ComPass – A graph-based algorithm for pathway analysis in

microbial communities
1 2 ∗1,3,4
Aarthi Ravikrishnan , Meghana Nasre and Karthik Raman
1. Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras
2. Department of Computer Science and Engineering, IIT Madras
3. Initiative for Biological Systems Engineering, IIT Madras
4. Interdisciplinary Laboratory for Data Sciences, IIT Madras, Chennai, India

Overview What is generated by SubNetHunter?

▶ Organisms in nature tend to interact with each other

▶ Most ubiquitous interaction – Metabolic exchanges1
∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅
▶ Interactions often contribute through division of labor2 for several applications such as ∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅

biodegradation, increased virulence and faster growth ∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅

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∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅
∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅
∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅
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▶ Understanding the metabolism of microbial consortia is crucial for exploiting the metabolic ∅ ∅ ∅ ∅ ∅ ∅ ∅ ∅

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diversity
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▶ Lack of machinery in one organism can be complemented by the other

Aim

▶ Can we efficiently identify multiple pathways from the metabolic networks of microbes? SubNetHunter can efficiently and rapidly identify multiple paths from source to target
▶ Can we also develop a computational framework to understand the metabolism in large
networks such as those of microbial communities?
▶ Computational framework consists of two major sections :
▶ SubNetHunter - builds sub-networks from metabolic networks
▶ Community Pathway Analysis (ComPass) - applies SubNetHunter over metabolic networks of communities

Previous work

▶ Network Expansion & MetaPath3,4 – Back-tracking to determine k-shortest paths on

expanded metabolic network - web implementation, does not easily scale to large networks
ComPass is a potent tool to identify metabolic exchanges in microbial consortia
▶ Rahnuma5 – Depth-first search on metabolic networks abstracted as hypergraph - Reported
only for shorter path lengths ▶ Consortia of Clostridium cellulolyticum(cc),
Desulfovibrio vulgaris(dv) & Geobacter
SubNetHunter – How to identify all pathways using Guided BFS?
Org_CC5
sulfurreducens(gs)6 =⇒ Directed Bipartite
graph constructed
CCbigg_cit_i
CCbigg_icit_i
CCbigg_nadph_i
Org_CC1

CCbigg_nadp_i CCbigg_ac_i CCbigg_ppi_i

Org_CC7

CCbigg_co2_i
CCbigg_oaa_i

Org_CC3
CCbigg_amp_i
▶ Size of the network – 14265 nodes, 29073
CCbigg_h2o_i
CCbigg_akg_i

CCbigg_h_i Org_CC2
CCbigg_coa_i
CCbigg_atp_i
edges; Size of scope – 1135 metabolites
Sub-networks of size 20, to all the
Org_CC6 CCbigg_nad_i CCbigg_accoa_i

▶
Org_CC9

CCbigg_nadh_i
CCbigg_pyr_i

CCbigg_glu_L_i
CCbigg_nh3_i
Org_CC4

Org_CC8
bigg_ac_i
metabolites within the scope of cellobiose
and other seed metabolites were
C F F A
bigg_pyr_i

Org_GS6

GSbigg_h2s_i
GSbigg_ac_i

Org_DV2
determined
Verified if the results contain subnetworks
Org_GS4

▶
DVbigg_pyr_i

Metabolic network of microbes are

GSbigg_accoa_i

▶ GSbigg_cys_L_i

demonstrating experimentally proven

DVbigg_h2o_i DVbigg_h_i
GSbigg_acser_i

modelled as directed bipartite graphs Org_GS3

Org_DV1

GSbigg_coa_i GSbigg_ser_L_i
DVbigg_nh3_i
metabolic exchanges
▶ Input – Directed bipartite graph, source Org_GS1 Org_GS5
DVbigg_cys_L_i DVbigg_h2s_i

Org_DV3 ▶ In all the paths, acetate (71.17%), pyruvate

& target metabolite nodes, set of seed GSbigg_nh3_i
GSbigg_pyr_i

bigg_cys_L_i

(58.38%) & ethanol (71.7%) were most

metabolites GSbigg_mal_L_i
Org_GS2

frequently exchanged as shown in Ref. 6

GSbigg_nadp_i

GSbigg_nadph_i
GSbigg_co2_i

▶ Guided Breadth First Search is carried out

▶ ComPass a potent tool to identify metabolic
exchanges on microbial consortium

Output – Scope of metabolites, Reaction set Summary

that can be visited, minimum number of
reactions required to produce the ▶ SubNetHunter – an efficient & scalable graph-based algorithm for larger networks
metabolites ▶ Can be used to identify multiple alternate routes of metabolic conversion
▶ Based on the concepts from dynamic programming and avoids recursive searches for
SubNetHunter – How to generate all sub-networks?
alternate pathways
▶ ComPass – SubNetHunter on a microbial community – a first-line investigatory tool
‫׎‬ ▶ Limitations
▶ Predictions rely heavily on the quality of the underlying metabolic network
ܾ݈ܶܽ݁ሾ݉ǡ ݇ሿ ݉ ൌ ‫݁ݐ݈݅݋ܾܽݐ݁݉ ݀݁݁ݏ‬ ▶ Few interactions predicted by ComPass could be due to model artifacts
▶ Other applications – ComPass can be extended to predict transporters for over-expression
ܾ݈ܶܽ݁ሾ݉ǡ ݇ሿ ൌ ‫݉ ׎‬ ݇
for a given target metabolite
• ( − 1)
ʹǡ Ǥ Ǥ ǡ ݆ ‫ܴאݎ‬ •
( 2,1) = ( 1, 0, ) ∪ 1 = 1, … , . ℎ
݆െͳ
References

݆ െͳ 1. Ponomarova & Patil (2015) Current Opinion in Microbiology 27: 34–44

2. Levy R & Borenstein E (2013) Proceedings of the National Academy of Sciences 110: 12804–12809
ܰ
3. Handorf et al (2005) Journal of Molecular Evolution 61: 498–512
4. Handorf & Ebenhöh (2007) Nucleic Acids Research 35: W613–W618
• ( − 1) 5. Mithani et al (2009) Bioinformatics 25: 1831–1832
ܾ݈ܶܽ݁ሾ݉ǡ ݇ሿ ܰ ܰ ݇ •
( 3,2) = ( 2, 0, ) ∪ 2 = 1, … , . ℎ 6. Miller et al (2010) BMC Microbiology 10:149

Acknowledgments
We gratefully acknowledge the grant offered by IC & SR, IIT Madras and the INSPIRE fellowship, Department of Science and Technology, Government of India (A.R.). Travel funding to ISMB/ECCB 2017 was generously provided by SysMod & ECCB.

https://home.iitm.ac.in/kraman/lab/ *kraman@iitm.ac.in