NetSyn: prokaryotic genomic context exploration of protein families
Abstract
Background The growing availability of large prokaryotic genomic datasets presents an opportunity to discover new metabolic pathways and enzymatic reactions useful for industrial or synthetic biological applications. Efforts to identify new enzyme functions in this vast number of sequences cannot be achieved without bioinformatics tools and the development of new strategies. Standard methods for assigning a biological function to a gene are based on sequence similarity. However, complementary approaches rely on mining databases to identify conserved gene clusters (e.g., syntenies). In prokaryotic genomes, genes involved in the same pathway are frequently encoded in a single locus with an operonic organisation. This genomic context conservation is considered as a reliable indicator of functional relationships, and is therefore a promising approach for improving gene function prediction. Methods Here we present NetSyn (Network Synteny), a tool to group protein sequences based on the conservation of their genomic context rather than solely on sequence similarity. From a list of protein sequence identifiers, NetSyn searches for the corresponding genome entries to retrieve neighbouring genes. Corresponding protein sequences are grouped into families to define homology relationships and compute a synteny conservation score between the different extracted genomic contexts. A network is then created in which the nodes represent the input proteins and the edges indicate that two proteins share a conserved synteny. Finally, the network is partitioned into clusters grouping proteins with similar genomic contexts, using a community detection algorithm. Results As a proof of concept, we used NetSyn on two different datasets. The first one is the BKACE protein family (formerly named DUF849) which has previously been divided into isofunctional sub-families. NetSyn was able to go a step further by providing additional sub-families beyond those already described. The second dataset corresponds to a set of non-homologous proteins belonging to three different glycoside hydrolase (GH) families. These GHs are known to work cooperatively in Polysaccharide-Utilization Loci (PUL) and are therefore grouped together in the same genomic contexts. NetSyn was able to identify a locus grouping 3 GHs, involved in the degradation of xyloglucan, in 162 prokaryotic genomes. Discussion By highlighting conserved synteny in distantly related prokaryotic species, NetSyn enables functional links between proteins to be established beyond sequence similarity alone. We showed that NetSyn is efficient for exploring large prokaryotic protein families, enabling the definition of isofunctional groups and the identification of functional interactions between non-homologous enzymes. These features enable the prediction of new genomic structures that have not yet been experimentally characterised. Finally, NetSyn is also useful for pinpointing annotation errors that have been propagated across databases, and for suggesting annotations for proteins lacking functional prediction. NetSyn is freely available at https://github.com/labgem/netsyn .
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BibTeX
@article{stam2026netsyn,
title = {{NetSyn: prokaryotic genomic context exploration of protein families}},
author = {Mark Stam and Jordan Langlois and Céline Chevalier and Jean Mainguy and Guillaume Reboul and Karine Bastard and Claudine Médigue and David Vallenet},
journal = {Peer Community Journal},
year = {2026},
month = sep,
doi = {10.24072/pcjournal.805},
url = {https://hal.science/hal-05777628v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - NetSyn: prokaryotic genomic context exploration of protein families
AU - Mark Stam
AU - Jordan Langlois
AU - Céline Chevalier
AU - Jean Mainguy
AU - Guillaume Reboul
AU - Karine Bastard
AU - Claudine Médigue
AU - David Vallenet
PY - 2026
DA - 2026/09/29
JO - Peer Community Journal
DO - 10.24072/pcjournal.805
UR - https://hal.science/hal-05777628v1
AB - Background The growing availability of large prokaryotic genomic datasets presents an opportunity to discover new metabolic pathways and enzymatic reactions useful for industrial or synthetic biological applications. Efforts to identify new enzyme functions in this vast number of sequences cannot be achieved without bioinformatics tools and the development of new strategies. Standard methods for assigning a biological function to a gene are based on sequence similarity. However, complementary approaches rely on mining databases to identify conserved gene clusters (e.g., syntenies). In prokaryotic genomes, genes involved in the same pathway are frequently encoded in a single locus with an operonic organisation. This genomic context conservation is considered as a reliable indicator of functional relationships, and is therefore a promising approach for improving gene function prediction. Methods Here we present NetSyn (Network Synteny), a tool to group protein sequences based on the conservation of their genomic context rather than solely on sequence similarity. From a list of protein sequence identifiers, NetSyn searches for the corresponding genome entries to retrieve neighbouring genes. Corresponding protein sequences are grouped into families to define homology relationships and compute a synteny conservation score between the different extracted genomic contexts. A network is then created in which the nodes represent the input proteins and the edges indicate that two proteins share a conserved synteny. Finally, the network is partitioned into clusters grouping proteins with similar genomic contexts, using a community detection algorithm. Results As a proof of concept, we used NetSyn on two different datasets. The first one is the BKACE protein family (formerly named DUF849) which has previously been divided into isofunctional sub-families. NetSyn was able to go a step further by providing additional sub-families beyond those already described. The second dataset corresponds to a set of non-homologous proteins belonging to three different glycoside hydrolase (GH) families. These GHs are known to work cooperatively in Polysaccharide-Utilization Loci (PUL) and are therefore grouped together in the same genomic contexts. NetSyn was able to identify a locus grouping 3 GHs, involved in the degradation of xyloglucan, in 162 prokaryotic genomes. Discussion By highlighting conserved synteny in distantly related prokaryotic species, NetSyn enables functional links between proteins to be established beyond sequence similarity alone. We showed that NetSyn is efficient for exploring large prokaryotic protein families, enabling the definition of isofunctional groups and the identification of functional interactions between non-homologous enzymes. These features enable the prediction of new genomic structures that have not yet been experimentally characterised. Finally, NetSyn is also useful for pinpointing annotation errors that have been propagated across databases, and for suggesting annotations for proteins lacking functional prediction. NetSyn is freely available at https://github.com/labgem/netsyn .
SN - 2804-3871
SN - 2804-3871
ER -