Predicting phenotypic variation in yeast from individual genome sequences

Jelier, Rob; Semple, Jennifer I.; Garcia-Verdugo, Rosa; Lehner, Ben

doi:10.1038/ng.1007

Cited by 67 publications

(71 citation statements)

References 34 publications

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“…Nevertheless, probing the influence of genetic variation on high-level system properties in vitro or in vivo, by testing the effects of functional changes in many interacting proteins, is a significant undertaking. To date, advances have been made in this direction only in the use of unicellular organisms [28]. For more complex organisms, it would be necessary to use in silico techniques to predict how functional changes will affect the phenotype.…”

Section: Discussionmentioning

confidence: 99%

Dynamic sensitivity and nonlinear interactions influence the system-level evolutionary patterns of phototransduction proteins

2015

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Determining the influence of complex, molecular-system dynamics on the evolution of proteins is hindered by the significant challenge of quantifying the control exerted by the proteins on system output. We have employed a combination of systems biology and molecular evolution analyses in a first attempt to unravel this relationship. We employed a comprehensive mathematical model of mammalian phototransduction to predict the degree of influence that each protein in the system exerts on the high-level dynamic behaviour. We found that the genes encoding the most dynamically sensitive proteins exhibit relatively relaxed evolutionary constraint. We also investigated the evolutionary and epistatic influences of the many nonlinear interactions between proteins in the system and found several pairs to have coevolved, including those whose interactions are purely dynamical with respect to system output. This evidence points to a key role played by nonlinear system dynamics in influencing patterns of molecular evolution.

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Section: Discussionmentioning

confidence: 99%

Dynamic sensitivity and nonlinear interactions influence the system-level evolutionary patterns of phototransduction proteins

2015

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“…It has been suggested that genome sequencing alone cannot give sufficient information to explain or predict complex phenotypes, as it does not consider the additional factors that affect protein expression such as epigenetics (Borrell and Gagneux 2011;Jelier et al 2011;Beltrao et al 2012;Bierne et al 2012). However, here we have shown that using robust statistical techniques on large collections of sequenced isolates alongside machine learning approaches can yield desired results.…”

Section: Genome Research 845mentioning

confidence: 99%

“…While some success has also been made in predicting phenotype from genotype, such as the antimicrobial resistance (Farhat et al 2013;Holden et al 2013), for more complex phenotypes, such as virulence, involving the contribution of several genes, this has not yet been possible. Furthermore, complex interactions between genes (epistasis) are not apparent from genome sequences alone, nor is the effect of epigenetics (Borrell and Gagneux 2011;Jelier et al 2011;Beltrao et al 2012;Bierne et al 2012).…”

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confidence: 99%

Predicting the virulence of MRSA from its genome sequence

et al. 2014

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Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites. Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen.

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“…Genome-wide association studies now provide an alternative approach, but are severely limited by the need for high-frequency alleles and very large samples (Marchini et al 2007;Cheng et al 2010). A need remains for additional phenotype-to-genotype strategies in, for example, the investigation of quantitative traits, natural variation, and disease loci (Hillier et al 2008;Jelier et al 2011;Liti and Louis 2012;Lehner 2013). In recent years, new and inexpensive deep sequencing technologies have created opportunities for forward genetic approaches (Hobert 2010).…”

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confidence: 99%

Exploiting the Extraordinary Genetic Polymorphism ofCionafor Developmental Genetics with Whole Genome Sequencing

et al. 2014

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Studies in tunicates such as Ciona have revealed new insights into the evolutionary origins of chordate development. Ciona populations are characterized by high levels of natural genetic variation, between 1 and 5%. This variation has provided abundant material for forward genetic studies. In the current study, we make use of deep sequencing and homozygosity mapping to map spontaneous mutations in outbred populations. With this method we have mapped two spontaneous developmental mutants. In Ciona intestinalis we mapped a short-tail mutation with strong phenotypic similarity to a previously identified mutant in the related species Ciona savignyi. Our bioinformatic approach mapped the mutation to a narrow interval containing a single mutated gene, a-laminin3,4,5, which is the gene previously implicated in C. savignyi. In addition, we mapped a novel genetic mutation disrupting neural tube closure in C. savignyi to a T-type Ca 2+ channel gene. The high efficiency and unprecedented mapping resolution of our study is a powerful advantage for developmental genetics in Ciona, and may find application in other outbred species.A valuable attribute of many model organisms is the ability to conduct forward and reverse genetics. The availability of sequenced genomes and transcriptomes have streamlined reverse genetic approaches, but forward genetic approaches remain time consuming and cumbersome. Even for organisms with well-developed mutation mapping strategies and resources, classical linkage analysis can be slow and subject to chance. Genome-wide association studies now provide an alternative approach, but are severely limited by the need for high-frequency alleles and very large samples (Marchini et al. 2007;Cheng et al. 2010). A need remains for additional phenotype-to-genotype strategies in, for example, the investigation of quantitative traits, natural variation, and disease loci (Hillier et al. 2008;Jelier et al. 2011;Liti and Louis 2012;Lehner 2013). In recent years, new and inexpensive deep sequencing technologies have created opportunities for forward genetic approaches (Hobert 2010). By taking a snapshot of variation across the genome of an outbred population, a researcher can now quickly identify a region of homozygosity unique to mutant individuals. Variations of this method then use a fine-mapping parameter to define a high-confidence mapping interval and to retrieve a list of variable sites in the interval as a list of possible causal mutations. Modeling shows that the mapping power using whole-genome sequencing (WGS) is a function of how many genomes are sampled from mutant individuals, the recombination rate, and genome coverage (Leshchiner et al. 2012;Obholzer et al. 2012). This approach has worked efficiently and accurately for the well-assembled, annotated, and inbred genomes of model organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Mus musculus (Blumenstiel et al. 2009;Andersen et al. 2012;Leshchiner et al. 2012).Tunicates, such as the ascidian Ciona intestinalis, are clas...

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Predicting phenotypic variation in yeast from individual genome sequences

Cited by 67 publications

References 34 publications

Dynamic sensitivity and nonlinear interactions influence the system-level evolutionary patterns of phototransduction proteins

Dynamic sensitivity and nonlinear interactions influence the system-level evolutionary patterns of phototransduction proteins

Predicting the virulence of MRSA from its genome sequence

Exploiting the Extraordinary Genetic Polymorphism ofCionafor Developmental Genetics with Whole Genome Sequencing

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