Biology subjects

Hammer, C.

Publications and source records attributed to Hammer, C..

9 recordsLinked to original sources

bioRxiv2023

A marine cryptochrome with an inverse photo-oligomerization mechanism

Cryptochromes (CRYs) are a structurally conserved but functionally diverse family of proteins that can confer unique sensory properties to organisms. In the marine bristle worm Platynereis dumerilii, its light receptive cryptochrome L-CRY (PdLCry) allows the animal to discriminate between sunlight and moonlight, an important requirement for synchronizing its lunar cycle-dependent mass spawning. Using cryo-electron microscopy, we show that in the dark, PdLCry adopts a dimer arrangement observed neither in plant nor insect CRYs. Intense illumination disassembles the dimer into monomers. Structural and functional data suggest a mechanistic coupling between the light-sensing flavin adenine dinucleotide chromophore, the dimer interface, and the C-terminal tail helix, with a likely involvement of the phosphate binding loop. Taken together, our work establishes PdLCry as a CRY protein with inverse photo-oligomerization with respect to plant CRYs, and provides molecular insights into how this protein might help discriminating the different light intensities associated with sunlight and moonlight.

biochemistry↗

bioRxiv2022

NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer

PD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Here, we show that KLRC1 (NKG2A) expression associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in CD8Ahigh bladder tumors. The loss of antigen presentation is a common mechanism for tumor escape in bladder cancer. NKG2A+ CD8 T cells are able to circumvent HLA-ABC loss through TCR-independent cytotoxicity, which is partly mediated by DNAM-1. In bladder tumors, NKG2A is acquired on a subset of PD-1+ CD8 T cells, alongside stronger tissue-residency memory features, TCR-independent cytotoxicity and evidence of recent proliferation. HLA-E is low but variably expressed on bladder tumors. When expressed, NKG2A+ CD8 T cell anti-tumor responses to HLA-ABC-deficient tumors are inhibited and partly restored upon NKG2A blockade. Overall, our study identifies an alternative path for CD8 T cell exhaustion, that is mediated by NKG2A upregulation and TCR-independent cytotoxicity.

immunology↗

bioRxiv2021

MiDAS - Meaningful Immunogenetic Data at Scale

Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. We present MiDAS, an R package enabling statistical association analysis and using immunogenetic data transformation functions for HLA amino acid fine mapping, analysis of HLA evolutionary divergence as well as HLA-KIR interactions. MiDAS closes the gap between inference of immunogenetic variation and its efficient utilization to make meaningful discoveries.

bioinformatics↗

bioRxiv2020

In silico tools for accurate HLA and KIR inference from clinical sequencing data empower immunogenetics on individual-patient and population scales

Immunogenetic variation in humans is important in research, clinical diagnosis and increasingly a target for therapeutic intervention. Two highly polymorphic loci play critical roles, namely the human leukocyte antigen (HLA) system, which is the human version of the major histocompatibility complex (MHC), and the Killer-cell immunoglobulin-like receptors (KIR) that are relevant for responses of Natural Killer (NK) cells and some subsets of T cells. Their accurate classification has typically required the use of dedicated biological specimens and a combination of in vitro and in silico efforts. Increased availability of next generation sequencing data has led to the development of ancillary computational solutions. Here, we report an evaluation of recently published algorithms to computationally infer complex immunogenetic variation in the form of HLA alleles and KIR haplotypes from whole-genome or whole-exome sequencing data. For both HLA allele and KIR gene typing, we identified tools that yielded >97% overall accuracy for 4-digit HLA types, and >99% overall accuracy for KIR gene presence, suggesting the readiness of in silico solutions for use in clinical and high-throughput research settings.

bioinformatics↗

bioRxiv2019

Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer

PD-1 and PD-L1 act to restrict T-cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.

genetics↗

bioRxiv2019

A Comprehensive Assessment of Demographic, Environmental and Host Genetic Associations with Gut Microbiome Diversity in Healthy Individuals

BackgroundThe gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Interieur Consortium, a total of 1,000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20 - 69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. ResultsAmong 110 demographic, clinical and environmental factors, 11 were identified as significantly correlated with -diversity, {beta}-diversity or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between >5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. ConclusionIn a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals.

genomics↗

bioRxiv2018

Human genomics of acute liver failure due to hepatitis B virus infection: an exome sequencing study in liver transplant recipients

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs antibodies but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.\n\nAuthor SummaryInfection with hepatitis B virus (HBV) is very common and causes a variety of liver diseases including acute and chronic hepatitis, cirrhosis and liver carcinoma. Acute HBV infection is often asymptomatic, still about 1% of newly infected people develop a rapid and severe disease known as acute liver failure or fulminant hepatitis. Acute liver failure has a high mortality rate and is an indication for urgent liver transplantation. It is not clear why some people, who are otherwise healthy, develop such severe symptoms upon infection with a common pathogen. Here, we hypothesized that rare DNA variants in the human genome could contribute to this unusual susceptibility. We sequenced the exome (i.e. the regions of the genome that encode the proteins) of 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and searched for rare genetic variants that could explain the clinical presentation. We did not identify any variant that could be convincingly linked to the extreme susceptibility to HBV observed in the study participants. This suggests that HBV-induced acute liver failure is more likely to result from the combined influence of multiple genetic and environmental factors.

genomics↗

bioRxiv2018

Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

IntroductionHumoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.\n\nMethodsWe characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1,000 healthy individuals (Milieu Interieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.\n\nResults and discussionWe identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DR{beta}1 and HLA-DP{beta}1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.\n\nConclusionsUsing extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.

genomics↗

bioRxiv2017

Correcting for population stratification reduces false positive and false negative results in joint analyses of host and pathogen genomes

Studies of host genetic determinants of pathogen sequence variation can identify sites of genomic conflicts, by highlighting variants that are implicated in immune response on the host side and adaptive escape on the pathogen side. However, systematic genetic differences in host and pathogen populations can lead to inflated type I (false positive) and type II (false negative) error rates in genome-wide association analyses. Here, we demonstrate through simulation that correcting for both host and pathogen stratification reduces spurious signals and increases power to detect real associations in a variety of tested scenarios. We confirm the validity of the simulations by showing comparable results in an analysis of paired human and HIV genomes.

genomics↗