Comprehensive genome analysis of 203 genomes provides structural genomics with new insights into protein family space

Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
Nucleic Acids Research (Impact Factor: 9.11). 02/2006; 34(3):1066-80. DOI: 10.1093/nar/gkj494
Source: PubMed


We present an analysis of 203 completed genomes in the Gene3D resource (including 17 eukaryotes), which demonstrates that
the number of protein families is continually expanding over time and that singleton-sequences appear to be an intrinsic part
of the genomes. A significant proportion of the proteomes can be assigned to fewer than 6000 well-characterized domain families
with the remaining domain-like regions belonging to a much larger number of small uncharacterized families that are largely
species specific. Our comprehensive domain annotation of 203 genomes enables us to provide more accurate estimates of the
number of multi-domain proteins found in the three kingdoms of life than previous calculations. We find that 67% of eukaryotic
sequences are multi-domain compared with 56% of sequences in prokaryotes. By measuring the domain coverage of genome sequences,
we show that the structural genomics initiatives should aim to provide structures for less than a thousand structurally uncharacterized
Pfam families to achieve reasonable structural annotation of the genomes. However, in large families, additional structures
should be determined as these would reveal more about the evolution of the family and enable a greater understanding of how
function evolves.

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    • "The concept of orphan genes was first described by Fischer and Eisenberg in 1999 from studies of microbial genomes (Fischer and Eisenberg, 1999). Although many have predicted that genes considered species specific would later turn out to be an artifact of sparse genome sequence, this has proved not to be the case (Arendsee et al., 2014; Gollery et al., 2006, 2007; Marsden et al., 2006; Neme and Tautz, 2013; Silveira et al., 2013; Tautz and Domazet-Loso, 2011). Orphan genes appear to be present in all species, and represent a significant fraction (approximately 0.5% to >8%) of analysed eukaryotic and prokaryotic genomes. "
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    • "Marsden et al. [13] analyzed 203 complete genomes in the Gene3D resource [14] to provide new insights into protein family space. The number of protein families was found to be continually expanding with time but a significant proportion of the proteomes could be assigned to relatively few large, well-characterized domain families while the vast majority of domain families were relatively rare and often species specific. "
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    ABSTRACT: The Midwest Center for Structural Genomics (MCSG) is one of the large-scale centres of the Protein Structure Initiative (PSI). During the first two phases of the PSI the MCSG has solved over a thousand protein structures. A criticism of structural genomics is that target selection strategies mean that some structures are solved without having a known function and thus are of little biomedical significance. Structures of unknown function have stimulated the development of methods for function prediction from structure. We show that the MCSG has met the stated goals of the PSI and use online resources and readily available function prediction methods to provide functional annotations for more than 90% of the MCSG structures. The structure-to-function prediction method ProFunc provides likely functions for many of the MCSG structures that cannot be annotated by sequence-based methods. Although the focus of the PSI was structural coverage, many of the structures solved by the MCSG can also be associated with functional classes and biological roles of possible biomedical value.
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    • "It is believed that evolution tends to conserve functions primarily on the preservation of the 3D structure rather than primary structure. A 3D alignment between structural relatives, even (or mainly) comprising a small number of residues within a protein active site, can be a powerful method to infer function [33]. "
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