Biology subjects

Xu, Z. M.

Publications and source records attributed to Xu, Z. M..

5 recordsLinked to original sources

bioRxiv2024

Human genetic ancestry, Mycobacterium tuberculosis diversity and tuberculosis disease severity in Dar es Salaam, Tanzania

Infectious diseases have affected humanity for millennia and are among the strongest selective forces. Tuberculosis (TB) is an ancient disease, caused by the human-adapted members of the Mycobacterium tuberculosis complex (MTBC). The outcome of TB infection and disease is highly variable, and co-evolution between human populations and MTBC strains may account for some of this variability. Particular human genetic ancestries have been associated with higher susceptibility to TB, but socio-demographic aspects of the disease can confound such associations. Here, we studied 1,000 TB patients from Dar es Salaam, Tanzania, together with their respective MTBC isolates, by combining human and bacterial genomics with clinical data. We found that the genetic background of the TB patient population was strongly influenced by migrationsof Bantu-speaking populations from West Africa, which is in contrast to the corresponding MTBC genotypes that were mainly introduced from outside Africa. These findings suggest a recent evolutionary history of co-existence between the human and MTBC populations in Dar es Salaam. We detected no evidence of an effect of human genetic ancestry, or MTBC phylogenetic diversity alone, nor their interaction, on TB disease severity. There was also no evidence of an association between human variation genome-wide and TB disease severity.Treatment-seeking, social and environmental factors are likely to be the main determinants of disease severity at the point of care in this patient population. Author SummaryTuberculosis (TB) is an ancient infectious disease that continues to challenge global health efforts. Here, we explored the interplay between human and bacterial genetics on TB in Dar es Salaam, Tanzania. We found that neither the genetic ancestry of the patient, nor the bacterial genotype alone, nor their interaction, influenced the severity of TB. Our finding indicate that in this patient population, social and environmental factors may be the main determinants of TB disease severity.

evolutionary biology↗

bioRxiv2023

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania

The Mycobacterium tuberculosis complex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. Here, we generated macrophages from cryopreserved blood mononuclear cells of Tanzanian tuberculosis patients, from which the infecting MTBC strains had previously been phylogenetically characterized. We infected these macrophages ex vivo with a phylogenetically similar MTBC strain ("matched infection") or with strains representative of other MTBC lineages ("mismatched infection"). We found that L1 infections resulted in a significantly lower bacterial burden and that the intra-cellular replication rate of L2 strains was significantly higher compared the other MTBC lineages, irrespective of the MTBC lineage originally infecting the patients. Moreover, L4-infected macrophages released significantly greater amounts of TNF-, IL-6, IL-10, MIP-1{beta}, and IL-1{beta} compared to macrophages infected by all other strains. Taken together, while our results revealed no measurable effect of local adaptation, they further highlight the strong impact of MTBC phylogenetic diversity on the variable outcome of the host-pathogen interaction in human tuberculosis.

microbiology↗

bioRxiv2023

G2GSnake: A Snakemake workflow for host-pathogen genomic association studies

SummaryJoint analyses of paired host and pathogen genome sequences have the potential to enhance our understanding of host-pathogen interactions. A systematic approach to conduct such a joint analysis is through a "genome-to-genome" (G2G) association study, which involves testing for associations between all host and pathogen genetic variants. Significant associations reveal host genetic factors that might drive pathogen variation, highlighting biological mechanisms likely to be involved in host control and pathogen escape. Here, we present a Snakemake workflow that allows researchers to conduct G2G studies in a reproducible and scalable manner. In addition, we have developed an intuitive R Shiny application that generates custom summaries of the results, enabling users to derive relevant insights. Availability and implementationG2GSnake is freely available at: https://github.com/zmx21/G2GSnake under the MIT license.

bioinformatics↗

bioRxiv2021

Using population-specific add-on polymorphisms to improve genotype imputation in underrepresented populations

Genome-wide association studies rely on the statistical inference of untyped variants, called imputation, to increase the coverage of genotyping arrays. However, the results are often suboptimal in populations underrepresented in existing reference panels and array designs, since the selected single nucleotide polymorphisms (SNPs) may fail to capture population-specific haplotype structures, hence the full extent of common genetic variation. Here, we propose to sequence the full genome of a small subset of an underrepresented study cohort to inform the selection of population-specific add-on SNPs, such that the remaining array-genotyped cohort could be more accurately imputed. Using a Tanzania-based cohort as a proof-of-concept, we demonstrate the validity of our approach by showing improvements in imputation accuracy after the addition of our designed addon SNPs to the base H3Africa array.

genetics↗

bioRxiv2018

Visualizing structure-mediated interactions in supercoiled DNA molecules

We directly visualize the topology-mediated interactions between an unwinding site on a supercoiled DNA plasmid and a specific probe molecule designed to bind to this site, as a function of DNA supercoiling and temperature. The visualization relies on containing the DNA molecules within an enclosed array of glass nanopits using the Convex Lens-induced Confinement (CLiC) imaging method. This method traps molecules within the focal plane while excluding signal from out-of-focus probes. Simultaneously, the molecules can freely diffuse within the nanopits, allowing for accurate measurements of exchange rates, unlike other methods which could introduce an artifactual bias in measurements of binding kinetics. We demonstrate that the plasmids structure influences the binding of the fluorescent probes to the unwinding site through the presence, or lack, of other secondary structures. With this method, we observe an increase in the binding rate of the fluorescent probe to the unwinding site with increasing temperature and negative supercoiling. This increase in binding is consistent with the results of our numerical simulations of the probability of site-unwinding. The temperature dependence of the binding rate has allowed us to distinguish the effects of competing higher order DNA structures, such as Z-DNA, in modulating local site-unwinding, and therefore binding.

biophysics↗