Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania

The risk and prognosis of tuberculosis (TB) are affected by both human and bacterial genetic factors. To identify interacting human and bacterial genetic loci, we leveraged paired human and Mycobacterium tuberculosis ( M.tb ) genomic data from 1000 Tanzanian TB patients. Through a genome-to-genome approach, we identified two pairs of human and M.tb genetic variants that are significantly associated. One of the human genetic variants maps to the intron of PRDM15 , a gene involved in apoptosis regulation. The other human variant maps to an intergenic region close to TIMM21 and FBXO15 . In addition, we observed that a group of linked M.tb epitope variants were significantly associated with HLA-DRB1 variation. This suggests that even though epitope variation is rare in M.tb in general, specific epitopes might still be under immune selective pressure. Overall, our study pinpoints sites of genomic conflicts between humans and M.tb , suggesting bacterial escape from host selection pressure. ### Competing Interest Statement O.N. is now an employee of SUN bioscience SA. S.R. is now an employee of Novartis AG. ### Funding Statement This work was supported by the Swiss National Science Foundation (Grants: CRSII5-177163 and 310030-188888) and the European Research Council (Grant: 883582). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the TB-DAR cohort has been obtained from the Ethikkomission Nordwest- und Zentralschweiz (EKNZ UBE-15/42), the Ifakara Health Institute-Institutional Review Board Board (IHI/IRB/EXT/No: 24-2020) and the National Institute for Medical Research in Tanzania-Medical Research Coordinating Committee (NIMR/HQ/R.8c/Vol.I/1622). A written informed consent has been obtained from every patient who has been recruited into the TB-DAR cohort. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The bacterial WGS data has been published under bioproject PRJEB49562. Human genotyping and WGS data are deposited on the European Genome-phenome Archive (EGA) under EGAS00001007216 and EGAS00001005850 respectively.