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Perspective

What is a gene, post-ENCODE? History and updated definition

¹ Program in Computational Biology & Bioinformatics, Yale University, New Haven, Connecticut 06511, USA; ² Molecular Biophysics & Biochemistry Department, Yale University, New Haven, Connecticut 06511, USA; ³ Computer Science Department, Yale University, New Haven, Connecticut 06511, USA; ⁴ Center for Medical Informatics, Yale University, New Haven, Connecticut 06511, USA; ⁵ European Molecular Biology Laboratory, 69117 Heidelberg, Germany; ⁶ Stockholm Bioinformatics Center, Albanova University Center, Stockholm University, SE-10691 Stockholm, Sweden; ⁷ Genetics Department, Yale University, New Haven, Connecticut 06511, USA; ⁸ Molecular, Cellular, & Developmental Biology Department, Yale University, New Haven, Connecticut 06511, USA

While sequencing of the human genome surprised us with how many protein-coding genes there are, it did not fundamentally change our perspective on what a gene is. In contrast, the complex patterns of dispersed regulation and pervasive transcription uncovered by the ENCODE project, together with non-genic conservation and the abundance of noncoding RNA genes, have challenged the notion of the gene. To illustrate this, we review the evolution of operational definitions of a gene over the past century—from the abstract elements of heredity of Mendel and Morgan to the present-day ORFs enumerated in the sequence databanks. We then summarize the current ENCODE findings and provide a computational metaphor for the complexity. Finally, we propose a tentative update to the definition of a gene: A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products. Our definition sidesteps the complexities of regulation and transcription by removing the former altogether from the definition and arguing that final, functional gene products (rather than intermediate transcripts) should be used to group together entities associated with a single gene. It also manifests how integral the concept of biological function is in defining genes.

E-mail Mark.Gerstein{at}yale.edu; fax (360) 838-7861.

Article is online at http://www.genome.org/cgi/doi/10.1101/gr.6339607

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