hammock and Young, 2005). The repeat locus is highly variable in populations, which sug￾gests an elevated mutation rate compared to that of other genomic regions (though the per-generation rate of repeat variation was not directly measured). Phenotypically, ex￾pansion of this repeat region increases promoter activity, and males with more repeat copies in the Avpr1a promoter show increased caretaking for their pups and increased pair bonding with partner females compared to individuals with fewer repeats. This repeat variation could therefore allow for rapid evolution of behavioral traits that may be of adaptive benefit in different environments. A second ex￾ample of repeat-associated phenotypic plasticity that is seemingly not pathogenic was found by Fondon and Gar￾ner (Fondon and Garner, 2004). These authors demon￾strate that repeat variability in the coding regions of the Alx-4 (aristaless-like 4) and Runx-2 (runt-related transcrip￾tion factor) genes is associated with quantitative differ￾ences in limb and skull morphology in dogs. Hence, these repeats may allow rapid evolution of morphological vari￾ants on a conserved basic body plan that may provide an adaptive advantage as the selective environment changes. Epigenetic Inheritance and Rapid Phenotype Switching Another class of phenotypes vary at rates similar to, or often even higher than those typically generated by contin￾gency loci. In most cases, this variation does not rely on mutations in the DNA sequence but rather relies on alterna￾tive, so-called ‘‘epigenetic’’ methods of inheritance. Like contingency loci, epigenetically heritable traits typically exhibit a limited repertoire of phenotypes and interconvert (‘‘switch’’) more rapidly than do phenotypes that change by point mutation. Epigenetic switches can be grouped according to the mechanism of inheritance, as epigenetic information is carried by substrates ranging from DNA methylation patterns to the folding of prion proteins. Methylation of DNA bases is one of the major mecha￾nisms of epigenetic inheritance and has been implicated in phenotypic inheritance in unicellular organisms, in cell-state inheritance in multicellular organisms (during one organismal generation), and in transgenerational in￾heritance in multicellular organisms. For example, al￾though some phase variation in bacteria is due to changes in genomic sequence (above), other cases rely on epige￾netic inheritance of methylation patterns. One of the best studied examples is found in control of the pyelonephri￾tis-associated pili (pap) operon by DNA methylation (Hern￾day et al., 2002). Here, the on and off states are distin￾guished by methylation of Lrp-binding sites found proximal and distal, respectively, to the papBA promoter. The switch from on to off occurs at 104 per generation, whereas the converse switch occurs at 102 per gener￾ation. An interesting example of heritable methylation￾mediated phenotypic variation in multicellular organisms is in the flowering plant Linaria vulgaris. Naturally occurring variation in methylation of the Lcyc gene distinguishes ‘‘peloric’’ morphological mutants with radial floral symme￾try from the wild-type variant with bilateral floral symmetry (Cubas et al., 1999). The accelerated phenotypic variation due to this ‘‘epimutation’’ may be adaptive in the context of the rapid timescale of plant-pollinator coevolution. Another classic example of epigenetic inheritance is the silencing of subtelomeric genes in microorganisms. Yeast Figure 2. Recombination in Intragenic Repeats Certain genes, such as the S. cerevisiae FLO1 gene, contain tandem repeats within their coding sequences. These repeats are highly unsta￾ble and recombine at frequencies around 105 per (mitotic or meiotic) generation, resulting in the net loss or gain of repeat units. If the repeat units are not a multiple of three nucleotides, recombination gives rise to frameshifts, resulting in switching on and off of the gene. Most repeats found within open reading frames, however, are a multiple of three nucleotides long. In this case, recombination results in longer or shorter alleles of the protein. The length variation can have func￾tional consequences. In FLO1, for example, longer alleles confer floc￾culation (i.e., the adhesion of yeast cells to each other to form a ‘‘floc’’ of cells that sediments in the medium; white arrow). Short FLO1 alleles confer gradually weaker flocculation, with the very shortest alleles resulting in completely planctonic (suspended) growth. 658 Cell 128, 655–668, February 23, 2007 ª2007 Elsevier Inc.