Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania
Abstract The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host–pathogen interactions...
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BMC
2025-06-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-025-02164-x |
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| author | Zhi Ming Xu Michaela Zwyer Hellen Hiza Sarah Schmidiger Mohamed Sasamalo Miriam Reinhard Anna Doetsch Sonia Borrell Olivier Naret Sina Rüeger Dylan Lawless Simon Tang Faima Isihaka Hosiana Temba Thomas Maroa Rastard Naftari Christian Beisel Jerry Hella Klaus Reither Daniela Brites Damien Portevin Sebastien Gagneux Jacques Fellay |
| author_facet | Zhi Ming Xu Michaela Zwyer Hellen Hiza Sarah Schmidiger Mohamed Sasamalo Miriam Reinhard Anna Doetsch Sonia Borrell Olivier Naret Sina Rüeger Dylan Lawless Simon Tang Faima Isihaka Hosiana Temba Thomas Maroa Rastard Naftari Christian Beisel Jerry Hella Klaus Reither Daniela Brites Damien Portevin Sebastien Gagneux Jacques Fellay |
| author_sort | Zhi Ming Xu |
| collection | DOAJ |
| description | Abstract The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host–pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.tb) genomic data from 1000 adult TB patients from Tanzania and used a “genome-to-genome” approach to search for associations between human and M.tb genetic variants and to identify interacting genetic loci. Our analyses revealed two significant host–pathogen genetic associations. The first significant association (p = 4.7e-11) links a human intronic variant in PRDM15 (rs12151990), a gene involved in apoptosis regulation, with an M.tb variant in Rv2348c (I101M), which encodes a T cell-stimulating antigen. The second significant association (p = 6.3e-11) connects a human intergenic variant near TIMM21 and FBXO15 (rs75769176) – also associated with TB severity (p = 0.04) – with an M.tb variant in FixA (T67M). While FBXO15 is involved in the regulation of antigen processing and TIMM21 affects mitochondrial function, FixA's role remains undefined due to limited functional characterization. Additionally, we observed that a group of M.tb T cell epitope variants were significantly associated with HLA-DRB1 variation, suggesting that, despite their rarity, certain epitopes may still be subjected to immune selective pressure. Together, these findings identify previously unknown sites of genomic conflicts between humans and M.tb, advancing our understanding of how this pathogen evades selection pressure and persist in human populations. |
| format | Article |
| id | doaj-art-aaee1709907f4540bdda4f1064573b78 |
| institution | OA Journals |
| issn | 1755-8794 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | BMC Medical Genomics |
| spelling | doaj-art-aaee1709907f4540bdda4f1064573b782025-08-20T02:05:16ZengBMCBMC Medical Genomics1755-87942025-06-0118111710.1186/s12920-025-02164-xGenome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from TanzaniaZhi Ming Xu0Michaela Zwyer1Hellen Hiza2Sarah Schmidiger3Mohamed Sasamalo4Miriam Reinhard5Anna Doetsch6Sonia Borrell7Olivier Naret8Sina Rüeger9Dylan Lawless10Simon Tang11Faima Isihaka12Hosiana Temba13Thomas Maroa14Rastard Naftari15Christian Beisel16Jerry Hella17Klaus Reither18Daniela Brites19Damien Portevin20Sebastien Gagneux21Jacques Fellay22School of Life Sciences, École Polytechnique Fédérale de LausanneSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteIfakara Health InstituteSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteSchool of Life Sciences, École Polytechnique Fédérale de LausanneSchool of Life Sciences, École Polytechnique Fédérale de LausanneSchool of Life Sciences, École Polytechnique Fédérale de LausanneSchool of Life Sciences, École Polytechnique Fédérale de LausanneIfakara Health InstituteIfakara Health InstituteIfakara Health InstituteIfakara Health InstituteDepartment of Biosystems Science and Engineering, ETH ZurichIfakara Health InstituteSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteSwiss Tropical and Public Health InstituteSchool of Life Sciences, École Polytechnique Fédérale de LausanneAbstract The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host–pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.tb) genomic data from 1000 adult TB patients from Tanzania and used a “genome-to-genome” approach to search for associations between human and M.tb genetic variants and to identify interacting genetic loci. Our analyses revealed two significant host–pathogen genetic associations. The first significant association (p = 4.7e-11) links a human intronic variant in PRDM15 (rs12151990), a gene involved in apoptosis regulation, with an M.tb variant in Rv2348c (I101M), which encodes a T cell-stimulating antigen. The second significant association (p = 6.3e-11) connects a human intergenic variant near TIMM21 and FBXO15 (rs75769176) – also associated with TB severity (p = 0.04) – with an M.tb variant in FixA (T67M). While FBXO15 is involved in the regulation of antigen processing and TIMM21 affects mitochondrial function, FixA's role remains undefined due to limited functional characterization. Additionally, we observed that a group of M.tb T cell epitope variants were significantly associated with HLA-DRB1 variation, suggesting that, despite their rarity, certain epitopes may still be subjected to immune selective pressure. Together, these findings identify previously unknown sites of genomic conflicts between humans and M.tb, advancing our understanding of how this pathogen evades selection pressure and persist in human populations.https://doi.org/10.1186/s12920-025-02164-xTuberculosisHuman genetics of infectionGenome-wiide association studyHost-pathogen interactions |
| spellingShingle | Zhi Ming Xu Michaela Zwyer Hellen Hiza Sarah Schmidiger Mohamed Sasamalo Miriam Reinhard Anna Doetsch Sonia Borrell Olivier Naret Sina Rüeger Dylan Lawless Simon Tang Faima Isihaka Hosiana Temba Thomas Maroa Rastard Naftari Christian Beisel Jerry Hella Klaus Reither Daniela Brites Damien Portevin Sebastien Gagneux Jacques Fellay Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania BMC Medical Genomics Tuberculosis Human genetics of infection Genome-wiide association study Host-pathogen interactions |
| title | Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania |
| title_full | Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania |
| title_fullStr | Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania |
| title_full_unstemmed | Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania |
| title_short | Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania |
| title_sort | genome to genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from tanzania |
| topic | Tuberculosis Human genetics of infection Genome-wiide association study Host-pathogen interactions |
| url | https://doi.org/10.1186/s12920-025-02164-x |
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