title: Connecting genotype to phenotype in the era of high-throughput sequencing.
abstract: 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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Argonne National Laboratory, Argonne, IL 60439, USA. chenry@mcs.anl.gov
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Henry
authors.forename: Ross
authors.initials: R
authors.lastname: Overbeek
authors.forename: Fangfang
authors.initials: F
authors.lastname: Xia
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Best
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Glass
authors.forename: Jack
authors.initials: J
authors.lastname: Gilbert
authors.forename: Peter
authors.initials: P
authors.lastname: Larsen
authors.forename: Rob
authors.initials: R
authors.lastname: Edwards
authors.forename: Terry
authors.initials: T
authors.lastname: Disz
authors.forename: Folker
authors.initials: F
authors.lastname: Meyer
authors.forename: Veronika
authors.initials: V
authors.lastname: Vonstein
authors.forename: Matthew
authors.initials: M
authors.lastname: Dejongh
authors.forename: Daniela
authors.initials: D
authors.lastname: Bartels
authors.forename: Narayan
authors.initials: N
authors.lastname: Desai
authors.forename: Mark
authors.initials: M
authors.lastname: D'Souza
authors.forename: Scott
authors.initials: S
authors.lastname: Devoid
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Keegan
authors.forename: Robert
authors.initials: R
authors.lastname: Olson
authors.forename: Andreas
authors.initials: A
authors.lastname: Wilke
authors.forename: Jared
authors.initials: J
authors.lastname: Wilkening
authors.forename: Rick L
authors.initials: RL
authors.lastname: Stevens
mesh_terms: D000818:Animals; D005838:Genotype; D006801:Humans; D056186:Metagenomics / Q000379:methods; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*