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Encounters with pathogens and other molecules can imprint long-lasting effects on our immune system, influencing future physiological outcomes. Given the wide range of microbes to which humans are exposed, their collective impact on health is not fully understood. To explore relations between exposures and biological aging and inflammation, we profiled an antibody-binding repertoire against 2,815 microbial, viral, and environmental peptides in a population cohort of 1,443 participants. Utilizing antibody-binding as a proxy for past exposures, we investigated their impact on biological aging, cell composition, and inflammation. Immune response against cytomegalovirus (CMV), rhinovirus, and gut bacteria relates with telomere length. Single-cell expression measurements identified an effect of CMV infection on the transcriptional landscape of subpopulations of CD8 and CD4 T-cells. This examination of the relationship between microbial exposures and biological aging and inflammation highlights a role for chronic infections (CMV and Epstein-Barr virus) and common pathogens (rhinoviruses and adenovirus C)., Peer Reviewed, "Article signat per 16 autors/es: Sergio Andreu-Sánchez, Aida Ripoll-Cladellas, Anna Culinscaia, Ozlem Bulut, Arno R. Bourgonje, Mihai G. Netea, Peter Lansdorp,Geraldine Aubert, Marc Jan Bonder, Lude Franke, Thomas Vogl, Monique G.P. van der Wijst, Marta Melé, Debbie Van Baarle, Jingyuan Fu , Alexandra Zhernakova", Postprint (published version)

Recent innovations in single-cell RNA-sequencing (scRNA-seq) provide the technology to investigate biological questions at cellular resolution. Pooling cells from multiple individuals has become a common strategy, and droplets can subsequently be assigned to a specific individual by leveraging their inherent genetic differences. An implicit challenge with scRNA-seq is the occurrence of doublets—droplets containing two or more cells. We develop Demuxafy, a framework to enhance donor assignment and doublet removal through the consensus intersection of multiple demultiplexing and doublet detecting methods. Demuxafy significantly improves droplet assignment by separating singlets from doublets and classifying the correct individual., This work was funded by the National Health and Medical Research Council (NHMRC) Investigator grant (1175781), and funding from the Goodridge foundation. J.E.P is also supported by a fellowship from the Fok Foundation., Peer Reviewed, "Article signat per 13 autors/es: Drew Neavin, Anne Senabouth, Himanshi Arora, Jimmy Tsz Hang Lee, Aida Ripoll-Cladellas, sc-eQTLGen Consortium, Lude Franke, Shyam Prabhakar, Chun Jimmie Ye, Davis J. McCarthy, Marta Melé, Martin Hemberg & Joseph E. Powel", Postprint (published version)

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease., This study was funded by the HumTranscriptom project with reference PID2019-107937GA-I00. R.G.-P. was supported by a Juan de la Cierva fellowship (FJC2020-044119-I) funded by MCIN/AEI/10.13039/501100011033 and ‘‘European Union NextGenerationEU/PRTR.’’ J.M.R. was supported by a predoctoral fellowship from ‘‘la Caixa’’ Foundation (ID 100010434) with code LCF/BQ/DR22/11950022. A.R.-C. was supported by a Formación Personal Investigador (FPI) fellowship (PRE2019-090193) funded by MCIN/AEI. R.C.-G. was supported by an FPI fellowship (PRE2020-092510) funded by MCIN/AEI. M.M. was supported by a Ramon y Cajal fellowship (RYC-2017-22249)., Peer Reviewed, Postprint (published version)

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle., We thank J. Dekens for management, A. Maatman and M. Platteel for technical support and K. Mc Intyre for English editing. This project was funded by the BBMRI grant for measuring telomere length and by a Rosalind Franklin Fellowship to A.Z. The researchers participated in this project are supported by Netherlands Heart Foundation (IN-CONTROL CVON grants 2012-03 and 2018-27); the Netherlands Organization for Scientific Research (NWO) Gravitation Netherlands Organ-on-Chip Initiative to J.F. and C.W.; NWO Gravitation Exposome-NL (024.004.017) to J.F., A.K. and A.Z.; NWO-VIDI (864.13.013) and NWO-VICI (VI.C.202.022) to J.F.; NWO-VIDI (016.178.056) to A.Z.; NWO-VIDI (917.14.374) to L.F.; NWO-VENI (194.006) to D.V.Z.; NWO-VENI (192.029) to M.W.; NWO Spinoza Prize SPI 92–266 to C.W.; the European Research Council (ERC) (FP7/2007–2013/ERC Advanced Grant 2012-322698) to C.W.; ERC Starting grant 637640 to L.F.; ERC Starting Grant 715772 to A.Z.; ERC Consolidator Grant (grant agreement No. 101001678) to J.F.; and RuG Investment Agenda Grant Personalized Health to C.W. MM work is supported by RYC- 2017-22249 and PID2019-107937GA-I00 grants. T.S. holds scholarships from the Junior Scientific Masterclass, University of Groningen[grant no. 17–34]. AR is funded by a Formación Personal Investigador (FPI) grant [grant no. PRE2019-090193]. The Lifelines Biobank initiative has been made possible by a subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Centre Groningen (UMCG, the Netherlands); the University of Groningen and the Northern Provinces of the Netherlands. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centres delivering data to Lifelines and all the study participants. Finally, we would like to acknowledge the Genomics Coordination Centre (GCC) at the University Medical College Groningen for the HPC support and the MOLGENIS team for the cloud storag, Peer Reviewed, "Article signat per 16 autors/es: Sergio Andreu-Sánchez, Geraldine Aubert, Aida Ripoll-Cladellas, Sandra Henkelman, Daria V. Zhernakova, Trishla Sinha, Alexander Kurilshikov, Maria Carmen Cenit, Marc Jan Bonder, Lude Franke, Cisca Wijmenga, Jingyuan Fu, Monique G. P. van der Wijst, Marta Melé, Peter Lansdorp & Alexandra Zhernakova", Postprint (published version)

Background: Although native to North America, the invasion of the aphid-like grape phylloxera Daktulosphaira vitifoliae across the globe altered the course of grape cultivation. For the past 150 years, viticulture relied on grafting-resistant North American Vitis species as rootstocks, thereby limiting genetic stocks tolerant to other stressors such as pathogens and climate change. Limited understanding of the insect genetics resulted in successive outbreaks across the globe when rootstocks failed. Here we report the 294-Mb genome of D. vitifoliae as a basic tool to understand host plant manipulation, nutritional endosymbiosis, and enhance global viticulture. Results: Using a combination of genome, RNA, and population resequencing, we found grape phylloxera showed high duplication rates since its common ancestor with aphids, but similarity in most metabolic genes, despite lacking obligate nutritional symbioses and feeding from parenchyma. Similarly, no enrichment occurred in development genes in relation to viviparity. However, phylloxera evolved > 2700 unique genes that resemble putative effectors and are active during feeding. Population sequencing revealed the global invasion began from the upper Mississippi River in North America, spread to Europe and from there to the rest of the world. Conclusions: The grape phylloxera genome reveals genetic architecture relative to the evolution of nutritional endosymbiosis, viviparity, and herbivory. The extraordinary expansion in effector genes also suggests novel adaptations to plant feeding and how insects induce complex plant phenotypes, for instance galls. Finally, our understanding of the origin of this invasive species and its genome provide genetics resources to alleviate rootstock bottlenecks restricting the advancement of viticulture.