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      Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity

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          Abstract

          The immune system comprises a complex network of specialized cells that protects against infection, eliminates cancerous cells, and regulates tissue repair, thus serving a critical role in homeostasis, health span, and life span. The subterranean-dwelling naked mole-rat (NM-R; Heterocephalus glaber) exhibits prolonged life span relative to its body size, is unusually cancer resistant, and manifests few physiological or molecular changes with advancing age. We therefore hypothesized that the immune system of NM-Rs evolved unique features that confer enhanced cancer immunosurveillance and prevent the age-associated decline in homeostasis. Using single-cell RNA-sequencing (scRNA-seq) we mapped the immune system of the NM-R and compared it to that of the short-lived, cancer-prone mouse. In contrast to the mouse, we find that the NM-R immune system is characterized by a high myeloid-to-lymphoid cell ratio that includes a novel, lipopolysaccharide (LPS)-responsive, granulocyte cell subset. Surprisingly, we also find that NM-Rs lack canonical natural killer (NK) cells. Our comparative genomics analyses support this finding, showing that the NM-R genome lacks an expanded gene family that controls NK cell function in several other species. Furthermore, we reconstructed the evolutionary history that likely led to this genomic state. The NM-R thus challenges our current understanding of mammalian immunity, favoring an atypical, myeloid-biased mode of innate immunosurveillance, which may contribute to its remarkable health span.

          Abstract

          A single-cell transcriptomic study of the immune system of the cancer-resistant naked mole-rat reveals that this animal lacks natural killer (NK) cells, thought to be crucial for cancer resistance. In contrast to dramatically expanded NK cell receptor and MHC-I gene families in human and mouse genomes, the naked mole-rat genome lacks the expansion of NK cell receptor genes and only has two MHC-I genes.

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            STAR: ultrafast universal RNA-seq aligner.

            Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
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              Basic local alignment search tool.

              A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score. Recent mathematical results on the stochastic properties of MSP scores allow an analysis of the performance of this method as well as the statistical significance of alignments it generates. The basic algorithm is simple and robust; it can be implemented in a number of ways and applied in a variety of contexts including straightforward DNA and protein sequence database searches, motif searches, gene identification searches, and in the analysis of multiple regions of similarity in long DNA sequences. In addition to its flexibility and tractability to mathematical analysis, BLAST is an order of magnitude faster than existing sequence comparison tools of comparable sensitivity.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Resources
                Role: Methodology
                Role: Formal analysis
                Role: Investigation
                Role: InvestigationRole: Resources
                Role: InvestigationRole: Resources
                Role: Resources
                Role: Resources
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                21 November 2019
                November 2019
                21 November 2019
                : 17
                : 11
                : e3000528
                Affiliations
                [1 ] Calico Life Sciences LLC, South San Francisco, California, United States of America
                [2 ] Comparative Pathology Laboratory, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
                National Cancer Institute, UNITED STATES
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: NDR, ATI, NB, NLF, KMW, MS, BM-M, MR, VJ, RB, HGH, PJ, and DF were employees of Calico Life Sciences at the time that the study was undertaken.

                Author information
                http://orcid.org/0000-0003-1488-7194
                http://orcid.org/0000-0002-0779-2843
                http://orcid.org/0000-0001-9685-0998
                http://orcid.org/0000-0003-3285-8311
                Article
                PBIOLOGY-D-19-02468
                10.1371/journal.pbio.3000528
                6894886
                31751331
                c1b2268b-700a-4d2c-9dc7-757d8772d914
                © 2019 Hilton et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 August 2019
                : 7 November 2019
                Page count
                Figures: 3, Tables: 0, Pages: 32
                Funding
                Funded by: Calico LLC
                Award ID: 1111
                Award Recipient :
                All authors of this manuscript, HGH, NDR, PJ, ATI, NB, NLF, KMW, MS, DF, BM-M, MR, DMI, VJ, and RB, as well as this work itself, have been entirely funded by Calico Life Sciences. The funders approved performing the study and its publication.
                Categories
                Short Reports
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Spleen
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Spleen
                Biology and life sciences
                Cell biology
                Cellular types
                Animal cells
                Blood cells
                White blood cells
                NK cells
                Biology and life sciences
                Cell biology
                Cellular types
                Animal cells
                Immune cells
                White blood cells
                NK cells
                Biology and life sciences
                Immunology
                Immune cells
                White blood cells
                NK cells
                Medicine and health sciences
                Immunology
                Immune cells
                White blood cells
                NK cells
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Marker Genes
                Research and Analysis Methods
                Molecular Biology Techniques
                Marker Genes
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Naked Mole Rats
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Rodents
                Naked Mole Rats
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                Biology and Life Sciences
                Genetics
                Genomics
                Animal Genomics
                Mammalian Genomics
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Neutrophils
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Neutrophils
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Neutrophils
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Neutrophils
                Biology and Life Sciences
                Genetics
                Gene Expression
                Custom metadata
                vor-update-to-uncorrected-proof
                2019-12-05
                Raw and processed data can be downloaded from GEO under accession number GSE132642. In addition, processed data are also provided as Supporting Information.

                Life sciences
                Life sciences

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