Publications by authors named "Simon Rasmussen"

107 Publications

Photoplethysmography for demarcation of cutaneous squamous cell carcinoma.

Sci Rep 2021 Nov 2;11(1):21467. Epub 2021 Nov 2.

Department of Otolaryngology at the Southdanish University Hospital, 7100, Vejle, Denmark.

A video processing algorithm designed to identify cancer suspicious skin areas is presented here. It is based on video recordings of squamous cell carcinoma in the skin. Squamous cell carcinoma is a common malignancy, normally treated by surgical removal. The surgeon should always balance sufficient tissue removal against unnecessary mutilation, and therefore methods for distinction of cancer boundaries are wanted. Squamous cell carcinoma has angiogenesis and increased blood supply. Remote photoplethysmography is an evolving technique for analysis of signal variations in video recordings in order to extract vital signs such as pulsation. We hypothesize that the remote photoplethysmography signal inside the area of a squamous cell carcinoma is significantly different from the surrounding healthy skin. Based on high speed video recordings of 13 patients with squamous cell carcinoma, we have examined temporal signal differences in cancer areas versus healthy skin areas. A significant difference in temporal signal changes between cancer areas and healthy areas was found. Our video processing algorithm showed promising results encouraging further investigation to clarify how detailed distinctions can be made.
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http://dx.doi.org/10.1038/s41598-021-00645-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563950PMC
November 2021

Defining NASH from a Multi-Omics Systems Biology Perspective.

J Clin Med 2021 Oct 12;10(20). Epub 2021 Oct 12.

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease affecting up to 6.5% of the general population. There is no simple definition of NASH, and the molecular mechanism underlying disease pathogenesis remains elusive. Studies applying single omics technologies have enabled a better understanding of the molecular profiles associated with steatosis and hepatic inflammation-the commonly accepted histologic features for diagnosing NASH, as well as the discovery of novel candidate biomarkers. Multi-omics analysis holds great potential to uncover new insights into disease mechanism through integrating multiple layers of molecular information. Despite the technical and computational challenges associated with such efforts, a few pioneering studies have successfully applied multi-omics technologies to investigate NASH. Here, we review the most recent technological developments in mass spectrometry (MS)-based proteomics, metabolomics, and lipidomics. We summarize multi-omics studies and emerging omics biomarkers in NASH and highlight the biological insights gained through these integrated analyses.
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http://dx.doi.org/10.3390/jcm10204673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538576PMC
October 2021

Extension of Plant Phenotypes by the Foliar Microbiome.

Annu Rev Plant Biol 2021 06;72:823-846

Department of Plant and Environmental Sciences, University of Copenhagen, 1871 Frederiksberg C, Denmark; email:

The foliar microbiome can extend the host plant phenotype by expanding its genomic and metabolic capabilities. Despite increasing recognition of the importance of the foliar microbiome for plant fitness, stress physiology, and yield, the diversity, function, and contribution of foliar microbiomes to plant phenotypic traits remain largely elusive. The recent adoption of high-throughput technologies is helping to unravel the diversityand spatiotemporal dynamics of foliar microbiomes, but we have yet to resolve their functional importance for plant growth, development, and ecology. Here, we focus on the processes that govern the assembly of the foliar microbiome and the potential mechanisms involved in extended plant phenotypes. We highlight knowledge gaps and provide suggestions for new research directions that can propel the field forward. These efforts will be instrumental in maximizing the functional potential of the foliar microbiome for sustainable crop production.
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http://dx.doi.org/10.1146/annurev-arplant-080620-114342DOI Listing
June 2021

A large-scale investigation into the role of classical HLA loci in multiple types of severe infections, with a focus on overlaps with autoimmune and mental disorders.

J Transl Med 2021 05 31;19(1):230. Epub 2021 May 31.

iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.

Background: Infections are a major disease burden worldwide. While they are caused by external pathogens, host genetics also plays a part in susceptibility to infections. Past studies have reported diverse associations between human leukocyte antigen (HLA) alleles and infections, but many were limited by small sample sizes and/or focused on only one infection.

Methods: We performed an immunogenetic association study examining 13 categories of severe infection (bacterial, viral, central nervous system, gastrointestinal, genital, hepatitis, otitis, pregnancy-related, respiratory, sepsis, skin infection, urological and other infections), as well as a phenotype for having any infection, and seven classical HLA loci (HLA-A, B, C, DPB1, DQA1, DQB1 and DRB1). Additionally, we examined associations between infections and specific alleles highlighted in our previous studies of psychiatric disorders and autoimmune disease, as these conditions are known to be linked to infections.

Results: Associations between HLA loci and infections were generally not strong. Highlighted associations included associations between DQB1*0302 and DQB1*0604 and viral infections (P = 0.002835 and P = 0.014332, respectively), DQB1*0503 and sepsis (P = 0.006053), and DQA1*0301 with "other" infections (a category which includes infections not included in our main categories e.g. protozoan infections) (P = 0.000369). Some HLA alleles implicated in autoimmune diseases showed association with susceptibility to infections, but the latter associations were generally weaker, or with opposite trends (in the case of HLA-C alleles, but not with alleles of HLA class II genes). HLA alleles associated with psychiatric disorders did not show association with susceptibility to infections.

Conclusions: Our results suggest that classical HLA alleles do not play a large role in the etiology of severe infections. The discordant association trends with autoimmune disease for some alleles could contribute to mechanistic theories of disease etiology.
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http://dx.doi.org/10.1186/s12967-021-02888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165335PMC
May 2021

Corrigendum to "Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders - Findings from a Danish population-based study" [Brain Behav. Immun. 91 (2021) 10-23].

Brain Behav Immun 2021 Aug 27;96:307-308. Epub 2021 May 27.

CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.05.019DOI Listing
August 2021

Improved metagenome binning and assembly using deep variational autoencoders.

Nat Biotechnol 2021 05 4;39(5):555-560. Epub 2021 Jan 4.

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Despite recent advances in metagenomic binning, reconstruction of microbial species from metagenomics data remains challenging. Here we develop variational autoencoders for metagenomic binning (VAMB), a program that uses deep variational autoencoders to encode sequence coabundance and k-mer distribution information before clustering. We show that a variational autoencoder is able to integrate these two distinct data types without any previous knowledge of the datasets. VAMB outperforms existing state-of-the-art binners, reconstructing 29-98% and 45% more near-complete (NC) genomes on simulated and real data, respectively. Furthermore, VAMB is able to separate closely related strains up to 99.5% average nucleotide identity (ANI), and reconstructed 255 and 91 NC Bacteroides vulgatus and Bacteroides dorei sample-specific genomes as two distinct clusters from a dataset of 1,000 human gut microbiome samples. We use 2,606 NC bins from this dataset to show that species of the human gut microbiome have different geographical distribution patterns. VAMB can be run on standard hardware and is freely available at https://github.com/RasmussenLab/vamb .
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http://dx.doi.org/10.1038/s41587-020-00777-4DOI Listing
May 2021

The ubiquitin ligase RFWD3 is required for translesion DNA synthesis.

Mol Cell 2021 02 14;81(3):442-458.e9. Epub 2020 Dec 14.

The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address:

Lesions on DNA uncouple DNA synthesis from the replisome, generating stretches of unreplicated single-stranded DNA (ssDNA) behind the replication fork. These ssDNA gaps need to be filled in to complete DNA duplication. Gap-filling synthesis involves either translesion DNA synthesis (TLS) or template switching (TS). Controlling these processes, ubiquitylated PCNA recruits many proteins that dictate pathway choice, but the enzymes regulating PCNA ubiquitylation in vertebrates remain poorly defined. Here we report that the E3 ubiquitin ligase RFWD3 promotes ubiquitylation of proteins on ssDNA. The absence of RFWD3 leads to a profound defect in recruitment of key repair and signaling factors to damaged chromatin. As a result, PCNA ubiquitylation is inhibited without RFWD3, and TLS across different DNA lesions is drastically impaired. We propose that RFWD3 is an essential coordinator of the response to ssDNA gaps, where it promotes ubiquitylation to drive recruitment of effectors of PCNA ubiquitylation and DNA damage bypass.
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http://dx.doi.org/10.1016/j.molcel.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864614PMC
February 2021

Streptococcus pseudopneumoniae: Use of Whole-Genome Sequences To Validate Species Identification Methods.

J Clin Microbiol 2021 01 21;59(2). Epub 2021 Jan 21.

The Regional Department of Clinical Microbiology, Slagelse, Region Zealand, Denmark.

A correct identification of is a prerequisite for investigating the clinical impact of the bacterium. The identification has traditionally relied on phenotypic methods. However, these phenotypic traits have been shown to be unreliable, with some strains giving conflicting results. Therefore, sequence-based identification methods have increasingly been used for identification of In this study, we used 64 strains, 59 strains, 22 strains, 24 strains, 6 strains, and 1 strain to test the capability of three single genes (, , and ), two multilocus sequence analysis (MLSA) schemes, the single nucleotide polymorphism (SNP)-based phylogeny tool CSI phylogeny, a k-mer-based identification method (KmerFinder), average nucleotide identity (ANI) using fastANI, and core genome analysis to identify Core genome analysis and CSI phylogeny were able to cluster all strains into distinct clusters related to their respective species. It was not possible to identify all strains correctly using only one of the single genes. The MLSA schemes were unable to identify some of the strains, which could be misidentified. KmerFinder identified all strains but misidentified one strain as , and fastANI differentiated between and using an ANI cutoff of 96%.
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http://dx.doi.org/10.1128/JCM.02503-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111133PMC
January 2021

A systemic review and metaanalysis of postoperative outcomes in urgent and elective bowel resection in patients with Crohn's disease.

Int J Colorectal Dis 2021 Feb 13;36(2):253-263. Epub 2020 Oct 13.

Department of surgery, Aalborg University Hospital, Hobrovej 22, 9000, Aalborg, Denmark.

Purpose: The study examined whether urgency of surgical intervention affects postoperative outcomes in patients with Crohn's disease (CD) undergoing bowel resection.

Method: The review was conducted according to a predefined, published study protocol in Prospero which is an international database of prospectively registered systematic reviews in health. The study reported according to PRIMSMA guidelines. We searched Embase and Pubmed for articles reporting postoperative outcome after urgent and elective surgery in patients with CD undergoing bowel resection. Primary outcome variable was 30-day overall postoperative complications while secondary outcome variables were intraabdominal septic complications (IASCs), mortality, reoperation, and readmission. Assessment of bias was performed using Newcastle-Ottawa score. Two authors independently extracted data on each study, patients, and outcome measures.

Results: The search identified 22 studies in which 955 patients underwent urgent surgeries while 6518 patients underwent elective surgeries. Based on the quality assessment, 19 studies were classified as having high risk of bias, one study as having a medium risk of bias and 2 studies as having low risk of bias (≥ 8 stars). Random-effect metaanalysis showed urgent surgery was associated with ~ 40% increase in overall complications compared to elective surgery (RR = 1.43, 95% CI [1.09; 1.87], p = 0.010). IASCs also increased in patients who had urgent surgery (RR = 1.44, 95% CI [1.08; 1.92], p = 0.013). No significant difference was shown in mortality and readmission rates.

Conclusion: Urgent bowel resection in patients with CD is associated with higher risk of overall postoperative complications and IASCs.
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http://dx.doi.org/10.1007/s00384-020-03786-6DOI Listing
February 2021

Paleogenomic insights into the red complex bacteria in Pre-Hispanic and Colonial individuals from Mexico.

Philos Trans R Soc Lond B Biol Sci 2020 11 5;375(1812):20190580. Epub 2020 Oct 5.

International Laboratory for Human Genome Research, National Autonomous University of México (UNAM), Querétaro, 76230, Mexico.

The 'red complex' is an aggregate of three oral bacteria (, and ) responsible for severe clinical manifestation of periodontal disease. Here, we report the first direct evidence of ancient DNA in dentin and dental calculus samples from archaeological skeletal remains that span from the Pre-Hispanic to the Colonial period in Mexico. We recovered twelve partial ancient genomes and observed a distinct phylogenetic placement of samples, suggesting that the strains present in Pre-Hispanic individuals likely arrived with the first human migrations to the Americas and that new strains were introduced with the arrival of European and African populations in the sixteenth century. We also identified instances of the differential presence of genes between periods in the ancient genomes, with certain genes present in Pre-Hispanic individuals and absent in Colonial individuals, and . This study highlights the potential for studying ancient genomes to unveil past social interactions through analysis of disease transmission. Our results illustrate the long-standing relationship between this oral pathogen and its human host, while also unveiling key evidence to understand its evolutionary history in Pre-Hispanic and Colonial Mexico. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.
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http://dx.doi.org/10.1098/rstb.2019.0580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702795PMC
November 2020

Population genomics of the Viking world.

Nature 2020 09 16;585(7825):390-396. Epub 2020 Sep 16.

NTNU University Museum, Department of Archaeology and Cultural History, Trondheim, Norway.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
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http://dx.doi.org/10.1038/s41586-020-2688-8DOI Listing
September 2020

Ancient Jomon genome sequence analysis sheds light on migration patterns of early East Asian populations.

Commun Biol 2020 08 25;3(1):437. Epub 2020 Aug 25.

Kitasato University School of Medicine, Sagamihara, Japan.

Anatomically modern humans reached East Asia more than 40,000 years ago. However, key questions still remain unanswered with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of the region may elucidate a more detailed picture of the peopling of East Eurasia. Here, we analyze the whole-genome sequence of a 2,500-year-old individual (IK002) from the main-island of Japan that is  characterized with a typical Jomon culture. The phylogenetic analyses support multiple waves of migration, with IK002 forming a basal lineage to the East and Northeast Asian genomes examined, likely representing some of the earliest-wave migrants who went north from Southeast Asia to East Asia. Furthermore, IK002 shows strong genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration. This study highlights the power of ancient genomics to provide new insights into the complex history of human migration into East Eurasia.
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http://dx.doi.org/10.1038/s42003-020-01162-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447786PMC
August 2020

A G(enomic)P(ositioning)S(ystem) for Plant RNAPII Transcription.

Trends Plant Sci 2020 08 11;25(8):744-764. Epub 2020 Apr 11.

Copenhagen Plant Science Centre, Department of Plant and Environmental Sciences, University of Copenhagen, Bülowsvej 34, 1870 Frederiksberg C, Denmark. Electronic address:

Post-translational modifications (PTMs) of histone residues shape the landscape of gene expression by modulating the dynamic process of RNA polymerase II (RNAPII) transcription. The contribution of particular histone modifications to the definition of distinct RNAPII transcription stages remains poorly characterized in plants. Chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) resolves the genomic distribution of histone modifications. Here, we review histone PTM ChIP-seq data in Arabidopsis thaliana and find support for a Genomic Positioning System (GPS) that guides RNAPII transcription. We review the roles of histone PTM 'readers', 'writers', and 'erasers', with a focus on the regulation of gene expression and biological functions in plants. The distinct functions of RNAPII transcription during the plant transcription cycle may rely, in part, on the characteristic histone PTM profiles that distinguish transcription stages.
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http://dx.doi.org/10.1016/j.tplants.2020.03.005DOI Listing
August 2020

Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders - Findings from a Danish population-based study.

Brain Behav Immun 2021 01 11;91:10-23. Epub 2020 Jun 11.

CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Previous studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders and investigated the genetic basis of overall autoimmune disease.

Methods: We used diagnostic information from patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort.

Results: Of 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (P = 2.67 × 10, OR = 1.38, 95%CI = 1.22-1.56), with an overall bidirectional association, wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR = 1.13, 95%CI: 1.07-1.21, P = 7.95 × 10) and vice versa (HR = 1.27, 95%CI = 1.16-1.39, P = 8.77 × 10). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00-1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10, OR = 1.80, 95% CI: 1.64-1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10, OR = 10.65, 95%CI = 3.21-35.36).

Conclusions: Our findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.
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http://dx.doi.org/10.1016/j.bbi.2020.06.014DOI Listing
January 2021

Similar genomic patterns of clinical infective endocarditis and oral isolates of Streptococcus sanguinis and Streptococcus gordonii.

Sci Rep 2020 02 17;10(1):2728. Epub 2020 Feb 17.

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark.

Streptococcus gordonii and Streptococcus sanguinis belong to the Mitis group streptococci, which mostly are commensals in the human oral cavity. Though they are oral commensals, they can escape their niche and cause infective endocarditis, a severe infection with high mortality. Several virulence factors important for the development of infective endocarditis have been described in these two species. However, the background for how the commensal bacteria, in some cases, become pathogenic is still not known. To gain a greater understanding of the mechanisms of the pathogenic potential, we performed a comparative analysis of 38 blood culture strains, S. sanguinis (n = 20) and S. gordonii (n = 18) from patients with verified infective endocarditis, along with 21 publicly available oral isolates from healthy individuals, S. sanguinis (n = 12) and S. gordonii (n = 9). Using whole genome sequencing data of the 59 streptococci genomes, functional profiles were constructed, using protein domain predictions based on the translated genes. These functional profiles were used for clustering, phylogenetics and machine learning. A clear separation could be made between the two species. No clear differences between oral isolates and clinical infective endocarditis isolates were found in any of the 675 translated core-genes. Additionally, random forest-based machine learning and clustering of the pan-genome data as well as amino acid variations in the core-genome could not separate the clinical and oral isolates. A total of 151 different virulence genes was identified in the 59 genomes. Among these homologs of genes important for adhesion and evasion of the immune system were found in all of the strains. Based on the functional profiles and virulence gene content of the genomes, we believe that all analysed strains had the ability to become pathogenic.
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http://dx.doi.org/10.1038/s41598-020-59549-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026040PMC
February 2020

Gut microbial changes of patients with psychotic and affective disorders: A systematic review.

Schizophr Res 2021 08 14;234:1-10. Epub 2020 Jan 14.

Copenhagen Research Centre for Mental Health - CORE, Mental Health Centre Copenhagen, Copenhagen University Hospital, Gentofte Hospitalsvej 15, 4. sal, 2900 Hellerup, Denmark. Electronic address:

Background: Many diverse inflammatory pathophysiologic mechanisms have been linked to mental disorders, and through the past decade an increasing interest in the gut microbiota and its relation to mental health has been arising. We aimed to systematically review studies of alterations in gut microbiota of patients suffering from psychotic disorders, bipolar disorder or depression compared to healthy controls.

Methods: We systematically searched the databases CENTRAL, PubMed, EMBASE, PsycINFO and LILACS. Primary outcome was to compare the gut microbiota of patients suffering from psychotic disorders, bipolar disorder or depression with healthy controls.

Results: We identified 17 studies, covering 744 patients and 620 healthy controls. The most consistent microbiota changes were a tendency towards higher abundance of Actinobacteria and lower abundance of Firmicutes at the phylum level, lower abundance of Lachnospiraceae at family level and lower abundance of Faecalibacterium at genus level for the mental disorders overall. However, we found that all studies had risk of bias and that the included studies displayed great variability in methods of storage, analysis of the fecal samples, reporting of results and statistics used.

Conclusion: Due to the many limitations of the included studies the findings should be interpreted with caution. Larger studies (especially of schizophrenia and major depressive disorder) are needed, but it is also of great importance to gather information of and control for factors that influence the result of a microbiota analysis including body mass index (BMI), smoking, alcohol consumption, diet habits, antibiotics, sample handling, wet laboratory methods and statistics.
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http://dx.doi.org/10.1016/j.schres.2019.12.014DOI Listing
August 2021

A draft genome sequence of the elusive giant squid, Architeuthis dux.

Gigascience 2020 01;9(1)

Centre for Sustainable Tropical Fisheries & Aquaculture, James Cook University, Townsville, Douglas QLD 4814, Australia.

Background: The giant squid (Architeuthis dux; Steenstrup, 1857) is an enigmatic giant mollusc with a circumglobal distribution in the deep ocean, except in the high Arctic and Antarctic waters. The elusiveness of the species makes it difficult to study. Thus, having a genome assembled for this deep-sea-dwelling species will allow several pending evolutionary questions to be unlocked.

Findings: We present a draft genome assembly that includes 200 Gb of Illumina reads, 4 Gb of Moleculo synthetic long reads, and 108 Gb of Chicago libraries, with a final size matching the estimated genome size of 2.7 Gb, and a scaffold N50 of 4.8 Mb. We also present an alternative assembly including 27 Gb raw reads generated using the Pacific Biosciences platform. In addition, we sequenced the proteome of the same individual and RNA from 3 different tissue types from 3 other species of squid (Onychoteuthis banksii, Dosidicus gigas, and Sthenoteuthis oualaniensis) to assist genome annotation. We annotated 33,406 protein-coding genes supported by evidence, and the genome completeness estimated by BUSCO reached 92%. Repetitive regions cover 49.17% of the genome.

Conclusions: This annotated draft genome of A. dux provides a critical resource to investigate the unique traits of this species, including its gigantism and key adaptations to deep-sea environments.
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http://dx.doi.org/10.1093/gigascience/giz152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962438PMC
January 2020

A 5700 year-old human genome and oral microbiome from chewed birch pitch.

Nat Commun 2019 12 17;10(1):5520. Epub 2019 Dec 17.

The Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1353, Denmark.

The rise of ancient genomics has revolutionised our understanding of human prehistory but this work depends on the availability of suitable samples. Here we present a complete ancient human genome and oral microbiome sequenced from a 5700 year-old piece of chewed birch pitch from Denmark. We sequence the human genome to an average depth of 2.3× and find that the individual who chewed the pitch was female and that she was genetically more closely related to western hunter-gatherers from mainland Europe than hunter-gatherers from central Scandinavia. We also find that she likely had dark skin, dark brown hair and blue eyes. In addition, we identify DNA fragments from several bacterial and viral taxa, including Epstein-Barr virus, as well as animal and plant DNA, which may have derived from a recent meal. The results highlight the potential of chewed birch pitch as a source of ancient DNA.
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http://dx.doi.org/10.1038/s41467-019-13549-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917805PMC
December 2019

The population history of northeastern Siberia since the Pleistocene.

Nature 2019 06 5;570(7760):182-188. Epub 2019 Jun 5.

Institute of Archaeology and Ethnography of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.

Northeastern Siberia has been inhabited by humans for more than 40,000 years but its deep population history remains poorly understood. Here we investigate the late Pleistocene population history of northeastern Siberia through analyses of 34 newly recovered ancient genomes that date to between 31,000 and 600 years ago. We document complex population dynamics during this period, including at least three major migration events: an initial peopling by a previously unknown Palaeolithic population of 'Ancient North Siberians' who are distantly related to early West Eurasian hunter-gatherers; the arrival of East Asian-related peoples, which gave rise to 'Ancient Palaeo-Siberians' who are closely related to contemporary communities from far-northeastern Siberia (such as the Koryaks), as well as Native Americans; and a Holocene migration of other East Asian-related peoples, who we name 'Neo-Siberians', and from whom many contemporary Siberians are descended. Each of these population expansions largely replaced the earlier inhabitants, and ultimately generated the mosaic genetic make-up of contemporary peoples who inhabit a vast area across northern Eurasia and the Americas.
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http://dx.doi.org/10.1038/s41586-019-1279-zDOI Listing
June 2019

Unraveling ancestry, kinship, and violence in a Late Neolithic mass grave.

Proc Natl Acad Sci U S A 2019 05 6;116(22):10705-10710. Epub 2019 May 6.

Lundbeck Foundation GeoGenetics Centre, Department of Biology, University of Copenhagen, 1350 Copenhagen K, Denmark;

The third millennium BCE was a period of major cultural and demographic changes in Europe that signaled the beginning of the Bronze Age. People from the Pontic steppe expanded westward, leading to the formation of the Corded Ware complex and transforming the genetic landscape of Europe. At the time, the Globular Amphora culture (3300-2700 BCE) existed over large parts of Central and Eastern Europe, but little is known about their interaction with neighboring Corded Ware groups and steppe societies. Here we present a detailed study of a Late Neolithic mass grave from southern Poland belonging to the Globular Amphora culture and containing the remains of 15 men, women, and children, all killed by blows to the head. We sequenced their genomes to between 1.1- and 3.9-fold coverage and performed kinship analyses that demonstrate that the individuals belonged to a large extended family. The bodies had been carefully laid out according to kin relationships by someone who evidently knew the deceased. From a population genetic viewpoint, the people from Koszyce are clearly distinct from neighboring Corded Ware groups because of their lack of steppe-related ancestry. Although the reason for the massacre is unknown, it is possible that it was connected with the expansion of Corded Ware groups, which may have resulted in competition for resources and violent conflict. Together with the archaeological evidence, these analyses provide an unprecedented level of insight into the kinship structure and social behavior of a Late Neolithic community.
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http://dx.doi.org/10.1073/pnas.1820210116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561172PMC
May 2019

Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders.

Eur J Hum Genet 2019 09 11;27(9):1445-1455. Epub 2019 Apr 11.

Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.

Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.
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http://dx.doi.org/10.1038/s41431-019-0402-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777475PMC
September 2019

GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling.

Cell Rep 2019 03;26(13):3511-3521.e4

Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address:

Inflammatory signaling is restricted through degradation and the translational repression of cytokine mRNAs. A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs. Here, we show that the RBP ZNF598 contributes to the same regulatory module in a TTP-like manner. Similar to TTP, ZNF598 harbors three proline-rich motifs that bind the GYF domain of GIGYF1. RNA sequencing experiments showed that ZNF598 is required for the regulation of known TTP targets, including IL-8 and CSF2 mRNA. Furthermore, we demonstrate that ZNF598 binds to IL-8 mRNA, but not TNF mRNA. Collectively, our findings highlight that ZNF598 functions as an RBP that buffers the level of a range of mRNAs. We propose that ZNF598 is a TTP-like factor that can contribute to the regulation of the inflammatory potential of cytokine-producing cells.
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http://dx.doi.org/10.1016/j.celrep.2019.03.006DOI Listing
March 2019

Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage.

Nat Commun 2019 03 8;10(1):1124. Epub 2019 Mar 8.

Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, UK.

Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use metagenomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.
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http://dx.doi.org/10.1038/s41467-019-08853-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408512PMC
March 2019

Ancient nuclear genomes enable repatriation of Indigenous human remains.

Sci Adv 2018 12 19;4(12):eaau5064. Epub 2018 Dec 19.

Australian Research Centre for Human Evolution, Environmental Futures Research Institute, Griffith University, Nathan, QLD, Australia.

After European colonization, the ancestral remains of Indigenous people were often collected for scientific research or display in museum collections. For many decades, Indigenous people, including Native Americans and Aboriginal Australians, have fought for their return. However, many of these remains have no recorded provenance, making their repatriation very difficult or impossible. To determine whether DNA-based methods could resolve this important problem, we sequenced 10 nuclear genomes and 27 mitogenomes from ancient pre-European Aboriginal Australians (up to 1540 years before the present) of known provenance and compared them to 100 high-coverage contemporary Aboriginal Australian genomes, also of known provenance. We report substantial ancient population structure showing strong genetic affinities between ancient and contemporary Aboriginal Australian individuals from the same geographic location. Our findings demonstrate the feasibility of successfully identifying the origins of unprovenanced ancestral remains using genomic methods.
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http://dx.doi.org/10.1126/sciadv.aau5064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300400PMC
December 2018

Emergence and Spread of Basal Lineages of Yersinia pestis during the Neolithic Decline.

Cell 2019 01 6;176(1-2):295-305.e10. Epub 2018 Dec 6.

Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet 208, 2800 Kongens Lyngby, Denmark. Electronic address:

Between 5,000 and 6,000 years ago, many Neolithic societies declined throughout western Eurasia due to a combination of factors that are still largely debated. Here, we report the discovery and genome reconstruction of Yersinia pestis, the etiological agent of plague, in Neolithic farmers in Sweden, pre-dating and basal to all modern and ancient known strains of this pathogen. We investigated the history of this strain by combining phylogenetic and molecular clock analyses of the bacterial genome, detailed archaeological information, and genomic analyses from infected individuals and hundreds of ancient human samples across Eurasia. These analyses revealed that multiple and independent lineages of Y. pestis branched and expanded across Eurasia during the Neolithic decline, spreading most likely through early trade networks rather than massive human migrations. Our results are consistent with the existence of a prehistoric plague pandemic that likely contributed to the decay of Neolithic populations in Europe.
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http://dx.doi.org/10.1016/j.cell.2018.11.005DOI Listing
January 2019

Early human dispersals within the Americas.

Science 2018 12 8;362(6419). Epub 2018 Nov 8.

Canadian Museum of History, Gatineau, Québec K1A 0M8, Canada.

Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are ≥10,000 years old (up to ~18× coverage). All are most closely related to Native Americans, including those from an Ancient Beringian individual and two morphologically distinct "Paleoamericans." We found evidence of rapid dispersal and early diversification that included previously unknown groups as people moved south. This resulted in multiple independent, geographically uneven migrations, including one that provides clues of a Late Pleistocene Australasian genetic signal, as well as a later Mesoamerican-related expansion. These led to complex and dynamic population histories from North to South America.
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http://dx.doi.org/10.1126/science.aav2621DOI Listing
December 2018

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.

Nat Commun 2018 10 17;9(1):4316. Epub 2018 Oct 17.

Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, 2100 Ø, Denmark.

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.
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http://dx.doi.org/10.1038/s41467-018-06618-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193003PMC
October 2018

Author Correction: 137 ancient human genomes from across the Eurasian steppes.

Nature 2018 11;563(7729):E16

Buketov Karaganda State University, Saryarka Archaeological Institute, Karaganda, Kazakhstan.

with In this Article, Angela M. Taravella and Melissa A. Wilson Sayres have been added to the author list (associated with: School of Life Sciences, Center for Evolution and Medicine, The Biodesign Institute, Arizona State University, Tempe, AZ, USA). The author list and Author Information section have been corrected online.
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http://dx.doi.org/10.1038/s41586-018-0488-1DOI Listing
November 2018
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