Biology subjects

Lenz, T. L.

Publications and source records attributed to Lenz, T. L..

7 recordsLinked to original sources

bioRxiv2023

Admixture as a source for HLA variation in Neolithic European farming communities

The northern European Neolithic is characterized by two major demographic events: immigration of early farmers (EF) from Anatolia (5500 BCE) and their admixture (from [~]4200 BCE) with western hunter-gatherers (WHG) forming late farmers (LF). The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied. Here, we conducted population and immunogenetic analyses on 83 individuals from six EF and LF sites located in present-day Germany. We observed significant shifts in HLA allele frequencies from EF to LF. The HLA diversity increased from EF to LF, likely due to admixture with WHG. However, it was considerably lower than in modern populations. Both EF and LF exhibited a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time. We additionally noted that LF resulted from sex-biased admixture from male WHG. TEASERMore restricted HLA allele spectrum and lower diversity in Neolithic farmers than in modern populations

genetics↗

bioRxiv2022

A microtubule associated protein is essential for malaria parasite transmission

Mature gametocytes of Plasmodium (P.) falciparum display a banana (falciform) shape conferred by a complex array of subpellicular microtubules (SPMT) associated to the inner membrane complex (IMC). Microtubule associated proteins (MAPs) define MT populations and modulate interaction to pellicular components. Several MAPs have been identified in Toxoplasma gondii and homologues can be found in the genome of Plasmodium species, but the function of these proteins for asexual and sexual development of malaria parasites is still unknown. Here we identified a novel subpellicular MAP, termed SPM3, that is conserved within the genus Plasmodium., especially within the Laverania subgenus, but absent in other Apicomplexa. Conditional knockdown and targeted gene disruption of Pfspm3 in P. falciparum cause severe morphological defects during gametocytogenesis leading to round, non-falciform gametocytes with an aberrant SPMT pattern. In contrast, Pbspm3 knockout in P. berghei, a species with round gametocytes, caused no defect in gametocytogenesis, but sporozoites displayed an aberrant motility and a dramatic defect in sporozoite invasion of salivary glands leading to a decreased efficiency in transmission. Electron microscopy revealed a dissociation of the SPMT from the IMC in Pbspm3 knockout parasites suggesting a function of SPM3 in anchoring MTs to the IMC. Overall, our results highlight SPM3 as a pellicular component with essential functions for malaria parasite transmission. IMPORTANCEA key structural feature driving the transition between different life cycle stages of the malaria parasite is the unique three membrane "pellicle", consisting of the parasite plasma membrane (PPM) and a double membrane structure underlying the PPM termed the "inner membrane complex" (IMC). Additionally, there are numerous linearly arranged intramembranous particles (IMPs) linked to the IMC, which likely link the IMC to the subpellicular microtubule cytoskeleton. Here we identify, localize and characterize a novel subpellicular microtubule associated protein unique to the genus Plasmodium (P.). The knockout of this protein in the human infecting P. falciparum species result in malformed gametocytes and aberrant microtubules. We confirmed the microtubule association in the P. berghei rodent malaria homologue and show that its knockout results in a perturbated microtubule architecture, aberrant sporozoite motility and decreased transmission efficiency.

molecular biology↗

bioRxiv2022

Predicting Peptide HLA-II Presentation Using Immunopeptidomics, Transcriptomics and Deep Multimodal Learning

The human leukocyte antigen (HLA) class II proteins present peptides to CD4+ T cells through an interaction with T cell receptors (TCRs). Thus, HLA proteins are key players in shaping immunogenicity and immunodominance. Nevertheless, factors governing peptide presentation by HLA-II proteins are still poorly understood. To address this problem, we profiled the blood transcriptome and immunopeptidome of 20 healthy individuals and integrated the profiles with publicly available immunopeptidomics datasets. In depth multi-omics analysis identified expression levels and subcellular locations as import sequence-independent features governing presentation. Levering this knowledge, we developed the Peptide Immune Annotator Multimodal (PIA-M) tool, as a novel pan multimodal transformer-based framework that utilises sequence-dependent along with sequence-independent features to model presentation by HLA-II proteins. PIA-M illustrated a consistently superior performance relative to existing tools across two independent test datasets (area under the curve: 0.93 vs. 0.84 and 0.95 vs. 0.86), respectively. Besides achieving a higher predictive accuracy, PIA-M with its Rust-based pre-processing engine, had significantly shorter runtimes. PIA-M is freely available with a permissive licence as a standalone pipeline and as a webserver (https://hybridcomputing.ikmb.uni-kiel.de/pia). In conclusion, PIA-M enables a new state-of-the-art accuracy in predicting peptide presentation by HLA-II proteins in vivo.

bioinformatics↗

bioRxiv2022

A statistical genetics guide to identifying HLA alleles driving complex disease

The human leukocyte antigen (HLA) locus is associated with more human complex diseases than any other locus. In many diseases it explains more heritability than all other known loci combined. Investigators have now demonstrated the accuracy of in silico HLA imputation methods. These approaches enable rapid and accurate estimation of HLA alleles in the millions of individuals that are already genotyped on microarrays. HLA imputation has been used to define causal variation in autoimmune diseases, such as type I diabetes, and infectious diseases, such as HIV infection control. However, there are few guidelines on performing HLA imputation, association testing, and fine-mapping. Here, we present comprehensive statistical genetics guide to impute HLA alleles from genotype data. We provide detailed protocols, including standard quality control measures for input genotyping data and describe options to impute HLA alleles and amino acids including a web-based Michigan Imputation Server. We updated the HLA imputation reference panel representing global populations (African, East Asian, European and Latino) available at the Michigan Imputation Server (n = 20,349) and achived high imputation accuracy (mean dosage correlation r = 0.981). We finally offer best practice recommendations to conduct association tests in order to define the alleles, amino acids, and haplotypes affecting human traits. This protocol will be broadly applicable to the large-scale genotyping data and contribute to defining the role of HLA in human diseases across global populations.

genetics↗

bioRxiv2022

VCF2Prot: An Efficient and Parallel Tool for Generating Personalized Proteomes from VCF Files

MotivationThe ability to generate sample-specific protein sequences is a crucial step in neo-antigen discovery, cancer vaccine development, and proteogenomics. The revolutionary increase in the throughput of sequencers has fueled large-scale genomic and transcriptomic studies, holding great promises for the emerging field of personalized medicine. However, most sequencing projects store their sequencing data in an abbreviated variant calling format (VCF) that is not immediately amenable to subsequent proteomic and peptidomic analyses. Furthermore, data processing of such increasingly massive genome-scale datasets calls for parallel and concurrent programming, and consequently refactoring of existing algorithms and/or the development of new parallel algorithms. ResultsHere, we introduce sequence intermediate representation (SIR), a novel and generic algorithm for generating personalized or sample-specific protein sequences from a consequence-called VCF file and the corresponding reference proteome. An implementation of SIR, named VCF2Prot, was developed to aid personalized medicine and proteogenomics by generating personalized proteomes in FASTA format from a collection of consequence-called genomic alterations stored in a VCF file. Benchmarking VCF2Prot against the recently published PrecisionProDB showed an ~1000-fold improvement in runtime (depending on the input size). Furthermore, in a scale-up study VCF2Prot processed a VCF file containing 99,254 variants observed across 8,192 patients in ~ 11 minutes, demonstrating the massive improvement in the execution speed and the utility of SIR and VCF2prot in bridging large-scale genomic and proteomic studies. Availability and ImplementationVCF2Prot comes with a permissive MIT-license, enabling the commercial and non-commercial utilization of the tool. The source code along with precompiled versions for Linux/Mac OS are available at https://github.com/ikmb/vcf2prot. The modular units used for building VCF2Prot are available as a Rust crate at https://crates.io/crates/ppgg with documentations and examples at https://docs.rs/ppgg/0.1.4/ppgg/ under the same MIT-license.

genomics↗

bioRxiv2019

Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

The Wartberg culture (WBC, 3,500-2,800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We perform a genome-wide analysis of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3,300-3,200 cal. BCE). Our results highlight that the Niedertiefenbach population indeed emerged at the beginning of the WBC. This farming community was genetically heterogeneous and carried a surprisingly large hunter-gatherer ancestry component (40%). We detect considerable differences in the human leukocyte antigen gene pool between contemporary Europeans and the Niedertiefenbach individuals whose immune response was primarily geared towards defending viral infections.

evolutionary biology↗

bioRxiv2018

HIV Peptidome-Wide Association Study Reveals Patient-Specific Epitope Repertoires Associated with HIV Control

Genetic variation in the peptide-binding groove of the highly polymorphic human leukocyte antigen (HLA) class I molecules has repeatedly been associated with HIV-1 control and progression to AIDS, accounting for up to 12% of the variation in HIV-1 set point viral load (spVL). This suggests a key role in disease control for HLA presentation of HIV-1 epitopes to cytotoxic T cells. However, a comprehensive understanding of the relevant HLA-bound HIV epitopes is still elusive. Here we developed a peptidome-wide association study (PepWAS) approach that integrates HLA genotypes and spVL data from 6,311 HIV-infected patients to interrogate the entire HIV-1 proteome (3,252 unique peptides) for disease-relevant peptides. This PepWAS approach revealed a core set of epitopes associated with spVL, including previously characterized epitopes but also several novel disease-relevant peptides. More importantly, each patient presents only 16 ({+/-}7) and 6 ({+/-}6) of these core epitopes through their individual HLA-B and HLA-A variants, respectively. Differences in these patient-specific epitope repertoires account for almost all the variation in spVL previously associated with HLA genetic variation. PepWAS thus enables a comprehensive functional interpretation of the robust but little understood association between HLA and HIV-1 control, prioritizing a short and targetable list of disease-associated epitopes for personalized immunotherapy.

genomics↗