Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect

JI Malowany, 2012, Pathology of sickle cell disease, Semin Diagn Pathol, 29, 49, 10.1053/j.semdp.2011.07.005

A Ferreira, 2011, Sickle hemoglobin confers tolerance to plasmodium infection, Cell, 145, 398, 10.1016/j.cell.2011.03.049

C Grimm, 2017, From mucolipidosis type IV to Ebola: TRPML and two-pore channels at the crossroads of endo-lysosomal trafficking and disease, Cell Calcium, 67, 148, 10.1016/j.ceca.2017.04.003

C Cang, 2013, MTOR regulates lysosomal ATP-sensitive two-pore Na+channels to adapt to metabolic state, Cell, 152, 778, 10.1016/j.cell.2013.01.023

W Sun, 2018, TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells, Exp Cell Res, 370, 478, 10.1016/j.yexcr.2018.07.013

X Wang, 2012, TPC Proteins Are Phosphoinositide-activated Sodium-selective Ion Channels in Endosomes and Lysosomes, Cell, 151, 372, 10.1016/j.cell.2012.08.036

Y Sakurai, 2015, Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment, Science, 347, 995, 10.1126/science.1258758

GS Gunaratne, 2018, NAADP-dependent Ca2+ signaling regulates Middle East Respiratory Syndrome-Coronavirus pseudovirus translocation through the endolysosomal system, Cell Calcium, 75, 30, 10.1016/j.ceca.2018.08.003

X Ou, Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV., Nat Commun. 2020, 11, 1620

C Grimm, 2014, High susceptibility to fatty liver disease in two-pore channel 2-deficient mice., Nat Comms., 5, 4699, 10.1038/ncomms5699

V. Lear P, 2015, Absence of intracellular ion channels TPC1 and TPC2 leads to mature-onset obesity in male mice, due to impaired lipid availability for thermogenesis in brown adipose tissue, Endocrinology, 156, 975, 10.1210/en.2014-1766

A Favia, 2014, VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca2+ signaling, Proc Natl Acad Sci, 111, 4706, 10.1073/pnas.1406029111

J Parrington, 2015, Calcium signals regulated by NAADP and two-pore channels -their role in development, differentiation and cancer, Int J Dev Biol, 59, 327, 10.1387/ijdb.150211jp

ONP Nguyen, 2017, Two-Pore Channel Function Is Crucial for the Migration of Invasive Cancer Cells, Cancer Res, 77, 1427, 10.1158/0008-5472.CAN-16-0852

C Grimm, 2018, Endolysosomal cation channels and cancer—a link with great potential., Pharmaceuticals, 11, 1, 10.3390/ph11010004

AF Alharbi, 2019, Endolysosomal Ca2+ Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis., Front Cell Dev Biol, 7, 1, 10.3389/fcell.2019.00302

AL Ambrosio, 2015, TPC2 mediates new mechanisms of platelet dense granule membrane dynamics through regulation of Ca2+ release, Mol Biol Cell, 26, 3263, 10.1091/mbc.e15-01-0058

AL Ambrosio, 2016, TPC2 controls pigmentation by regulating melanosome pH and size, Proc Natl Acad Sci U S A, 113, 5622, 10.1073/pnas.1600108113

NW Bellono, 2016, A melanosomal two-pore sodium channel regulates pigmentation., Sci Rep, 6, 1

LC Davis, 2012, NAADP Activates two-pore channels on t cell cytolytic granules to stimulate exocytosis and killing, Curr Biol, 22, 2331, 10.1016/j.cub.2012.10.035

Y-K Chao, 2017, TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms, Proc Natl Acad Sci, 114, E8595, 10.1073/pnas.1705739114

C Grimm, 2017, From mucolipidosis type IV to Ebola: TRPML and two-pore channels at the crossroads of endo-lysosomal trafficking and disease, Cell Calcium, 67, 148, 10.1016/j.ceca.2017.04.003

A Arredouani, 2015, Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic beta-Cells., J Biol Chem, 290, 21376, 10.1074/jbc.M115.671248

MC Cane, 2016, Cell Calcium The two pore channel TPC2 is dispensable in pancreatic ␤ -cells for normal Ca 2 + dynamics and insulin secretion, Cell Calcium, 59, 32, 10.1016/j.ceca.2015.12.004

A Hamilton, 2018, Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells, Diabetes, 67, 1128, 10.2337/db17-1102

S Mallick, 2016, The Simons Genome Diversity Project: 300 genomes from 142 diverse populations, Nature, 538, 201, 10.1038/nature18964

A Auton, 2015, A global reference for human genetic variation, Nature, 526, 68, 10.1038/nature15393

KJ Karczewski, Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of- function intolerance across human protein-coding genes., bioRxiv

M Sun, 2000, Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel, Hum Mol Genet, 9, 2471, 10.1093/hmg/9.17.2471

C-C Chen, 2014, A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV., Nat Commun, 5, 4681, 10.1038/ncomms5681

J She, 2019, Structural mechanisms of phospholipid activation of the human TPC2 channel., Elife, 8, e45222, 10.7554/eLife.45222

A Buniello, 2019, The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019, Nucleic Acids Res, 47, D1005, 10.1093/nar/gky1120

AMP-T2D Consortium. Type 2 Diabetes Knowledge Portal. [cited 18 Mar 2020]. Available: http://www.type2diabetesgenetics.org/

P Sulem, 2008, Two newly identified genetic determinants of pigmentation in Europeans, Nat Genet, 40, 835, 10.1038/ng.160

JA Morris, 2019, An atlas of genetic influences on osteoporosis in humans and mice, Nat Genet, 51, 258, 10.1038/s41588-018-0302-x

A Mahajan, 2018, Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes, Nat Genet, 50, 559, 10.1038/s41588-018-0084-1

T Notomi, 2017, Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions, J Biol Chem, 292, 20998, 10.1074/jbc.M117.780072

X Zhang, 2019, Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ channels., Elife, 8, e51423, 10.7554/eLife.51423

S Gerndt, 2020, Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function., Elife., 9, e54712, 10.7554/eLife.54712

MR Nelson, 2015, The support of human genetic evidence for approved drug indications, Nat Genet, 47

J Flannick, 2014, Loss-of-function mutations in SLC30A8 protect against type 2 diabetes, Nat Publ Gr, 46, 357

J Flannick, 2019, Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls, Nature, 570, 71, 10.1038/s41586-019-1231-2

K Prüfer, 2017, A high-coverage Neandertal genome from Vindija Cave in Croatia, Science, 358, 655, 10.1126/science.aao1887

S. Pääbo, A high-quality Neandertal genome sequence

F Broushaki, 2016, Early Neolithic genomes from the eastern Fertile Crescent, Science, 353, 499, 10.1126/science.aaf7943

C Gamba, 2014, Genome flux and stasis in a five millennium transect of European prehistory, Nat Commun, 5, 1, 10.1038/ncomms6257

ME Allentoft, 2015, Population genomics of Bronze Age Eurasia, Nature, 522, 167, 10.1038/nature14507

CM Schlebusch, 2017, Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago, Science, 358, 652, 10.1126/science.aao6266

JV Moreno-Mayar, 2018, Terminal Pleistocene Alaskan genome reveals first founding population of Native Americans, Nature, 553, 203, 10.1038/nature25173

GM Kılınç, 2016, The Demographic Development of the First Farmers in Anatolia, Curr Biol, 26, 2659, 10.1016/j.cub.2016.07.057

M Rasmussen, 2014, The genome of a Late Pleistocene human from a Clovis burial site in western Montana, Nature, 506, 225, 10.1038/nature13025

Q Fu, 2014, Genome sequence of a 45,000-year-old modern human from western Siberia, Nature, 514, 445, 10.1038/nature13810

A-S Malaspinas, 2014, Two ancient human genomes reveal Polynesian ancestry among the indigenous Botocudos of Brazil, Curr Biol, 24, R1035, 10.1016/j.cub.2014.09.078

ER Jones, 2015, Upper Palaeolithic genomes reveal deep roots of modern Eurasians., Nat Commun., 6, 1, 10.1038/ncomms9912

Pääbo S, Mafessoni F. High coverage Chagyrskaya Neandertal.

M Meyer, 2012, A High-Coverage Genome Sequence from an Archaic Denisovan Individual, Science, 338, 222, 10.1126/science.1224344

M Rasmussen, 2011, An aboriginal Australian genome reveals separate human dispersals into Asia, Science, 334, 94, 10.1126/science.1211177

M Gallego Llorente, 2015, Ancient Ethiopian genome reveals extensive Eurasian admixture in Eastern Africa, Science, 350, 821

M Sikora, 2017, Ancient genomes show social and reproductive behavior of early Upper Paleolithic foragers, Science, 662, 659, 10.1126/science.aao1807

I Lazaridis, 2014, Ancient human genomes suggest three ancestral populations for present-day Europeans, Nature, 513, 409, 10.1038/nature13673

I Olalde, 2014, Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European, Nature, 507, 225, 10.1038/nature12960

Z Hofmanová, 2016, Early farmers from across Europe directly descended from Neolithic Aegeans, Proc Natl Acad Sci, 113, 6886, 10.1073/pnas.1523951113

C-C Chen, 2017, Patch-clamp technique to characterize ion channels in enlarged individual endolysosomes., Nat Protoc, 12, 1639, 10.1038/nprot.2017.036

S. Chinn, 2000, A simple method for converting an odds ratio to effect size for use in meta-analysis., Stat Med, 19, 3127, 10.1002/1097-0258(20001130)19:22<3127::AID-SIM784>3.0.CO;2-M

S Kumar, 2018, MEGA X: Molecular evolutionary genetics analysis across computing platforms, Mol Biol Evol, 35, 1547, 10.1093/molbev/msy096