Protein function space: viewing the limits or limited by our view?

Abstract

| Given that the number of protein functions on earth is finite, the rapid expansion of biological knowledge and the concomitant exponential increase in the number of protein sequences should, at some point, enable the estimation of the limits of protein function space. The functional coverage of protein sequences can be investigated using computational methods, especially given the massive amount of data being generated by large-scale environmental sequencing (metagenomics). In completely sequenced genomes, the fraction of proteins to which at least some functional features can be assigned has recently risen to as much as ~85%. Although this fraction is more uncertain in metagenomics surveys, because of environmental complexities and differences in analysis protocols, our global knowledge of protein functions still appears to be considerable. However, when we consider protein families, continued sequencing seems to yield an ever-increasing number of novel families. Until we reconcile these two views, the limits of protein space will remain obscured.

Molecular eco-systems biology: towards an understanding of community function

“…In addition, the phylogenetic assignment of sequence reads, which is of paramount importance to the linking of molecular functions to species, remains a serious challenge in complex samples [23,29]. However, for most metagenomic samples, up to 75% of genes can be functionally characterized using targeted computational methodologies that combine homology and gene neighbourhood [8,9], and in simple communities, genes can be assigned to species (because complete genomes can be assembled), which means a parts list -the proteins, their function and their host organism -can be established. Given that more and more bioinformatics tools are being developed to analyse metagenomes and the standardization of data and analysis is being discussed (indispensable for comparison of independent studies [29]), it is likely that in the near future, metagenomic sequencing will provide a workable parts list for a large number of different ecosystems.…”

“…Metagenomic sequencing has so far added more than 10 billion bp to sequence databases [9,28]. The larger projects usually sequence approximately 50-100 Mb per environment, which should provide a firm foundation to start investigating the functioning of the underlying communities.…”

“…This promise has led researchers from all over the world to initiate metagenomic sequencing projects -more than 100 projects have been completed or are currently underway [28]. In addition, novel sequencing technologies with increasingly longer read lengths and the rapidly falling cost of sequencing will only expedite this process.Metagenomic sequencing has so far added more than 10 billion bp to sequence databases [9,28]. The larger projects usually sequence approximately 50-100 Mb per environment, which should provide a firm foundation to start investigating the functioning of the underlying communities.…”

“…Fig.1 shows the current status of these three data levels at various system scales. In single-organism systems biology, the parts list is generally established; almost 700 complete bacterial and archaeal genomes are available and some functional knowledge is available for approximately 70-80% of the encoded genes [8,9]. For several model organisms, large-scale efforts have determined the connectivity among the parts (the physical and genetic interactions between genes) [2].…”

Phylogeny, classification and metagenomic bioprospecting of microbial acetyl xylan esterases

“…It is widely acknowledged that metagenomic screening approaches result in low hit rates [122,123], the reasons for which (low gene frequency, promoter incompatibility, rare codon usage, nascent protein folding limitations etc.) have been extensively reviewed [113,124,125].…”