About the dark corners in the gene function space of Escherichia coli remaining without illumination by scientific literature

Abstract

Background Although Escherichia coli (E. coli) is the most studied prokaryote organism in the history of life sciences, many molecular mechanisms and gene functions encoded in its genome remain to be discovered. This work aims at quantifying the illumination of the E. coli gene function space by the scientific literature and how close we are towards the goal of a complete list of E. coli gene functions. Results The scientific literature about E. coli protein-coding genes has been mapped onto the genome via the mentioning of names for genomic regions in scientific articles both for the case of the strain K-12 MG1655 as well as for the 95%-threshold softcore genome of 1324 E. coli strains with known complete genome. The article match was quantified with the ratio of a given gene name’s occurrence to the mentioning of any gene names in the paper. The various genome regions have an extremely uneven literature coverage. A group of elite genes with ≥ 100 full publication equivalents (FPEs, FPE = 1 is an idealized publication devoted to just a single gene) attracts the lion share of the papers. For K-12, ~ 65% of the literature covers just 342 elite genes; for the softcore genome, ~ 68% of the FPEs is about only 342 elite gene families (GFs). We also find that most genes/GFs have at least one mentioning in a dedicated scientific article (with the exception of at least 137 protein-coding transcripts for K-12 and 26 GFs from the softcore genome). Whereas the literature growth rates were highest for uncharacterized or understudied genes until 2005–2010 compared with other groups of genes, they became negative thereafter. At the same time, literature for anyhow well-studied genes started to grow explosively with threshold T10 (≥ 10 FPEs). Typically, a body of ~ 20 actual articles generated over ~ 15 years of research effort was necessary to reach T10. Lineage-specific co-occurrence analysis of genes belonging to the accessory genome of E. coli together with genomic co-localization and sequence-analytic exploration hints previously completely uncharacterized genes yahV and yddL being associated with osmotic stress response/motility mechanisms. Conclusion If the numbers of scientific articles about uncharacterized and understudied genes remain at least at present levels, full gene function lists for the strain K-12 MG1655 and the E. coli softcore genome are in reach within the next 25–30 years. Once the literature body for a gene crosses 10 FPEs, most of the critical fundamental research risk appears overcome and steady incremental research becomes possible.

Uncharacterized yeast geneYBR238C,an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging viaHAP4- andRMD9-dependent mechanisms

“…TORC1 positively regulates aging, and its inhibition increases lifespan in various eukaryotic organisms including yeast and mammalian 13,26,27,29,30 . The drug rapamycin, initially discovered as an antifungal natural product produced by Streptomyces hygroscopicus , inhibits TORC1 and increases lifespan (Figures S1A and S1B) 13,17,19,21,23,25,29 .…”

“…Since rapamycin increases the lifespan by an inhibitory effect on TORC1 activity 13,17,19,21,23,25,29 , it appears most interesting to focus on AAGs with a deletion phenotype of increased CLS/RLS and being down-regulated by rapamycin application. A manual analysis of these gene lists reveals that, among the uncharacterized or severely understudied AAGs, there is a single one known to increase both CLS and RLS upon deletion and being downregulated by rapamycin treatment.…”

“…Understanding the mechanism of aging will also require understanding the role of many genes of yet unknown function as YBR238C at the beginning of this work. Unfortunately, the group of uncharacterized genes coding proteins of unknown function has received dramatically decreasing attention during the past two decades [18][19][20] .…”

“…These lists are a rich resource to identify unique genetic regulators, functional networks, and interactions of aging hallmarks relevant to cellular lifespan 1,4,7,[11][12][13][14] . At the same, these lists are rich in genes of unknown function, a class of genes that, unfortunately, got increasingly ignored by the attention of research teams [19][20][21] .…”

Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms

“…These lists are a rich resource to identify unique genetic regulators, functional networks, and interactions of aging hallmarks relevant to cellular lifespan ( Kennedy et al, 2014 ; Gladyshev, 2016 ; Cohen et al, 2022 ; López-Otín et al, 2013 ; López-Otín et al, 2023 ; Partridge et al, 2020 ; Singh et al, 2019 ). At the same, these lists are rich in genes of unknown function, a class of genes that, unfortunately, got increasingly ignored by the attention of research teams ( Eisenhaber, 2012 ; Sinha et al, 2018 ; Tantoso et al, 2023 ).…”