Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems

Phillips, Patrick C.

doi:10.1038/nrg2452

Cited by 1,364 publications

(1,282 citation statements)

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“…Other recent studies have found large-scale epistasis in HIV-1 virus genes [5,6], and in mitochondrial transfer RNA from eukaryotes [7]. These three examples constitute only a very small snapshot of a much larger body of literature, which suggests that epistasis is widespread throughout the living world [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Epistasis can lead to fragmented neutral spaces and contingency in evolution

2011

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In evolution, the effects of a single deleterious mutation can sometimes be compensated for by a second mutation which recovers the original phenotype. Such epistatic interactions have implications for the structure of genome space-namely, that networks of genomes encoding the same phenotype may not be connected by single mutational moves. We use the folding of RNA sequences into secondary structures as a model genotype -phenotype map and explore the neutral spaces corresponding to networks of genotypes with the same phenotype. In most of these networks, we find that it is not possible to connect all genotypes to one another by single point mutations. Instead, a network for a phenotypic structure with n bonds typically fragments into at least 2 n neutral components, often of similar size. While components of the same network generate the same phenotype, they show important variations in their properties, most strikingly in their evolvability and mutational robustness. This heterogeneity implies contingency in the evolutionary process.

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Section: Introductionmentioning

confidence: 99%

“…In the context of evolution, it is helpful to quantify epistasis in terms of the fitness that selection can act on 1 [9]. Epistasis manifests in many different ways.…”

Section: Introductionmentioning

confidence: 99%

Epistasis can lead to fragmented neutral spaces and contingency in evolution

2011

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“…interactions, where the effect of one locus depends on the genotype of another locus (Phillips 2008) may also play a role, especially given that we have earlier detected epistatic interactions between tameness QTL (Albert et al 2009). The large number of genes and pathways described in the literature influencing behavioral traits related to tameness such as anxiety and aggression makes it plausible that genes in multiple biological pathways could have reacted to the strong selection in these rats (Hovatta and Barlow 2008;Le-Niculescu et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Heyne

Lautenschlaeger²,

Nelson

et al. 2014

Preprint

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Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F 2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for .64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F 2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F 2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. B EHAVIORAL differences among members of a species are in part due to genetic variation. The identification of the genes and variants that influence behavior remains challenging. In human genome-wide association studies of psychiatric and cognitive traits, the identified loci typically explain only a small fraction of the heritability, i.e., the additive genetic contribution to the trait (Watanabe et al. 2007;Hovatta and Barlow 2008;Deary et al. 2009;Otowa et al. 2009;Calboli et al. 2010;Terracciano et al. 2010;Flint and Munafo 2013;Rietveld et al. 2013;Sokolowska and Hovatta 2013). In experimental crosses in model species, especially between inbred lines, the identified loci (termed quantitative trait loci, QTL), often explain much more of the heritability (Lynch and Walsh 1998). However, in this design the spatial resolution is limited-the QTL are wide and contain many, sometimes hundreds of genes. With the exception of a handful of identified genes with quantitative effects on behavioral traits (Yalcin et al. 2004;Watanabe et al. 2007;McGrath et al. 2009;Bendesky et al. 2012;Goodson et al. 2012), gene identification is particularly difficult for behavioral QTL that often have modest effect sizes (Flint 2003;Willis-Owen and Flint 2006;Wright et al. 2006;Hovatta and Barlow 2008).The causal variants within a QTL can alter the protein sequence encoded by a gene or affect gene expression. Such Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al. 2004;De Jong et al. 2011;Saba et al. 2011;Kelly et al. 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental...

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“…Genetic architecture involves not only the number of genes and the distribution of fitness effects, but also the interactions between alleles at various loci (epistasis), the degree to which variation in a particular gene affects multiple traits (pleiotropy), and the form (if any) of interactions between a genotype and environment. For example, epistasis may affect the chances that beneficial alleles will spread [4,5] and pleiotropy may constrain adaptive evolution [6]. A related and as yet unresolved controversy has long surrounded the relative importance of proteincoding versus cis-regulatory adaptive changes.…”

Section: Introductionmentioning

confidence: 99%

The genomics of adaptation

Radwan

Babik

2012

Proc. R. Soc. B.

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The amount and nature of genetic variation available to natural selection affect the rate, course and outcome of evolution. Consequently, the study of the genetic basis of adaptive evolutionary change has occupied biologists for decades, but progress has been hampered by the lack of resolution and the absence of a genome-level perspective. Technological advances in recent years should now allow us to answer many long-standing questions about the nature of adaptation. The data gathered so far are beginning to challenge some widespread views of the way in which natural selection operates at the genomic level. Papers in this Special Feature of Proceedings of the Royal Society B illustrate various aspects of the broad field of adaptation genomics. This introductory article sets up a context and, on the basis of a few selected examples, discusses how genomic data can advance our understanding of the process of adaptation.

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Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems

Cited by 1,364 publications

References 109 publications

Epistasis can lead to fragmented neutral spaces and contingency in evolution

Epistasis can lead to fragmented neutral spaces and contingency in evolution

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

The genomics of adaptation

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