{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:53:15Z","timestamp":1787003595966,"version":"build-2736575974"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["372\/17"],"award-info":[{"award-number":["372\/17"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006754","name":"Army Research Laboratory","doi-asserted-by":"publisher","award":["LS67993"],"award-info":[{"award-number":["LS67993"]}],"id":[{"id":"10.13039\/100006754","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mitochondrial gene expression is pivotal to cell metabolism. Nevertheless, it is unknown whether it diverges within a given cell type. Here, we analysed single-cell RNA-seq experiments from human pancreatic alpha (N\u2009=\u20093471) and beta cells (N\u2009=\u20091989), as well as mouse beta cells (N\u2009=\u20091094). Cluster analysis revealed two distinct human beta cells populations, which diverged by mitochondrial (mtDNA) and nuclear DNA (nDNA)-encoded oxidative phosphorylation (OXPHOS) gene expression in healthy and diabetic individuals, and in newborn but not in adult mice. Insulin gene expression was elevated in beta cells with higher mtDNA gene expression in humans and in young mice. Such human beta cell populations also diverged in mitochondrial RNA mutational repertoire, and in their selective signature, thus implying the existence of two previously overlooked distinct and conserved beta cell populations. While applying our approach to human alpha cells, two sub-populations of cells were identified which diverged in mtDNA gene expression, yet these cellular populations did not consistently diverge in nDNA OXPHOS genes expression, nor did they correlate with the expression of glucagon, the hallmark of alpha cells. Thus, pancreatic beta cells within an individual are divided into distinct groups with unique metabolic-mitochondrial signature.<\/jats:p>","DOI":"10.1038\/s41598-020-80334-w","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T06:49:18Z","timestamp":1610347758000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mitochondrial gene expression in single cells shape pancreatic beta cells' sub-populations and explain variation in insulin pathway"],"prefix":"10.1038","volume":"11","author":[{"given":"H.","family":"Medini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Mishmar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"80334_CR1","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/S0092-8674(00)81125-3","volume":"92","author":"BB Kahn","year":"1998","unstructured":"Kahn, B. B. Type 2 diabetes: When insulin secretion fails to compensate for insulin resistance. Cell 92, 593\u2013596 (1998).","journal-title":"Cell"},{"key":"80334_CR2","doi-asserted-by":"publisher","first-page":"2540","DOI":"10.1016\/j.bbamcr.2016.03.012","volume":"1863","author":"T Brun","year":"2016","unstructured":"Brun, T. & Maechler, P. Beta-cell mitochondrial carriers and the diabetogenic stress response. Biochem. Biophys. Acta. 1863, 2540\u20132549 (2016).","journal-title":"Biochem. Biophys. Acta."},{"issue":"Suppl 1","key":"80334_CR3","doi-asserted-by":"publisher","first-page":"S37","DOI":"10.2337\/diabetes.51.2007.S37","volume":"51","author":"CB Wollheim","year":"2002","unstructured":"Wollheim, C. B. & Maechler, P. Beta-cell mitochondria and insulin secretion: Messenger role of nucleotides and metabolites. Diabetes 51(Suppl 1), S37-42 (2002).","journal-title":"Diabetes"},{"key":"80334_CR4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1146\/annurev-genom-082509-141720","volume":"11","author":"SE Calvo","year":"2010","unstructured":"Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 11, 25\u201344 (2010).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"80334_CR5","doi-asserted-by":"publisher","first-page":"2665","DOI":"10.1093\/gbe\/evu208","volume":"6","author":"M Gershoni","year":"2014","unstructured":"Gershoni, M. et al. Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health. Genome Biol. Evol. 6, 2665\u20132680 (2014).","journal-title":"Genome Biol. Evol."},{"key":"80334_CR6","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.jmb.2010.09.029","volume":"404","author":"M Gershoni","year":"2010","unstructured":"Gershoni, M. et al. Coevolution predicts direct interactions between mtDNA-encoded and nDNA-encoded subunits of oxidative phosphorylation complex i. J. Mol. Biol. 404, 158\u2013171 (2010).","journal-title":"J. Mol. Biol."},{"key":"80334_CR7","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1146\/annurev.biochem.76.081205.150955","volume":"76","author":"DC Wallace","year":"2007","unstructured":"Wallace, D. C. Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu. Rev. Biochem. 76, 781\u2013821 (2007).","journal-title":"Annu. Rev. Biochem."},{"key":"80334_CR8","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/j.tig.2018.05.009","volume":"34","author":"G Barshad","year":"2018","unstructured":"Barshad, G., Marom, S., Cohen, T. & Mishmar, D. Mitochondrial DNA transcription and its regulation: An evolutionary perspective. Trends Genet. 34, 682\u2013692 (2018).","journal-title":"Trends Genet."},{"key":"80334_CR9","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1073\/pnas.68.8.1757","volume":"68","author":"Y Aloni","year":"1971","unstructured":"Aloni, Y. & Attardi, G. Symmetrical in vivo transcription of mitochondrial DNA in HeLa cells. Proc. Natl. Acad. Sci. USA 68, 1757\u20131761 (1971).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"80334_CR10","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1101\/gr.226324.117","volume":"28","author":"G Barshad","year":"2018","unstructured":"Barshad, G., Blumberg, A., Cohen, T. & Mishmar, D. Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes. Genome Res. 28, 952\u2013967 (2018).","journal-title":"Genome Res."},{"key":"80334_CR11","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.mito.2010.09.011","volume":"11","author":"E Fernandez-Vizarra","year":"2011","unstructured":"Fernandez-Vizarra, E., Enriquez, J. A., Perez-Martos, A., Montoya, J. & Fernandez-Silva, P. Tissue-specific differences in mitochondrial activity and biogenesis. Mitochondrion 11, 207\u2013213 (2011).","journal-title":"Mitochondrion"},{"key":"80334_CR12","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.molmet.2017.05.014","volume":"6","author":"H Mulder","year":"2017","unstructured":"Mulder, H. Transcribing beta-cell mitochondria in health and disease. Mol. Metab. 6, 1040\u20131051 (2017).","journal-title":"Mol. Metab."},{"key":"80334_CR13","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/81649","volume":"26","author":"JP Silva","year":"2000","unstructured":"Silva, J. P. et al. Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat. Genet. 26, 336\u2013340 (2000).","journal-title":"Nat. Genet."},{"key":"80334_CR14","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.molmet.2017.05.005","volume":"6","author":"LM Nicholas","year":"2017","unstructured":"Nicholas, L. M. et al. Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic beta-cells. Mol. Metab. 6, 651\u2013663 (2017).","journal-title":"Mol. Metab."},{"key":"80334_CR15","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1007\/s00125-010-1685-0","volume":"53","author":"S Jitrapakdee","year":"2010","unstructured":"Jitrapakdee, S., Wutthisathapornchai, A., Wallace, J. C. & MacDonald, M. J. Regulation of insulin secretion: Role of mitochondrial signalling. Diabetologia 53, 1019\u20131032 (2010).","journal-title":"Diabetologia"},{"key":"80334_CR16","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1007\/s00125-017-4326-z","volume":"60","author":"D Avrahami","year":"2017","unstructured":"Avrahami, D., Klochendler, A., Dor, Y. & Glaser, B. Beta cell heterogeneity: An evolving concept. Diabetologia 60, 1363\u20131369 (2017).","journal-title":"Diabetologia"},{"key":"80334_CR17","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.cmet.2016.06.020","volume":"24","author":"NR Johnston","year":"2016","unstructured":"Johnston, N. R. et al. Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab. 24, 389\u2013401 (2016).","journal-title":"Cell Metab."},{"issue":"Suppl 1","key":"80334_CR18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1111\/dom.13019","volume":"19","author":"D Avrahami","year":"2017","unstructured":"Avrahami, D. et al. beta-Cells are not uniform after all-Novel insights into molecular heterogeneity of insulin-secreting cells. Diabetes Obes. Metab. 19(Suppl 1), 147\u2013152 (2017).","journal-title":"Diabetes Obes. Metab."},{"key":"80334_CR19","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.mce.2011.07.016","volume":"353","author":"A Wiederkehr","year":"2012","unstructured":"Wiederkehr, A. & Wollheim, C. B. Mitochondrial signals drive insulin secretion in the pancreatic beta-cell. Mol. Cell. Endocrinol. 353, 128\u2013137 (2012).","journal-title":"Mol. Cell. Endocrinol."},{"key":"80334_CR20","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1101\/gr.212720.116","volume":"27","author":"N Lawlor","year":"2017","unstructured":"Lawlor, N. et al. Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes. Genome Res. 27, 208\u2013222 (2017).","journal-title":"Genome Res."},{"key":"80334_CR21","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.cmet.2016.08.018","volume":"24","author":"Y Xin","year":"2016","unstructured":"Xin, Y. et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab. 24, 608\u2013615 (2016).","journal-title":"Cell Metab."},{"issue":"346\u2013360","key":"80334_CR22","first-page":"e344","volume":"3","author":"M Baron","year":"2016","unstructured":"Baron, M. et al. A single-cell transcriptomic map of the human and mouse pancreas reveals inter- and intra-cell population structure. Cell Syst. 3(346\u2013360), e344 (2016).","journal-title":"Cell Syst."},{"key":"80334_CR23","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.1007\/s00125-011-2283-5","volume":"54","author":"C Dorrell","year":"2011","unstructured":"Dorrell, C. et al. Transcriptomes of the major human pancreatic cell types. Diabetologia 54, 2832\u20132844 (2011).","journal-title":"Diabetologia"},{"key":"80334_CR24","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1007\/s00125-014-3279-8","volume":"57","author":"P Rorsman","year":"2014","unstructured":"Rorsman, P., Ramracheya, R., Rorsman, N. J. & Zhang, Q. ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: Similar functions but reciprocal effects on secretion. Diabetologia 57, 1749\u20131761 (2014).","journal-title":"Diabetologia"},{"key":"80334_CR25","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411\u2013420 (2018).","journal-title":"Nat. Biotechnol."},{"key":"80334_CR26","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/j.celrep.2014.03.035","volume":"7","author":"AR Wolf","year":"2014","unstructured":"Wolf, A. R. & Mootha, V. K. Functional genomic analysis of human mitochondrial RNA processing. Cell Rep. 7, 918\u2013931 (2014).","journal-title":"Cell Rep."},{"key":"80334_CR27","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.cell.2008.06.016","volume":"134","author":"DJ Pagliarini","year":"2008","unstructured":"Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112\u2013123 (2008).","journal-title":"Cell"},{"key":"80334_CR28","doi-asserted-by":"publisher","unstructured":"Osorio, D. & Cai, J. J. Systematic determination of the mitochondrial proportion in human and mice tissues for single-cell RNA sequencing data quality control. Bioinformatics. https:\/\/doi.org\/10.1093\/bioinformatics\/btaa751 (2020).","DOI":"10.1093\/bioinformatics\/btaa751"},{"key":"80334_CR29","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.tem.2014.03.008","volume":"25","author":"HW Davidson","year":"2014","unstructured":"Davidson, H. W., Wenzlau, J. M. & O\u2019Brien, R. M. Zinc transporter 8 (ZnT8) and beta cell function. Trends Endocrinol. Metab. 25, 415\u2013424 (2014).","journal-title":"Trends Endocrinol. Metab."},{"key":"80334_CR30","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1042\/BJ20121753","volume":"454","author":"M Gutierrez-Aguilar","year":"2013","unstructured":"Gutierrez-Aguilar, M. & Baines, C. P. Physiological and pathological roles of mitochondrial SLC25 carriers. Biochem. J. 454, 371\u2013386 (2013).","journal-title":"Biochem. J."},{"key":"80334_CR31","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.2337\/diabetes.48.9.1873","volume":"48","author":"L Heron","year":"1999","unstructured":"Heron, L., Virsolvy, A., Apiou, F., Le Cam, A. & Bataille, D. Isolation, characterization, and chromosomal localization of the human ENSA gene that encodes alpha-endosulfine, a regulator of beta-cell K(ATP) channels. Diabetes 48, 1873\u20131876 (1999).","journal-title":"Diabetes"},{"key":"80334_CR32","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/j.1753-0407.2010.00076.x","volume":"2","author":"E Pepin","year":"2010","unstructured":"Pepin, E. et al. Short-chain 3-hydroxyacyl-CoA dehydrogenase is a negative regulator of insulin secretion in response to fuel and non-fuel stimuli in INS832\/13 beta-cells. J. Diabetes 2, 157\u2013167 (2010).","journal-title":"J. Diabetes"},{"key":"80334_CR33","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1007\/s00125-012-2531-3","volume":"55","author":"I Stutzer","year":"2012","unstructured":"Stutzer, I., Esterhazy, D. & Stoffel, M. The pancreatic beta cell surface proteome. Diabetologia 55, 1877\u20131889 (2012).","journal-title":"Diabetologia"},{"key":"80334_CR34","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.cmet.2006.07.007","volume":"4","author":"KL Lipson","year":"2006","unstructured":"Lipson, K. L. et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 4, 245\u2013254 (2006).","journal-title":"Cell Metab."},{"key":"80334_CR35","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.2337\/db18-0365","volume":"67","author":"Y Xin","year":"2018","unstructured":"Xin, Y. et al. Pseudotime ordering of single human beta-cells reveals states of insulin production and unfolded protein response. Diabetes 67, 1783\u20131794 (2018).","journal-title":"Diabetes"},{"key":"80334_CR36","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1172\/JCI43871","volume":"121","author":"H She","year":"2011","unstructured":"She, H. et al. Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients. J. Clin. Invest. 121, 930\u2013940 (2011).","journal-title":"J. Clin. Invest."},{"issue":"385\u2013394","key":"80334_CR37","first-page":"e383","volume":"3","author":"MJ Muraro","year":"2016","unstructured":"Muraro, M. J. et al. A Single-cell transcriptome atlas of the human pancreas. Cell Syst. 3(385\u2013394), e383 (2016).","journal-title":"Cell Syst."},{"key":"80334_CR38","doi-asserted-by":"publisher","first-page":"11756","DOI":"10.1038\/ncomms11756","volume":"7","author":"C Dorrell","year":"2016","unstructured":"Dorrell, C. et al. Human islets contain four distinct subtypes of beta cells. Nat. Commun. 7, 11756 (2016).","journal-title":"Nat. Commun."},{"key":"80334_CR39","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1101\/gr.161265.113","volume":"23","author":"D Bar-Yaacov","year":"2013","unstructured":"Bar-Yaacov, D. et al. RNA-DNA differences in human mitochondria restore ancestral form of 16S ribosomal RNA. Genome Res. 23, 1789\u20131796 (2013).","journal-title":"Genome Res."},{"key":"80334_CR40","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nature24456","volume":"551","author":"M Safra","year":"2017","unstructured":"Safra, M. et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251\u2013255 (2017).","journal-title":"Nature"},{"key":"80334_CR41","doi-asserted-by":"publisher","first-page":"e1002557","DOI":"10.1371\/journal.pbio.1002557","volume":"14","author":"D Bar-Yaacov","year":"2016","unstructured":"Bar-Yaacov, D. et al. Mitochondrial 16S rRNA is methylated by tRNA methyltransferase TRMT61B in all vertebrates. PLoS Biol. 14, e1002557 (2016).","journal-title":"PLoS Biol."},{"key":"80334_CR42","doi-asserted-by":"publisher","first-page":"3293","DOI":"10.1073\/pnas.1602306113","volume":"113","author":"Y Xin","year":"2016","unstructured":"Xin, Y. et al. Use of the fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. Proc. Natl. Acad. Sci. USA 113, 3293\u20133298 (2016).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"1160\u20131175","key":"80334_CR43","first-page":"e1111","volume":"25","author":"C Zeng","year":"2017","unstructured":"Zeng, C. et al. Pseudotemporal ordering of single cells reveals metabolic control of postnatal beta cell proliferation. Cell Metab. 25(1160\u20131175), e1111 (2017).","journal-title":"Cell Metab."},{"key":"80334_CR44","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/emboj.2011.392","volume":"31","author":"B Ruzzenente","year":"2012","unstructured":"Ruzzenente, B. et al. LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs. EMBO J. 31, 443\u2013456 (2012).","journal-title":"EMBO J."},{"issue":"Suppl 4","key":"80334_CR45","doi-asserted-by":"publisher","first-page":"S15","DOI":"10.1186\/1471-2105-13-S4-S15","volume":"13","author":"FM Calabrese","year":"2012","unstructured":"Calabrese, F. M., Simone, D. & Attimonelli, M. Primates and mouse NumtS in the UCSC genome browser. BMC Bioinform. 13(Suppl 4), S15 (2012).","journal-title":"BMC Bioinform."},{"issue":"1294\u20131308","key":"80334_CR46","first-page":"e1297","volume":"27","author":"TT Lu","year":"2018","unstructured":"Lu, T. T. et al. The polycomb-dependent epigenome controls beta cell dysfunction, dedifferentiation, and diabetes. Cell Metab. 27(1294\u20131308), e1297 (2018).","journal-title":"Cell Metab."},{"issue":"115\u2013125","key":"80334_CR47","first-page":"e114","volume":"48","author":"L Farack","year":"2019","unstructured":"Farack, L. et al. Transcriptional heterogeneity of beta cells in the intact pancreas. Dev. Cell 48(115\u2013125), e114 (2019).","journal-title":"Dev. Cell"},{"key":"80334_CR48","doi-asserted-by":"publisher","first-page":"18572","DOI":"10.1074\/jbc.272.30.18572","volume":"272","author":"F Schuit","year":"1997","unstructured":"Schuit, F. et al. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. J. Biol. Chem. 272, 18572\u201318579 (1997).","journal-title":"J. Biol. Chem."},{"key":"80334_CR49","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1529\/biophysj.105.069906","volume":"90","author":"I Quesada","year":"2006","unstructured":"Quesada, I., Todorova, M. G. & Soria, B. Different metabolic responses in alpha-, beta-, and delta-cells of the islet of Langerhans monitored by redox confocal microscopy. Biophys. J . 90, 2641\u20132650 (2006).","journal-title":"Biophys. J ."},{"key":"80334_CR50","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.cmet.2016.03.005","volume":"23","author":"E Yoshihara","year":"2016","unstructured":"Yoshihara, E. et al. ERRgamma is required for the metabolic maturation of therapeutically functional glucose-responsive beta cells. Cell Metab. 23, 622\u2013634 (2016).","journal-title":"Cell Metab."},{"key":"80334_CR51","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1073\/pnas.0510790103","volume":"103","author":"O Cabrera","year":"2006","unstructured":"Cabrera, O. et al. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. USA 103, 2334\u20132339 (2006).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"80334_CR52","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s00125-009-1562-x","volume":"53","author":"M Cnop","year":"2010","unstructured":"Cnop, M. et al. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 53, 321\u2013330 (2010).","journal-title":"Diabetologia"},{"key":"80334_CR53","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/s42255-019-0075-2","volume":"1","author":"V Salem","year":"2019","unstructured":"Salem, V. et al. Leader beta-cells coordinate Ca(2+) dynamics across pancreatic islets in vivo. Nat. Metab. 1, 615\u2013629 (2019).","journal-title":"Nat. Metab."},{"key":"80334_CR54","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics 29, 15\u201321 (2013).","journal-title":"Bioinformatics"},{"key":"80334_CR55","doi-asserted-by":"publisher","first-page":"e1006407","DOI":"10.1371\/journal.pgen.1006407","volume":"12","author":"T Cohen","year":"2016","unstructured":"Cohen, T., Levin, L. & Mishmar, D. Ancient out-of-africa mitochondrial DNA variants associate with distinct mitochondrial gene expression patterns. PLoS Genet. 12, e1006407 (2016).","journal-title":"PLoS Genet."},{"key":"80334_CR56","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1002\/humu.10304","volume":"23","author":"D Mishmar","year":"2004","unstructured":"Mishmar, D., Ruiz-Pesini, E., Brandon, M. & Wallace, D. C. Mitochondrial DNA-like sequences in the nucleus (NUMTs): Insights into our African origins and the mechanism of foreign DNA integration. Hum. Mutat. 23, 125\u2013133 (2004).","journal-title":"Hum. Mutat."},{"key":"80334_CR57","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows\u2013Wheeler transform. Bioinformatics 25, 1754\u20131760 (2009).","journal-title":"Bioinformatics"},{"key":"80334_CR58","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2014A Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169 (2015).","journal-title":"Bioinformatics"},{"key":"80334_CR59","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1101\/gr.209601.116","volume":"27","author":"T Smith","year":"2017","unstructured":"Smith, T., Heger, A. & Sudbery, I. UMI-tools: Modeling sequencing errors in unique molecular identifiers to improve quantification accuracy. Genome Res. 27, 491\u2013499 (2017).","journal-title":"Genome Res."},{"key":"80334_CR60","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13059-016-0888-1","volume":"17","author":"T Ilicic","year":"2016","unstructured":"Ilicic, T. et al. Classification of low quality cells from single-cell RNA-seq data. Genome Biol. 17, 29 (2016).","journal-title":"Genome Biol."},{"key":"80334_CR61","doi-asserted-by":"publisher","first-page":"6427","DOI":"10.1128\/MCB.25.15.6427-6435.2005","volume":"25","author":"S Slomovic","year":"2005","unstructured":"Slomovic, S., Laufer, D., Geiger, D. & Schuster, G. Polyadenylation and degradation of human mitochondrial RNA: The prokaryotic past leaves its mark. Mol. Cell. Biol. 25, 6427\u20136435 (2005).","journal-title":"Mol. Cell. Biol."},{"key":"80334_CR62","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1093\/bioinformatics\/bts714","volume":"29","author":"A McDavid","year":"2013","unstructured":"McDavid, A. et al. Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments. Bioinformatics 29, 461\u2013467 (2013).","journal-title":"Bioinformatics"},{"key":"80334_CR63","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1101\/gr.3715005","volume":"15","author":"A Siepel","year":"2005","unstructured":"Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034\u20131050 (2005).","journal-title":"Genome Res."},{"key":"80334_CR64","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1101\/gr.097857.109","volume":"20","author":"KS Pollard","year":"2010","unstructured":"Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110\u2013121 (2010).","journal-title":"Genome Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80334-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80334-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80334-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T20:43:42Z","timestamp":1670013822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80334-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["80334"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-80334-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,11]]},"assertion":[{"value":"29 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"466"}}