Biology subjects

Abel, L.

Publications and source records attributed to Abel, L..

At least 19 recordsLinked to original sources

bioRxiv2024

High-throughput proteome profiling with low variation in a multi-center study using dia-PASEF

High throughput proteomics is gaining increasing traction as it facilitates screening of large sample cohorts required in clinical research and systems biology studies. Recent developments in mass spectrometry-based proteomics resulted in improved hardware and software providing deep proteome coverage, robustness, and scale accessible to a wide range of laboratories. Here, we benchmark dia-PASEF, a data-independent acquisition scheme that integrates trapped ion mobility with high scan speed, with a high-resolution time-of-flight mass analyzer (timsTOF HT) for the deep proteome analysis of a human cell line applying short 5-minute gradients. To show intra-and interlaboratory reproducibility, we performed a multi-laboratory study including 11 sites. We demonstrate that on average 7,072 protein groups and 99,835 peptides were identified in human chronic myelogenous leukemia cells on the timsTOF HT with low variation. Our results underline that dia-PASEF data acquisition combined with reproducible chromatography enables high robustness and data consistency across instruments and laboratories, which is a prerequisite for translational biomedical insights.

systems biology↗

bioRxiv2023

Visual cortex anodal tDCS does not alter reading performance for Chinese presented character-by-character to normal peripheral vision

Visual cortex transcranial direct current stimulation (tDCS) reduces crowding in normal peripheral vision and may improve reading of English words in patients with macular degeneration. Given the different visual requirements of reading English words and Chinese characters, the effect of tDCS on peripheral reading performance in English might be different from Chinese. This study recruited seventeen participants (59 to 73 years of age) with normal vision and tested the hypothesis that anodal tDCS would improve reading of Chinese characters presented at 10{degrees} eccentricity compared with sham stimulation. Chinese sentences of different print sizes and exposure durations were presented one character at a time 10{degrees} below or to the left of fixation, and the individual critical print size (CPS) - the smallest print size eliciting the maximum reading speed (MRS) was determined. Reading accuracies for characters presented 0.2 logMAR smaller than the CPS were measured before, during, 5 mins, and 30 mins after receiving active or sham anodal visual cortex tDCS. Participants completed both the active and sham sessions in a random order following a double-blind, within-subject design. No effect of active anodal-tDCS on reading accuracy was observed, implying that a single session of tDCS did not improve Chinese character reading in normal peripheral vision. This may suggest that tDCS does not significantly reduce the crowding elicited within a single Chinese character. However, the effect of tDCS on between-character crowding is yet to be determined.

neuroscience↗

bioRxiv2022

Superinfection plays an important role in the acquisition of complex Plasmodium falciparum infections among female Anopheles mosquitoes

Studies of human malaria infections with multiple, genetically distinct parasites have illuminated mechanisms of malaria transmission. However, few studies have used the genetic diversity in mosquito infections to understand how transmission is sustained. We identified likely human sources of mosquito infections from a longitudinal cohort in Western Kenya based on genetic similarity between parasites and the timing of infections. We found that several human infections were required to reconstitute each mosquito infection and that multiple parasite clones were likely transmitted from infected humans to mosquitoes in each bite, suggesting that superinfection and co-transmission occur simultaneously and are important mechanisms of transmission. We further investigated this using an individual human and mosquito simulation model and found that co-transmission alone was unlikely to reproduce the high complexity of mosquito infections. We concluded that the superinfection of mosquitoes likely plays an important, but under studied, role in sustaining moderate to high malaria transmission.

systems biology↗

bioRxiv2022

Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Humans display vast clinical variability upon SARS-CoV-2 infection1-3, partly due to genetic and immunological factors4. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

genomics↗

bioRxiv2022

Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe

Ancient genomics can directly detect human genetic adaptation to environmental cues. However, it remains unclear how pathogens have exerted selective pressures on human genome diversity across different epochs and affected present-day inflammatory disease risk. Here, we use an ancestry-aware approximate Bayesian computation framework to estimate the nature, strength, and time of onset of selection acting on 2,879 ancient and modern European genomes from the last 10,000 years. We found that the bulk of genetic adaptation occurred after the start of the Bronze Age, <4,500 years ago, and was enriched in genes relating to host-pathogen interactions. Furthermore, we detected directional selection acting on specific leukocytic lineages and experimentally demonstrated that the strongest negatively selected immunity gene variant -- the lipopolysaccharide-binding protein gene (LBP) D283G -- is hypomorphic. Finally, our analyses suggest that the risk of inflammatory disorders has progressively increased in post-Neolithic Europeans, partly due to antagonistic pleiotropy following genetic adaptation to pathogens.

genetics↗

bioRxiv2022

Plasmodium falciparum genetic diversity in coincident human and mosquito hosts

Population genetic diversity of P. falciparum antigenic loci is high despite large bottlenecks in population size during the parasite life cycle. The extent of this diversity in human blood-stage infections, following expansion from a small number of liver-stage schizonts, has been well described. However, little is known about parasite genetic diversity in the vector, where a similar bottleneck and expansion occurs following parasite mating and where parasite genotypes from several different human infections may accumulate. We assessed parasite genetic diversity within human and mosquito P. falciparum infections collected from the same households during a 14-month longitudinal cohort study using amplicon deep sequencing of two antigenic gene fragments (ama1 and csp). To a prior set of infected humans (n=1175/2813; 86.2% sequencing success) and mosquito abdomens (n=199/1448; 95.5% sequencing success), we added sequences from infected mosquito heads (n=134/1448; 98.5% sequencing success). Across all sample types we observed 456 ama1 and 289 csp unique haplotypes. While both hosts contained many rare haplotypes, population genetic metrics indicated that the overall and sample-level parasite populations were more diverse in mosquitoes than in humans, and infections were more likely to harbor a dominant haplotype in humans than in mosquitoes (based on relative read abundance). Finally, within a given mosquito there was little overlap in genetic composition of abdomen and head infections, suggesting that infections may be cleared from the abdomen during a mosquitos lifespan. Taken together, our observations provide evidence for the role of the mosquito vector in maintaining sequence diversity of malaria parasite populations. Significance statementConcurrent infections with multiple strains of Plasmodium falciparum, the leading causative agent of death due to malaria, are common in highly endemic regions. During transitions within and between the parasites mosquito and human hosts, population bottlenecks occur, and distinct parasite strains may have differential fitness in the various environments encountered. These bottlenecks and fitness differences may lead to differences in strain prevalence and diversity between hosts. We investigated differences in genetic diversity between P. falciparum parasites in human and mosquito hosts and found that, compared to human parasite populations and infections, mosquito populations and infections were more diverse. This suggests that the mosquito vector may play a role in in maintaining sequence diversity in malaria parasite populations.

microbiology↗

bioRxiv2022

Genome-wide detection of human variants that disrupt intronic branchpoints

Pre-mRNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Fifty-six rare variants in 44 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach has been available to efficiently detect such variants in next-generation sequencing (NGS) data. We established a comprehensive human genome-wide BP database by integrating existing BP data, and by generating new BP data from RNA-seq of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We in-depth characterize multiple features of BP in major and minor introns, and find that BP and BP-2 (two-nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, whilst being comparable to the exonic background. We develop BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition in NGS data. BPHunter retrospectively identifies 48 of the 56 known pathogenic BP mutations in which we summarize a strategy for prioritizing BP mutation candidates, and the remaining 8 all create AG dinucleotides between BP and acceptor site which is probably the reason for mis-splicing. We demonstrate the utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of STAT2 in a patient with critical COVID-19 pneumonia, and a novel somatic intronic 59-nucleotide deletion of ITPKB in a lymphoma patient, both of which we validate experimentally. BPHunter is publicly available from https://hgidsoft.rockefeller.edu/BPHunter and https://github.com/casanova-lab/BPHunter.

genetics↗

bioRxiv2022

Effect of habitual reading direction on saccadic eye movements

Cognitive processes can influence the characteristics of saccadic eye movements. Reading habits, including habitual reading direction, also affects cognitive and visuospatial processes, favouring attention to the side where reading begins. Few studies have investigated the effect of habitual reading direction on saccade directionality of low-cognitive-demand stimuli (such as dots). The current study examined horizontal prosaccade, antisaccade and self-paced saccade in subjects with two primary habitual reading directions. We hypothesised that saccades responding to the target in subjects habitual reading direction would show a longer prosaccade latency and lower antisaccade error rate (errors being a reflexive glance to a sudden-appearing target, rather than a saccade away from it). Sixteen young Chinese participants with primary habitual reading direction from left to right and sixteen young Arabic and Persian participants with primary habitual reading direction from right to left were recruited. Subjects needed to look towards a 5{degrees}/ 10{degrees}target in the prosaccade task or look towards the mirror image location of the target in the antisaccade task and look between two 10-degree targets in the self-paced saccade task. Only Arabic and Persian participants showed a shorter and directional prosaccade latency towards 5{degrees}target against their habitual reading direction. No significant effect of primary reading direction on antisaccade latency towards the correct directions was found. However, we found that Chinese readers generated significantly shorter prosaccade latencies and higher antisaccade directional errors compared with Arabic and Persian readers. The present study provides an insight into the effect of reading habits on saccadic eye movements in response to low-cognitive-demand stimuli and offers a platform for future studies to investigate the relationship between reading habits and neural mechanisms of eye movement behaviours.

neuroscience↗

bioRxiv2020

Basal Expression of Interferon-Stimulated Genes Drives Population Differences in Monocyte Susceptibility to Influenza Infection

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use an ex vivo model to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. Using single-cell RNA-sequencing, we show widespread inter-individual variability in the percentage of IAV-infected monocytes. We show that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. While this host defense strategy is shared between CD16+/CD16- monocytes, we also uncover CD16+-specific mRNA expression of IL6 and TNF in response to IAV, and a stronger resistance of CD16+ monocytes to IAV infection. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1, and OAS3. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Collectively, our results reveal the effects of IAV infection on the transcriptional landscape of human monocytes and highlight previously unappreciated differences in cellular susceptibility to IAV infection between individuals of African and European ancestry, which may account for the greater susceptibility of Africans to severe influenza. Significance StatementMonocytes may play a critical role during severe viral infections. Our study tackles how heterogeneity in monocyte subsets and activation contributes to shape individual differences in the transcriptional response to viral infections. Using single-cell RNA-sequencing, we reveal heterogeneity in monocyte susceptibility to IAV infection, both between CD16+/CD16- monocytes and across individuals, driven by differences in basal activation of an IRF/STAT-induced antiviral program. Furthermore, we show a decreased ability of IAV to infect and replicate in monocytes from African-ancestry individuals, with possible implications for antigen presentation and lymphocyte activation. These results highlight the importance of early cellular activation in determining an individuals innate immune response to viral infection.

genomics↗

bioRxiv2020

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Inborn errors of human IFN-{gamma} immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and V{delta}2+ {gamma}{delta} T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-{gamma}. Other IFN-{gamma}-producing lymphocyte subsets however develop normally, but with low levels of IFN-{gamma} production, with exception of V{delta}2- {gamma}{delta} T lymphocytes, which produce normal amounts of IFN-{gamma} in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-{gamma} normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-{gamma} production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and V{delta}2+ {gamma}{delta} T cells), with mycobacterial-specific, IFN-{gamma}-producing, purely adaptive {beta} TH1* cells unable to compensate for this deficit.

immunology↗

bioRxiv2020

Detection of homozygous and hemizygous partial exon deletions by whole-exome sequencing

The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in typical laboratory cohorts that are generated over time under different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder-opt to identify HMZ partial deletions of exons that are otherwise undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in laboratory cohorts, which are typically heterogeneous.

bioinformatics↗

bioRxiv2020

Development and Characterization of Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases

IntroductionThe purpose of this study was to establish and characterize a direct-from patient-derived xenograft (PDX) model of non-small cell lung cancer (NSCLC) brain metastases. MethodsSurgically obtained tissue was implanted subcutaneously and as orthotopic intracranial implants into immunodeficient mice. Histology and DNA loci were compared between original tumor and subsequent PDX passages. Tumors underwent RNA and DNA sequencing and relevant therapeutic targets were identified. Tumor growth rates were assessed following treatment with radiation, MEK inhibitor selumetinib, or MET inhibitor savolitinib. Cell lines were established. ResultsNine NSCLC brain metastases PDXs were established. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumor and subcutaneous and intracranial tumors. Short tandem repeat analysis demonstrated strong concordance between patient tumors and subsequent PDX passages. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples. Significant growth inhibition occurred with radiation, with selumetinib in tumors harboring KRAS G12C mutations and with savolitinib in a tumor with MET exon 14 skipping mutation. The combination of radiation and savolitinib resulted in significant tumor growth delay compared to radiation or savolitinib alone our MET exon 14 skipping mutation PDX. Early passage cell strains showed high consistency between patient and PDX tumors. ConclusionWe have established a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

cancer biology↗

bioRxiv2020

Controlling for Human Population Stratification in Rare Variant Association Studies

Population stratification is a strong confounding factor in human genetic association studies. In analyses of rare variants, the main correction strategies based on principal components (PC) and linear mixed models (LMM), may yield conflicting conclusions, due to both the specific type of structure induced by rare variants and the particular statistical features of association tests. Studies evaluating these approaches generally focused on specific situations with limited types of simulated structure and large sample sizes. We investigated the properties of several correction methods in the context of a large simulation study using real exome data, and several within- and between- continent stratification scenarios. We also considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. In this context, we focused on a genetic model with a phenotype driven by rare deleterious variants well suited for a burden test. For analyses of large samples, we found that accounting for stratification was more difficult with a continental structure than with a worldwide structure. LMM failed to maintain a correct type I error in many scenarios, whereas PCs based on common variants failed only in the presence of extreme continental stratification. When a sample of 50 cases was considered, an inflation of type I errors was observed with PC for small numbers of controls ([≤]100), and with LMM for large numbers of controls ([≥]1000). We also tested a promising novel adapted local permutation method (LocPerm), which maintained a correct type I error in all situations. All approaches capable of correcting for stratification properly had similar powers for detecting actual associations pointing out that the key issue is to properly control type I errors. Finally, we found that adding a large panel of external controls (e.g. extracted from publicly available databases) was an efficient way to increase the power of analyses including small numbers of cases, provided an appropriate stratification correction was used. Author SummaryGenetic association studies focusing on rare variants using next generation sequencing (NGS) data have become a common strategy to overcome the shortcomings of classical genome-wide association studies for the analysis of rare and common diseases. The issue of population stratification remains however a substantial question that has not been fully resolved when analyzing NGS data. In this work, we propose a comprehensive evaluation of the main strategies to account for stratification, that are principal components and linear mixed model, along with a novel approach based on local permutations (LocPerm). We compared these correction methods in many different settings, considering several types of population structures, sample sizes or types of variants. Our results highlighted important limitations of some classical methods as those using principal components (in particular in small samples) and linear mixed models (in several situations). In contrast, LocPerm maintained a correct type I error in all situations. Also, we showed that adding a large panel of external controls, e.g coming from publicly available databases, is an efficient strategy to increase the power of an analysis including a low number of cases, as long as an appropriate stratification correction is used. Our findings provide helpful guidelines for many researchers working on rare variant association studies.

genetics↗

bioRxiv2020

Negative selection on human genes causing severe inborn errors depends on disease outcome and both the mode and mechanism of inheritance

BackgroundGenetic variants underlying severe diseases are less likely to be transmitted to the next generation, and are thus gradually and selectively eliminated from the population through negative selection. Here, we study the determinants of this evolutionary process in genes underlying severe diseases in humans. ResultsWe propose a novel approach, CoNeS, integrating known negative selection scores through principal component projection. We compare evidence for negative selection at 319 genes underlying inborn errors of immunity (IEI), which are life-threatening monogenic disorders. We find that genes underlying autosomal dominant (AD) or X-linked IEI are under stronger negative selection than those underlying autosomal recessive (AR) IEI, which are under no stronger selection than genes not known to be disease-causing. However, we find that genes with mutations causing AR IEI that are lethal before reproductive maturity and that display complete penetrance are under stronger negative selection than other genes underlying AR IEI. We also find that genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. Finally, we replicate these results in a study of 1,140 genes causing inborn errors of neurodevelopment. ConclusionsThese findings collectively show that the clinical outcomes of inborn errors, together with the mode and mechanism of inheritance of these errors, determine the strength of negative selection acting on severe disease-causing genes. These findings suggest that estimating the intensity of negative selection with CoNeS may facilitate the selection of candidate genes in patients suspected to carry an inborn error.

genetics↗

bioRxiv2020

A genome-wide case-only test for the detection of digenic inheritance in human exomes

Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a novel two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene x gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment and bias of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we validated our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients. Significance statementDespite a growing number of reports of rare disorders not fully explained by monogenic lesions, digenic inheritance has been reported for only 54 diseases to date. The very few existing methods for detecting gene x gene interactions from next-generation sequencing data were generally studied in rare-variant association studies with limited simulation analyses for short genomic regions, under a case-control design. We describe the first case-only approach designed specifically to search for digenic inheritance, which avoids recruitment and bias related to controls. We show, through both extensive simulation studies on real WES datasets and application to a real example of craniosynostosis, that our method is robust and powerful for the genome-wide identification of digenic lesions.

genetics↗

bioRxiv2020

Impact of immediate cryopreservation on the establishment of patient derived xenografts from head and neck cancer patients.

BackgroundPatient-derived xenografts established from human cancers are important tools for investigating novel anti-cancer therapies. Establishing PDXs requires a significant investment and many PDXs may be used infrequently due to their similarity to existing models, their growth rate, or the lack of relevant mutations. We performed this study to determine whether we could efficiently establish PDXs after cryopreservation to allow molecular profiling to be completed prior to implanting the human cancer. MethodsFresh tumor was split with half used to establish a PDX immediately and half cryopreserved for later implantation. Resulting tumors were assessed histologically and tumors established from fresh or cryopreserved tissues compared as to the growth rate, extent of tumor necrosis, mitotic activity, keratinization, and grade. All PDXs were subjected to short tandem repeat testing to confirm identity and assess similarity between methods. ResultsTumor growth was seen in 70% of implanted cases. No growth in either condition was seen in 30% of tumors. One developed a SCC from the immediate implant but a lymphoproliferative mass without SCC from the cryopreserved specimen. No difference in growth rate was seen. No difference between histologic parameters was seen between the two approaches. ConclusionsFresh human cancer tissue can be immediately cryopreserved and later thawed and implanted to establish PDXs. This resource saving approach allows for tumor profiling prior to implantation into animals thus maximizing the probability that the tumor will be utilized for future research.

cancer biology↗

bioRxiv2020

Taking population stratification into account by local permutations in rare-variant association studies on small samples

Many methods for rare variant association studies require permutations to assess the significance of tests. Standard permutations assume that all individuals are exchangeable and do not take population stratification (PS), a known confounding factor in genetic studies, into account. We propose a novel strategy, LocPerm, in which individuals are permuted only with their closest ancestry-based neighbors. We performed a simulation study, focusing on small samples, to evaluate and compare LocPerm with standard permutations and classical adjustment on first principal components. Under the null hypothesis, LocPerm was the only method providing an acceptable type I error, regardless of sample size and level of stratification. The power of LocPerm was similar to that of standard permutation in the absence of PS, and remained stable in different PS scenarios. We conclude that LocPerm is a method of choice for taking PS and/or small sample size into account in rare variant association studies.

genomics↗

bioRxiv2020

High syphilis seropositivity in European brown hares, Lower Saxony, Germany

Treponema paraluisleporidarum infects lagomorphs and is a close relative of the human syphilis-bacterium Treponema pallidum. There is paucity of information on the epidemiology of hare syphilis and its relationship to rabbit- and human-infecting Treponema. We have found a high seropositivity (405/734) for Treponema paraluisleporidarum-infection in hares of Lower Saxony, Germany.

ecology↗