Connecting genotype to phenotype in the era of high-throughput sequencing

Christopher S. Henry, Ross Overbeek, Fangfang Xia, Aaron A. Best, Elizabeth Glass, Jack Gilbert, Peter Larsen, Rob Edwards, Terry Disz, Folker Meyer, Veronika Vonstein, Matthew Dejongh, Daniela Bartels, Narayan Desai, Mark D'Souza, Scott Devoid, Kevin P. Keegan, Robert Olson, Andreas Wilke, Jared WilkeningRick L. Stevens

Research output: Contribution to journalReview articlepeer-review

27 Citations (Scopus)


Background: The development of next generation sequencing technology is rapidly changing the face of the genome annotation and analysis field. One of the primary uses for genome sequence data is to improve our understanding and prediction of phenotypes for microbes and microbial communities, but the technologies for predicting phenotypes must keep pace with the new sequences emerging. Scope of review: This review presents an integrated view of the methods and technologies used in the inference of phenotypes for microbes and microbial communities based on genomic and metagenomic data. Given the breadth of this topic, we place special focus on the resources available within the SEED Project. We discuss the two steps involved in connecting genotype to phenotype: sequence annotation, and phenotype inference, and we highlight the challenges in each of these steps when dealing with both single genome and metagenome data. Major conclusions: This integrated view of the genotype-to-phenotype problem highlights the importance of a controlled ontology in the annotation of genomic data, as this benefits subsequent phenotype inference and metagenome annotation. We also note the importance of expanding the set of reference genomes to improve the annotation of all sequence data, and we highlight metagenome assembly as a potential new source for complete genomes. Finally, we find that phenotype inference, particularly from metabolic models, generates predictions that can be validated and reconciled to improve annotations. General significance: This review presents the first look at the challenges and opportunities associated with the inference of phenotype from genotype during the next generation sequencing revolution. This article is part of a Special Issue entitled: Systems Biology of Microorganisms.

Original languageEnglish
Pages (from-to)967-977
Number of pages11
JournalBiochimica et Biophysica Acta - General Subjects
Issue number10
Publication statusPublished - Oct 2011
Externally publishedYes


  • Assembly
  • Genome-scale metabolic models
  • Metagenomics
  • RAST
  • SEED


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