ABSTRACT
Mouse lemurs are the smallest, fastest reproducing, and among the most abundant primates, and an emerging model organism for primate biology, behavior, health and conservation. Although much has been learned about their physiology and their Madagascar ecology and phylogeny, little is known about their cellular and molecular biology. Here we used droplet- and plate-based single cell RNA-sequencing to profile 226,000 cells from 27 mouse lemur organs and tissues opportunistically procured from four donors clinically and histologically characterized. Using computational cell clustering, integration, and expert cell annotation, we defined and biologically organized over 750 mouse lemur molecular cell types and their full gene expression profiles. These include cognates of most classical human cell types, including stem and progenitor cells, and the developmental programs for spermatogenesis, hematopoiesis, and other adult tissues. We also described dozens of previously unidentified or sparsely characterized cell types and subtypes. We globally compared cell type expression profiles to define the molecular relationships of cell types across the body, and explored primate cell type evolution by comparing mouse lemur cell profiles to those of the homologous cells in human and mouse. This revealed cell type specific patterns of primate cell specialization even within a single tissue compartment, as well as many cell types for which lemur provides a better human model than mouse. The atlas provides a cellular and molecular foundation for studying this primate model organism, and establishes a general approach for other emerging model organisms.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵‡ Co-first authors
Leadership and coordination
Trainees: Camille Ezran1, 2, Shixuan Liu1, 2, 3, Stephen Chang1, 2, 4
Principal investigators: Mark A. Krasnow1, 2, Stephen R. Quake7, 8, 23, Angela Wu21, 22, Norma Neff7, Jim Karkanias7, Angela Oliveira Pisco7
Donor recruitment and animal husbandry
Megan A. Albertelli20, Caitlin J. Karanewsky1, 2, Jozeph L. Pendleton1, 2, Fabienne Aujard16, Martine Perret16, Liza Shapiro24, Andriamahery Razafindrakoto25, Hajanirina Noëline Ravelonjanahary25, Patricia Wright26, Anne D. Yoder27, Cathy V. Williams28, Robert Schopler28, Ute Radespiel29, Jean-Michel Verdier30, Corinne Lautier30, E. Christopher Kirk24, Rebecca Lewis24
Necropsy, sample collection, biobanking, histology, and pathology
Kerriann M. Casey20, Megan A. Albertelli20, Caitlin J. Karanewsky1, 2, Jozeph L. Pendleton1, 2, Camille Ezran1, 2, Shixuan Liu1, 2, 3, Kyle J. Travaglini1, 2, Astrid Gillich1, 2, Zicheng Zhao2, 20, Stephen Chang1, 2, 4, Elias Godoy20, Jérémy Terrien16, Jacques Epelbaum16, 31, Dita Gratzinger32, Katherine Lucot32, Tom Montine32
Tissue processing, annotation, and analysis [Principal investigators]
Aorta: Jessica D’Addabbo33, 34, Isaac Bakerman4, [Patricia Nguyen12, 33, 34]
Bladder: Aaron Kershner1, 35, Karim Mrouj36, [Philip Beachy3, 13, 36, 37]
Blood: Rahul Sinha14, Camille Ezran1, 2, Yue Zhang2, 15, Shixuan Liu1, 2, 3, Caitlin J. Karanewsky1, 2, [Irving L. Weissman14, Mark A. Krasnow1, 2]
Bone (limb, spine): Thomas Ambrosi36, Malachia Hoover36, Alina Alam36, [Charles Chan36]
Bone marrow: Rahul Sinha14, SoRi Jang1, 2, Camille Ezran1, 2, [Irving L. Weissman14, Mark A. Krasnow1, 2]
Brain (cortex, brainstem, cerebellum): Avin Veerakumar1, 2, 8, 38, Peng Li1, 2, Andrea R. Yung1, 2, Connor V. Duffy2, 18, Song-Lin Ding39, [Ed S. Lein39, Silvana Konermann1,2, Liqun Luo2, 15, Trygve E. Bakken39, Justus Kebschull40, Rebecca D. Hodge39, Mark A. Krasnow1, 2]
Colon/Small intestine: Taichi Isobe41, [Michael F. Clarke36]
Diaphragm/Limb muscle: Antoine de Morree9, 10, Biter Bilen9, Jean Farup9, 10, Andoni Urtasun9, Jengmin Kang9, [Thomas A. Rando9]
Eye: Ming Chen18, Bao Xiang42, Varun Ramanan Subramaniam42, Shravani Mukherjee42, Aditi Swarup42, Lily Kim18, Bronwyn Scott42, Ahmad Al-Moujahed42, [Albert Y. Wu42, Douglas Vollrath18, Lubert Stryer17]
Fat: Nicholas Schaum9, Jingsi Ming5, 6, Shixuan Liu1, 2, 3, Amanda L. Wiggenhorn32, 43, [Tony Wyss-Coray9, 44, Jonathan Z. Long32, 45, Angela Wu21, 22]
Ganglion (vagus nerve): Yin Liu1, 2, [Mark A. Krasnow1, 2]
Heart: Stephen Chang1, 2, 4, [Mark A. Krasnow1, 2]
Hypothalamus & Pituitary: Andrea R. Yung1, 2, Shixuan Liu1, 2, 3, [Mark A. Krasnow1, 2]
Kidney: Shixuan Liu1, 2, 3, Ahmad Nabhan1, 2, Lolita Penland7, Yue Zhang2, 15, Andrea R. Yung1,2, [Gabriel Loeb46, Mark A. Krasnow1, 2]
Liver: Shengda Lin47, Shixuan Liu1, 2, 3, Honor Paine48, Deviana Burhan48, Aris Taychameekiatchai48, [Steven Artandi1, 11, 12, Bruce Wang48]
Lung: Kyle J. Travaglini1, 2, Ahmad Nabhan1, 2, F. Hernán Espinoza1, 2, Astrid Gillich1, 2, [Christin Kuo49, Ross Metzger49, 50, Mark A. Krasnow1, 2]
Lymph node: SoRi Jang1, 2, Lolita Penland7, [Norma Neff7, Mark A. Krasnow1, 2]
Mammary gland: Zhen Qi36, [Michael F. Clarke36]
Microbiome: Rebecca Culver18, [Kerwyn C. Huang7, 8, 51]
Pancreas: Patrick Neuhöfer1, 11, 12, Charles A. Chang13, 52, Yan Hang13, 52, [Seung K. Kim12, 13, 52,53, Steven Artandi1, 11, 12]
Prostate: Hannah Weinstein54, 55, 56, Paul Allegakoen54, [Franklin W. Huang54]
Salivary gland: Sivakamasundari V36, [Philip Beachy3, 13, 36, 37]
Skin: Song Eun Lee9, 44, [Tony Wyss-Coray9, 44]
Spleen: Lolita Penland7, Hannah K. Frank32, Dita Gratzinger32, [Norma Neff7, Scott D. Boyd32]
Testes: Kazuteru Hasegawa1, 11, 12, Hosu Sin13, Jingsi Ming5, 6, [Steven Artandi1, 11, 12, Margaret Fuller13, 18, Angela Wu21, 22]
Thymus: Isaac Bakerman4, Jessica D’Addabbo33, 34, [Patricia Nguyen12, 33, 34]
Tongue: Wan-Jin Lu36, Ankit Baghel15, [Philip Beachy3, 13, 36, 37]
Trachea/Thyroid/Parathyroid: William Kong36, [Philip Beachy3, 13, 36, 37]
Uterus/Abdominal mass: Lolita Penland7, [Norma Neff7]
Library processing, sorting, and sequencing
Stephen Chang1, 2, 4, Lolita Penland7, Carly Israel7, Rene Sit7, Jennifer Okamoto7, Yue Zhang2, 15, Rahul Sinha14, Shixuan Liu1, 2, 3, Camille Ezran1, 2, Kyle J. Travaglini1, 2, Antoine de Morree9, 10, Ahmad Nabhan1, 2, Youcef Ouadah1, 58, Jalal Baruni1, 2, 15, 59, Robert C. Jones8, Norma Neff7, Maurizio Morri7, Spyros Darmanis7, Sheela Crasta7, Jia Yan7, Aditi Agrawal7, Shelly Huynh7, Brian Yu7, James Webber7
Global data analysis [Principal investigators]
General analysis: Camille Ezran1, 2, Shixuan Liu1, 2, 3, [Mark A. Krasnow1, 2]
Sequence alignment: Stephen Chang1, 2, 4, Kyle J. Travaglini1, 2, Rahul Sinha14, Rene Sit7, [Mark A. Krasnow1, 2, Irving L. Weissman14, Stephen R. Quake7, 8, 23]
FIRM integration: Jingsi Ming5, 6, Jinxurong Yang21, [Angela Wu21, 22, Can Yang6]
Molecular trajectory: Shixuan Liu1, 2, 3, Camille Ezran1, 2, Weilun Tan7, [Mark A. Krasnow1, 2]
Global cell type comparison: Shixuan Liu1, 2, 3, [Mark A. Krasnow1, 2]
Cross-species comparison: Olga Botvinnik7, Alexander Tarashansky7, 8, Shixuan Liu1, 2, 3, Camille Ezran1, 2, Kyle J. Travaglini1, 2, Antoine de Morree9, 10, Jia Zhao6, Gefei Wang6, [Jim Karkanias7, Bo Wang8, Stephen R. Quake7, 8, 23, Mark A. Krasnow1, 2, Thomas A. Rando9, Angela Wu21, 22, Can Yang6]
Spermatogenesis: Jingsi Ming5, 6, Hosu Sin13, Kazuteru Hasegawa1, 11, 12, Camille Ezran1, 2, [Angela Wu21, 22, Margaret Fuller13, 18, Steven Artandi1, 11, 12, Can Yang6, Mark A. Krasnow1,2]
uTAR: Michael F.Z. Wang19, 60, [Iwijn De Vlaminck19]
SICILIAN: Roozbeh Dehghannasiri1, 61, Julia Olivieri62, [Julia Salzman1, 61]
SAMap: Alexander Tarashansky7, 8, [Bo Wang8]
Major histocompatibility locus: Lisbeth A. Guethlein51, 63, Camille Ezran1, 2, [Peter Parham51, 63, Mark A. Krasnow1, 2]
B cell receptor locus: Hannah K. Frank32, 57, Camille Ezran1, 2, [Scott D. Boyd32, Mark A. Krasnow1, 2]
Cross-tissue neutrophil trajectory: Camille Ezran1, 2, Shixuan Liu1, 2, 3, [Mark A. Krasnow1, 2]
Cross-tissue monocyte and macrophage comparison: Qiuyu Jing21, Camille Ezran1, 2, Shixuan Liu1, 2, 3, [Angela Wu21, 22, Mark A. Krasnow1, 2]
Chemokine expression: Camille Ezran1, 2, [Mark A. Krasnow1, 2]
Metastatic tumor: Jane Antony36, Camille Ezran1, 2, [Michael F. Clarke36, Mark A. Krasnow1, 2]
Endothelium: Camille Ezran1, 2, Astrid Gillich1, 2, Geoff Stanley8, [Ross Metzger49, 50, Mark A. Krasnow1, 2, Stephen R. Quake7, 8, 23]
Adipocytes: Jinxurong Yang21, Jingsi Ming5, 6, Camille Ezran1, 2, Shixuan Liu1, 2, 3, [Jonathan Z. Long32, 45, Angela Wu21, 22, Mark A. Krasnow1, 2, Can Yang6]
Primate-specific genes: Winston Koh64, Camille Ezran1, 2, [Mark A. Krasnow1, 2]
Global hormone signaling: Shixuan Liu1, 2, 3, [James E. Ferrell Jr.1, 3, Mark A. Krasnow1, 2]
OnClass: [Sheng Wang65]
Data portal/Online histology atlas: Zicheng Zhao2, 20, Snigdha Agarwal7, Kyle Awayan7, Aaron McGeever7, Venkata Naga Pranathi Vemuri7, Saba Nafees7, [Stephen R. Quake7, 8, 23, Angela Oliveira Pisco7]
Principal investigators (A-Z)
Megan A. Albertelli20, Steven Artandi1, 11, 12, Fabienne Aujard16, Trygve E. Bakken39, Philip Beachy3, 13, 36, 37, Scott D. Boyd32, Kerriann M. Casey20, Charles Chan36, Michael F. Clarke36, Jacques Epelbaum16, 31, James E. Ferrell Jr.1, 3, Margaret Fuller13, 18, Dita Gratzinger32, Franklin W. Huang54, Kerwyn C. Huang7, 8, 51, Jim Karkanias7, Justus Kebschull40, Seung K. Kim12, 13, 52, 53, Silvana Konermann1,2, Mark A. Krasnow1, 2, Christin Kuo49, Ed S. Lein39, Shengda Lin47, Gabriel Loeb46, Jonathan Z. Long32, 45, Liqun Luo2, 15, Ross Metzger49, 50, Jingsi Ming5, 6, Tom Montine32, Norma Neff7, Patricia Nguyen12, 33, 34, Peter Parham51, 63, Martine Perret16, Angela Oliveira Pisco7, Stephen R. Quake7, 8, 23, Thomas A. Rando9, Ute Radespiel29, Julia Salzman1, 61, Liza Shapiro24, Lubert Stryer17, Jérémy Terrien16, Jean-Michel Verdier30, Iwijn De Vlaminck19, Douglas Vollrath18, Bo Wang8, Bruce Wang48, Sheng Wang65, Irving L. Weissman14, Patricia Wright26, Tony Wyss-Coray9, 44, Albert Y. Wu42, Angela Wu21, 22, Can Yang6, Anne D. Yoder27
Writing
Camille Ezran1, 2, Shixuan Liu1, 2, 3, Stephen Chang1, 2, 4, Jingsi Ming5, 6, Antoine de Morree9, 10, Lubert Stryer17, Angela Wu21, 22, Stephen R. Quake7, 8, 23, Mark A. Krasnow1, 2
24. Department of Anthropology, University of Texas at Austin, Austin, TX, USA.
25. Department of Animal Biology, Faculty of Science, University of Antananarivo, Antananarivo 101, BP 566, Madagascar.
26. Department of Anthropology, Stony Brook University, NY, USA.
27. Department of Biology, University Program in Genetics & Genomics, Duke University, Durham, NC, USA.
28. Duke Lemur Center, Durham, NC, USA.
29. Institute of Zoology, University of Veterinary Medicine Hannover, Germany.
30. MMDN, University of Montpellier, EPHE-PSL, INSERM, Montpellier, France.
31. Unité Mixte de Recherche en Santé 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne, Paris, France
32. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
33. Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
34. Stanford Cardiovascular Institute, Stanford, CA, USA.
35. Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
36. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
37. Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
38. Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
39. Human Cell Types Department, Allen Institute for Brain Science, Seattle, WA, USA.
40. Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.
41. Department of Oncology and Social Medicine, Kyushu University, Japan.
42. Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA.
43. Department of Chemistry, Stanford University, Stanford, CA, USA.
44. Wu Tsai Neurosciences Institute, Stanford, CA, USA.
45. Stanford ChEM-H, Stanford, CA, USA.
46. Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
47. Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
48. Department of Medicine and Liver Center, University of California San Francisco, San Francisco, CA, USA.
49. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
50. Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
51. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
52. Stanford Diabetes Research Center, Stanford, CA, USA.
53. JDRF Center of Excellence, Stanford, CA, USA.
54. Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
55. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
56. Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA.
57. Department of Ecology and Evolutionary Biology, Tulane University, New Orleans, LA, USA.
58. Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA, USA.
59. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
60. Department of Computational Biology, Cornell University, Ithaca, NY, USA.
61. Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
62. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
63. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
64. Institute of Molecular and Cell Biology, Agency of Science Technology and Research, Singapore.
65. Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA, USA.
