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Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach

Zack Saud, Yujuan Luo, Martyn J Wood, Ian Boostrom, Bruce J MacLachlan, Richard J Stanton, Chengshu Wang, Tariq Butt Orcid Logo

Frontiers in Cellular and Infection Microbiology, Volume: 16, Start page: 1800461

Swansea University Authors: Zack Saud, Tariq Butt Orcid Logo

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DOI (Published version): 10.3389/fcimb.2026.1800461

Abstract

Introduction: Fungi have been a rich source of pharmaceuticals such as antibiotics, immunosuppressants, and cholesterol-lowering drugs; however, their therapeutic potential remains largely untapped due to difficulties in culturing and elucidating the genetic basis of beneficial traits. Fungi contain...

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Published in: Frontiers in Cellular and Infection Microbiology
ISSN: 2235-2988
Published: Frontiers Media SA 2026
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Fungi contain &#x2018;cryptic&#x2019; genes that are expressed under certain, and often obscure, growth conditions and can produce complex compounds that are difficult to synthesize economically. Developments in genome sequencing and DNA-synthesis technologies offer new opportunities to produce such compounds using biotechnological techniques, however, accurately identifying useful and novel genes, a prerequisite for such approaches, remains challenging.Methods: We present a novel &#x2018;two-by-two&#x2019; comparative genomics pipeline for comprehensive gene analysis of selected fungal groups, enabling more confident identification of unique genes across the analyzed species. The approach compares gene sets from two strains of the same species with those from two strains of different species or families within a fungal order. Self-clustering orthologs that are unique to strains from the same species provide higher confidence in identifying species-specific proteins and help reduce noise from low-quality genome assemblies and gene prediction errors.Results: We validated our method in a well-studied fungal group, correctly identifying known species-specific genes and gene clusters, and discovering a novel functional myco-serpin and a fungal Tc toxin complex in Metarhizium.Discussion: Elucidating the genes underlying beneficial traits in fungi presents significant challenges, largely due to the unique and relatively complex aspects of their lifestyles. The two-by-two approach shows broad potential for fungal genome mining and bioprospecting, demonstrated by our discovery of the first fungal Tc toxin complex and a functional myco-serpin in Metarhizium (Hypocreales), and is applicable to other fungal orders such as Eurotiales and Xylariales. 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spelling 2026-06-17T13:02:11.7574292 v2 72098 2026-06-17 Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach b4bba3ec2ff9600c4cead048e1969984 Zack Saud Zack Saud true false 85d1c2ddde272a1176e74978e25ebece 0000-0002-8789-9543 Tariq Butt Tariq Butt true false 2026-06-17 Introduction: Fungi have been a rich source of pharmaceuticals such as antibiotics, immunosuppressants, and cholesterol-lowering drugs; however, their therapeutic potential remains largely untapped due to difficulties in culturing and elucidating the genetic basis of beneficial traits. Fungi contain ‘cryptic’ genes that are expressed under certain, and often obscure, growth conditions and can produce complex compounds that are difficult to synthesize economically. Developments in genome sequencing and DNA-synthesis technologies offer new opportunities to produce such compounds using biotechnological techniques, however, accurately identifying useful and novel genes, a prerequisite for such approaches, remains challenging.Methods: We present a novel ‘two-by-two’ comparative genomics pipeline for comprehensive gene analysis of selected fungal groups, enabling more confident identification of unique genes across the analyzed species. The approach compares gene sets from two strains of the same species with those from two strains of different species or families within a fungal order. Self-clustering orthologs that are unique to strains from the same species provide higher confidence in identifying species-specific proteins and help reduce noise from low-quality genome assemblies and gene prediction errors.Results: We validated our method in a well-studied fungal group, correctly identifying known species-specific genes and gene clusters, and discovering a novel functional myco-serpin and a fungal Tc toxin complex in Metarhizium.Discussion: Elucidating the genes underlying beneficial traits in fungi presents significant challenges, largely due to the unique and relatively complex aspects of their lifestyles. The two-by-two approach shows broad potential for fungal genome mining and bioprospecting, demonstrated by our discovery of the first fungal Tc toxin complex and a functional myco-serpin in Metarhizium (Hypocreales), and is applicable to other fungal orders such as Eurotiales and Xylariales. Furthermore, the two-by-two approach can be adapted to other organisms with genome architectures similar to fungi. Journal Article Frontiers in Cellular and Infection Microbiology 16 1800461 Frontiers Media SA 2235-2988 bioinformatics, biosynthetic gene cluster, comparative genomics, fungi, hypocreales, infection, serpin, Tc toxin 22 5 2026 2026-05-22 10.3389/fcimb.2026.1800461 COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee ZS was supported by a Wellcome Trust grant (226615/Z/22/Z) awarded to RJS. YL was supported by grants from the National Natural Science Foundation of China (No. 32021001 and 32230087) awarded to CW. 2026-06-17T13:02:11.7574292 2026-06-17T12:53:37.1488961 Faculty of Science and Engineering School of Biosciences, Geography and Physics - Biosciences Zack Saud 1 Yujuan Luo 2 Martyn J Wood 3 Ian Boostrom 4 Bruce J MacLachlan 5 Richard J Stanton 6 Chengshu Wang 7 Tariq Butt 0000-0002-8789-9543 8 72098__36987__b33a25e4a31f4e72af1f63d52de6fa5d.pdf 72098.VOR.pdf 2026-06-17T12:59:24.1892779 Output 2669490 application/pdf Version of Record true © 2026 Saud, Luo, Wood, Boostrom, MacLachlan, Stanton, Wang and Butt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
spellingShingle Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
Zack Saud
Tariq Butt
title_short Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
title_full Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
title_fullStr Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
title_full_unstemmed Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
title_sort Discovery of a fungal Tc toxin complex and functional mycoserpin through a novel two-by-two comparative genomics approach
author_id_str_mv b4bba3ec2ff9600c4cead048e1969984
85d1c2ddde272a1176e74978e25ebece
author_id_fullname_str_mv b4bba3ec2ff9600c4cead048e1969984_***_Zack Saud
85d1c2ddde272a1176e74978e25ebece_***_Tariq Butt
author Zack Saud
Tariq Butt
author2 Zack Saud
Yujuan Luo
Martyn J Wood
Ian Boostrom
Bruce J MacLachlan
Richard J Stanton
Chengshu Wang
Tariq Butt
format Journal article
container_title Frontiers in Cellular and Infection Microbiology
container_volume 16
container_start_page 1800461
publishDate 2026
institution Swansea University
issn 2235-2988
doi_str_mv 10.3389/fcimb.2026.1800461
publisher Frontiers Media SA
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Biosciences, Geography and Physics - Biosciences{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Biosciences, Geography and Physics - Biosciences
document_store_str 1
active_str 0
description Introduction: Fungi have been a rich source of pharmaceuticals such as antibiotics, immunosuppressants, and cholesterol-lowering drugs; however, their therapeutic potential remains largely untapped due to difficulties in culturing and elucidating the genetic basis of beneficial traits. Fungi contain ‘cryptic’ genes that are expressed under certain, and often obscure, growth conditions and can produce complex compounds that are difficult to synthesize economically. Developments in genome sequencing and DNA-synthesis technologies offer new opportunities to produce such compounds using biotechnological techniques, however, accurately identifying useful and novel genes, a prerequisite for such approaches, remains challenging.Methods: We present a novel ‘two-by-two’ comparative genomics pipeline for comprehensive gene analysis of selected fungal groups, enabling more confident identification of unique genes across the analyzed species. The approach compares gene sets from two strains of the same species with those from two strains of different species or families within a fungal order. Self-clustering orthologs that are unique to strains from the same species provide higher confidence in identifying species-specific proteins and help reduce noise from low-quality genome assemblies and gene prediction errors.Results: We validated our method in a well-studied fungal group, correctly identifying known species-specific genes and gene clusters, and discovering a novel functional myco-serpin and a fungal Tc toxin complex in Metarhizium.Discussion: Elucidating the genes underlying beneficial traits in fungi presents significant challenges, largely due to the unique and relatively complex aspects of their lifestyles. The two-by-two approach shows broad potential for fungal genome mining and bioprospecting, demonstrated by our discovery of the first fungal Tc toxin complex and a functional myco-serpin in Metarhizium (Hypocreales), and is applicable to other fungal orders such as Eurotiales and Xylariales. Furthermore, the two-by-two approach can be adapted to other organisms with genome architectures similar to fungi.
published_date 2026-05-22T06:03:07Z
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