#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice


Autoři: Rena M. Schweizer aff001;  Jonathan P. Velotta aff001;  Catherine M. Ivy aff002;  Matthew R. Jones aff001;  Sarah M. Muir aff002;  Gideon S. Bradburd aff003;  Jay F. Storz aff004;  Graham R. Scott aff002;  Zachary A. Cheviron aff001
Působiště autorů: Division of Biological Sciences, University of Montana, Missoula, Montana, United States of America aff001;  Department of Biology, McMaster University, Hamilton, ON, Canada aff002;  Ecology, Evolutionary Biology, and Behavior Graduate Group, Department of Integrative Biology, Michigan State University, East Lansing, Michigan, United States of America aff003;  School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, United States of America aff004
Vyšlo v časopise: Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008420
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008420

Souhrn

Evolutionary adaptation to extreme environments often requires coordinated changes in multiple intersecting physiological pathways, but how such multi-trait adaptation occurs remains unresolved. Transcription factors, which regulate the expression of many genes and can simultaneously alter multiple phenotypes, may be common targets of selection if the benefits of induced changes outweigh the costs of negative pleiotropic effects. We combined complimentary population genetic analyses and physiological experiments in North American deer mice (Peromyscus maniculatus) to examine links between genetic variation in transcription factors that coordinate physiological responses to hypoxia (hypoxia-inducible factors, HIFs) and multiple physiological traits that potentially contribute to high-altitude adaptation. First, we sequenced the exomes of 100 mice sampled from different elevations and discovered that several SNPs in the gene Epas1, which encodes the oxygen sensitive subunit of HIF-2α, exhibited extreme allele frequency differences between highland and lowland populations. Broader geographic sampling confirmed that Epas1 genotype varied predictably with altitude throughout the western US. We then discovered that Epas1 genotype influences heart rate in hypoxia, and the transcriptomic responses to hypoxia (including HIF targets and genes involved in catecholamine signaling) in the heart and adrenal gland. Finally, we used a demographically-informed selection scan to show that Epas1 variants have experienced a history of spatially varying selection, suggesting that differences in cardiovascular function and gene regulation contribute to high-altitude adaptation. Our results suggest a mechanism by which Epas1 may aid long-term survival of high-altitude deer mice and provide general insights into the role that highly pleiotropic transcription factors may play in the process of environmental adaptation.

Klíčová slova:

Catecholamines – Deer – Evolutionary adaptation – Gene expression – Heart rate – Hypoxia – Medical hypoxia – Variant genotypes


Zdroje

1. Storz JF, Bridgham JT, Kelly SA, Garland T Jr. Genetic approaches in comparative and evolutionary physiology. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology. 2015;309: R197–R214. doi: 10.1152/ajpregu.00100.2015 26041111

2. Wagner A. Metabolic networks and their evolution. Soyer OS, editor. Evolutionary Systems Biology. 2012;: 29–52. doi: 10.1007/978-1-4614-3567-9

3. Wagner GP, Lynch VJ. The gene regulatory logic of transcription factor evolution. Trends in Ecology & Evolution. 2008;23: 377–385. doi: 10.1016/j.tree.2008.03.006 18501470

4. Lynch VJ, Wagner GP. Resurrecting the role of transcription factor change in developmental evolution. Evolution. 2008;62: 2131–2154. doi: 10.1111/j.1558-5646.2008.00440.x 18564379

5. Stern DL, Orgogozo V. Is Genetic Evolution Predictable? Science. American Association for the Advancement of Science; 2009;323: 746–751. doi: 10.1126/science.1158997 19197055

6. Carroll SB. Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution. Cell. 2008;134: 25–36. doi: 10.1016/j.cell.2008.06.030 18614008

7. Bouverot P. Adaptation to altitude-hypoxia in vertebrates. 1985. Springer Science & Business Media, Berlin, Germany.

8. Beall CM, Cavalleri GL, Deng L. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci. 2010;107: 11459–11464. doi: 10.1073/pnas.1002443107 20534544

9. Scott GR, Milsom WK. Control of breathing and adaptation to high altitude in the bar-headed goose. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology. 2007;293: R379–R391. doi: 10.1152/ajpregu.00161.2007 17491113

10. Storz JF, Scott GR, Cheviron ZA. Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J Exp Biol. 2010;213: 4125–4136. doi: 10.1242/jeb.048181 21112992

11. Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends in Molecular Medicine. 2001; 7:345–350. 11516994

12. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, et al. Genetic Evidence for High-Altitude Adaptation in Tibet. Science. 2010;329: 72–75. doi: 10.1126/science.1189406 20466884

13. Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZXP, Pool JE, et al. Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude. Science. 2010;329: 75–78. doi: 10.1126/science.1190371 20595611

14. Zhang W, Fan Z, Han E, Hou R, Zhang L, Galaverni M, et al. Hypoxia Adaptations in the Grey Wolf (Canis lupus chanco) from Qinghai-Tibet Plateau. PLoS Genet. 2014;10: e1004466. doi: 10.1371/journal.pgen.1004466 25078401

15. Pan S, Zhang T, Rong Z, Hu L, Gu Z, Wu Q, et al. Population transcriptomes reveal synergistic responses of DNA polymorphism and RNA expression to extreme environments on the Qinghai-Tibetan Plateau in a predatory bird. Molecular Ecology. 2017;26: 2993–3010. doi: 10.1111/mec.14090 28277617

16. Hodson EJ, Nicholls LG, Turner PJ, Llyr R, Fielding JW, Douglas G, et al. Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway. J Physiol. 2015;594: 1179–1195. doi: 10.1113/JP271050 26337139

17. Befani C, Liakos P. The role of hypoxia-inducible factor-2 alpha in angiogenesis. J Cell Physiol. 2018;233: 9087–9098. doi: 10.1002/jcp.26805 29968905

18. Petousi N, Croft QPP, Cavalleri GL, Cheng H-Y, Formenti F, Ishida K, et al. Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia. Journal of Applied Physiology. 2014;116: 893–904. doi: 10.1152/japplphysiol.00535.2013 24030663

19. Lorenzo FR, Huff C, Myllymäki M, Olenchock B, Swierczek S, Tashi T, et al. A genetic mechanism for Tibetan high-altitude adaptation. Nature. 2014;46: 951–956. doi: 10.1038/ng.3067 25129147

20. Fielding JW, Hodson EJ, Cheng X, Ferguson DJP, Eckardt L, Adam J, et al. PHD2 inactivation in Type I cells drives HIF‐2α‐dependent multilineage hyperplasia and the formation of paraganglioma‐like carotid bodies. J Physiol. 2018;596: 4393–4412. doi: 10.1113/JP275996 29917232

21. Brown ST, Kelly KF, Daniel JM, Nurse CA. Hypoxia inducible factor (HIF)-2α is required for the development of the catecholaminergic phenotype of sympathoadrenal cells. Journal of Neurochemistry. 2009;110: 622–630. doi: 10.1111/j.1471-4159.2009.06153.x 19457096

22. Cowburn AS, Crosby A, Macias D, Branco C, Colaço RDDR, Southwood M, et al. HIF2α–arginase axis is essential for the development of pulmonary hypertension. PNAS. 2016;113: 8801–8806. doi: 10.1073/pnas.1602978113 27432976

23. Chappell MA, Snyder LR. Biochemical and physiological correlates of deer mouse alpha-chain hemoglobin polymorphisms. PNAS. 1984;81: 5484–5488. doi: 10.1073/pnas.81.17.5484 6591201

24. Cheviron ZA, Bachman GC, Storz JF. Contributions of phenotypic plasticity to differences in thermogenic performance between highland and lowland deer mice. J Exp Biol. 2013;216: 1160–1166. doi: 10.1242/jeb.075598 23197099

25. Cheviron ZA, Bachmana GC, Connaty AD, McClelland GB, Storz JF. Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice. PNAS. 2012;109: 8635–8640. doi: 10.1073/pnas.1120523109 22586089

26. Scott GR, Elogio TS, Lui MA, Storz JF, Cheviron ZA. Adaptive Modifications of Muscle Phenotype in High-Altitude Deer Mice Are Associated with Evolved Changes in Gene Regulation. Molecular Biology and Evolution. 2015;32: 1962–1976. doi: 10.1093/molbev/msv076 25851956

27. Hayes J, O'Connor C. Natural selection on thermogenic capacity of high-altitude deer mice. Evolution. 1999;53: 1280–1287. doi: 10.1111/j.1558-5646.1999.tb04540.x 28565539

28. Storz JF, Runck AM, Moriyama H, Weber RE, Fago A. Genetic differences in hemoglobin function between highland and lowland deer mice. J Exp Biol. 2010;213: 2565–2574. doi: 10.1242/jeb.042598 20639417

29. Snyder LRG. Deer Mouse Hemoglobins: Is There Genetic Adaptation to High Altitude? BioScience. 1981;31: 299–304. doi: 10.2307/1308147

30. Snyder LR, Born S, Lechner AJ. Blood oxygen affinity in high- and low-altitude populations of the deer mouse. Respir Physiol. 1982;48: 89–105. doi: 10.1016/0034-5687(82)90052-4 7111920

31. Cheviron ZA, Connaty AD, McClelland GB, Storz JF. Functional genomics of adaptation to hypoxic cold-stress in high-altitude deer mice: transcriptomic plasticity and thermogenic performance. Evolution. 2014;68: 48–62. doi: 10.1111/evo.12257 24102503

32. Lui MA, Mahalingam S, Patel P, Connaty AD, Ivy CM, Cheviron ZA, et al. High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology. 2015;308: R779–R791. doi: 10.1152/ajpregu.00362.2014 25695288

33. Velotta JP, Jones J, Wolf CJ, Cheviron ZA. Transcriptomic plasticity in brown adipose tissue contributes to an enhanced capacity for nonshivering thermogenesis in deer mice. Molecular Ecology. 2016;25: 2870–2886. doi: 10.1111/mec.13661 27126783

34. Ivy CM, Scott GR. Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes. Acta Physiol. 1st ed. 2017;112: 123–17. doi: 10.1111/apha.12912 28640969

35. Tate KB, Ivy CM, Velotta JP, Storz JF, McClelland GB, Cheviron ZA, et al. Circulatory mechanisms underlying adaptive increases in thermogenic capacity in high-altitude deer mice. Journal of Experimental Biology. 2017;220: 3616–3620. doi: 10.1242/jeb.164491 28839010

36. Velotta JP, Ivy CM, Wolf CJ, Scott GR, Cheviron ZA. Maladaptive phenotypic plasticity in cardiac muscle growth is suppressed in high-altitude deer mice. Evolution. 2018;431: 261–16. doi: 10.1111/evo.13626 30318588

37. Dawson NJ, Lyons SA, Henry DA, Scott GR. Effects of chronic hypoxia on diaphragm function in deer mice native to high altitude. Acta Physiol. 2018;223: e13030–16. doi: 10.1111/apha.13030 29316265

38. Mahalingam S, McClelland GB, Scott GR. Evolved changes in the intracellular distribution and physiology of muscle mitochondria in high-altitude native deer mice. J Physiol. 2017;595: 4785–4801. doi: 10.1113/JP274130 28418073

39. Lau DS, Connaty AD, Mahalingam S, Wall N, Cheviron ZA, Storz JF, et al. Acclimation to hypoxia increases carbohydrate use during exercise in high-altitude deer mice. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology. 2017;312: R400–R411. doi: 10.1152/ajpregu.00365.2016 28077391

40. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81: 559–575. doi: 10.1086/519795 17701901

41. Alexander D, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. Genome Research. 2009;19: 1655. doi: 10.1101/gr.094052.109 19648217

42. Weir B, Cockerham C. Estimating F-statistics for the analysis of population structure. Evolution. 1984;38: 1358–1370. doi: 10.1111/j.1558-5646.1984.tb05657.x 28563791

43. Storz JF, Natarajan C, Cheviron ZA, Hoffmann FG, Kelly JK. Altitudinal Variation at Duplicated -Globin Genes in Deer Mice: Effects of Selection, Recombination, and Gene Conversion. Genetics. 2012;190: 203–216. doi: 10.1534/genetics.111.134494 22042573

44. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9: 677–684. doi: 10.1038/nm0603-677 12778166

45. Lohman BK, Weber JN, Bolnick DI. Evaluation of TagSeq, a reliable low-cost alternative for RNAseq. Mol Ecol Resour. 2016;16: 1315–1321. doi: 10.1111/1755-0998.12529 27037501

46. Scott AL, Pranckevicius NA, Nurse CA, Scott GR. The regulation of catecholamine release from the adrenal medulla is altered in deer mice (Peromyscus maniculatus) native to high altitudes. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology. 2019;584: 149–R417. doi: 10.1152/ajpregu.00005.2019

47. Hamid SA, Baxter GF. Adrenomedullin: regulator of systemic and cardiac homeostasis in acute myocardial infarction. Pharmacology & Therapeutics. 2005;105: 95–112. doi: 10.1016/j.pharmthera.2004.08.012 15670621

48. Bohm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovascular Research. 2007;76: 8–18. doi: 10.1016/j.cardiores.2007.06.004 17617392

49. Song W, Wang H, Wu Q. Atrial natriuretic peptide in cardiovascular biology and disease (NPPA). Gene. 2015;569: 1–6. doi: 10.1016/j.gene.2015.06.029 26074089

50. Gutenkunst R, Hernandez R, Williamson S, Bustamante C. Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data. PLoS Genet. 2009;5: e1000695. doi: 10.1371/journal.pgen.1000695 19851460

51. Tine M, Kuhl H, Gagnaire P-A, Louro B, Desmarais E, Martins RST, et al. European sea bass genome and its variation provide insights into adaptation to euryhalinity and speciation. Nature Communications. 2014;5: 1–10. doi: 10.1038/ncomms6770 25534655

52. Coffman AJ, Hsieh PH, Gravel S. Computationally efficient composite likelihood statistics for demographic inference. Molecular Biology and Evolution. 2016. doi: 10.1093/molbev/msv255/-/DC1

53. Ewing G, Hermisson J. MSMS: a coalescent simulation program including recombination, demographic structure and selection at a single locus. Bioinformatics. 2010;26: 2064–2065. doi: 10.1093/bioinformatics/btq322 20591904

54. Mayer U, Saher G, Fässler R, Bornemann A, Echtermeyer F, Mark von der H, et al. Absence of integrin alpha 7 causes a novel form of muscular dystrophy. Nat Genet. 1997;17: 318–323. doi: 10.1038/ng1197-318 9354797

55. Tomás M, Vázquez E, Fernández-Fernández JM, Subirana I, Plata C, Heras M, et al. Genetic variation in the KCNMA1 potassium channel α subunit as risk factor for severe essential hypertension and myocardial infarction. Journal of Hypertension. 2008;26: 2147–2153. doi: 10.1097/HJH.0b013e32831103d8 18854754

56. Harned J, Ferrell J, Nagar S, Goralska M, Fleisher LN, McGahan MC. Ceruloplasmin alters intracellular iron regulated proteins and pathways: Ferritin, transferrin receptor, glutamate and hypoxia-inducible factor-1α. Experimental Eye Research. 2012;97: 90–97. doi: 10.1016/j.exer.2012.02.001 22343016

57. Simonson TS, Yang Y, Huff CD, Yun H, Qin G. Genetic evidence for high-altitude adaptation in Tibet. Science. 2010;329: 72–75. doi: 10.1126/science.1189406 20466884

58. Liu X, Zhang Y, Li Y, Pan J, Wang D, Chen W, et al. EPAS1 gain-of-function mutation contributes to high-altitude adaptation in Tibetan horses. Molecular Biology and Evolution. 2019;19: 1655. doi: 10.1093/molbev/msz158 31273382

59. Julian CG, Moore LG. Human Genetic Adaptation to High Altitude: Evidence from the Andes. Genes. 2019;10: 150–21. doi: 10.3390/genes10020150 30781443

60. Nelson TC, Jones MR, Velotta JP, Dhawanjewar AS, Schweizer RM. UNVEILing connections between genotype, phenotype, and fitness in natural populations. Molecular Ecology. 2019;28: 1–31. doi: 10.1111/mec.14976

61. Dempsey JA, Morgan BJ. Humans In Hypoxia: A Conspiracy Of Maladaptation?! Physiology. 2015;30: 304–316. doi: 10.1152/physiol.00007.2015 26136544

62. Wu T, Kayser B. High altitude adaptation in Tibetans. High Altitude Medicine & Biology. 2006;7: 193–208. doi: 10.1089/ham.2006.7.193 16978132

63. Meyer M, Kircher M. Illumina Sequencing Library Preparation for Highly Multiplexed Target Capture and Sequencing. Cold Spring Harbor Protocols. 2010. doi: 10.1101/pdb.prot5448 20516186

64. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26: 589–595. doi: 10.1093/bioinformatics/btp698 20080505

65. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

66. Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, et al. The variant call format and VCFtools. Bioinformatics. 2011;27: 2156–2158. doi: 10.1093/bioinformatics/btr330 21653522

67. McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics. 2010;26: 2069–2070. doi: 10.1093/bioinformatics/btq330 20562413

68. Bradley R, Durish ND, Rogers DS, Miller JR, Engstrom MD, Kilpatrick CW. Toward a molecular phylogeny for Peromyscus: evidence from mitochondrial cytochrome-b sequences. Journal of Mammalogy. 2007;88: 1146–1159. doi: 10.1644/06-MAMM-A-342R.1 19924266

69. Miller JR, Engstrom MD. The Relationships of Major Lineages within Peromyscine Rodents: A Molecular Phylogenetic Hypothesis and Systematic Reappraisal. Journal of Mammalogy. 2008;89: 1279–1295. doi: 10.2307/25145219

70. Natarajan C, Hoffmann FG, Lanier HC, Wolf CJ, Cheviron ZA, Spangler ML, et al. Intraspecific Polymorphism, Interspecific Divergence, and the Origins of Function-Altering Mutations in Deer Mouse Hemoglobin. Molecular Biology and Evolution. 2015;32: 978–997. doi: 10.1093/molbev/msu403 25556236

71. Derryberry EP, Derryberry GE, Maley JM, Brumfield RT. hzar: hybrid zone analysis using an R software package. Mol Ecol Resour. 2013;14: 652–663. doi: 10.1111/1755-0998.12209 24373504

72. Ivy CM, Scott GR. Ventilatory acclimatization to hypoxia in mice: Methodological considerations. Respiratory Physiology & Neurobiology. 2017;235: 95–103. doi: 10.1016/j.resp.2016.10.012 27989891

73. Lighton JR. Measuring Metabolic Rates: A Manual for Scientists: A Manual for Scientists: Oxford University Press. 2008.

74. Rosenmann M, Morrison P. Maximum oxygen consumption and heat loss facilitation in small homeotherms by He-O2. Am J Physiol. 1974;226: 490–495. doi: 10.1152/ajplegacy.1974.226.3.490 4817400

75. Scherle W. A simple method for volumetry of organs in quantitative stereology. Mikroskopie. 1970;26: 57–60. 5530651

76. Nikel KE, Shanishchara NK, Ivy CM, Dawson NJ, Scott GR. Effects of hypoxia at different life stages on locomotory muscle phenotype in deer mice native to high altitudes. Comparative Biochemistry and Physiology, Part B. 2017;224: 98–104. doi: 10.1016/j.cbpb.2017.11.009 29175484

77. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9: 671–675. doi: 10.1038/nmeth.2089 22930834

78. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30: 923–930. doi: 10.1093/bioinformatics/btt656 24227677

79. Robinson MD, Smyth GK. Moderated statistical tests for assessing differences in tag abundance. Bioinformatics. 2007;23: 2881–2887. doi: 10.1093/bioinformatics/btm453 17881408

80. Robinson MD, Oshlack A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biology. 2010;11: R25. doi: 10.1186/gb-2010-11-3-r25 20196867

81. McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Research. 2012;40: 4288–4297. doi: 10.1093/nar/gks042 22287627

82. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. 1995;57: 289–300.

83. Dengler VL, Galbraith MD, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Critical Reviews in Biochemistry and Molecular Biology. 2014;49: 1–15. doi: 10.3109/10409238.2013.838205 24099156

84. Ortiz-Barahona A, Villar D, Pescador N, Amigo J, del Peso L. Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction. Nucleic Acids Research. 2010;38: 2332–2345. doi: 10.1093/nar/gkp1205 20061373

85. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Research. 2000;28: 27–30. doi: 10.1093/nar/28.1.27 10592173

86. Uchimura A, Higuchi M, Minakuchi Y, Ohno M, Toyoda A, Fujiyama A, et al. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice. Genome Research. 2015;25: 1125–1134. doi: 10.1101/gr.186148.114 26129709

87. Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, et al. g:Profiler—a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Research. 2016;: gkw199. doi: 10.1093/nar/gkw199 27098042

Štítky
Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics


2019 Číslo 11
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

plice
INSIGHTS from European Respiratory Congress
nový kurz

Současné pohledy na riziko v parodontologii
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Svět praktické medicíny 3/2024 (znalostní test z časopisu)

Kardiologické projevy hypereozinofilií
Autoři: prof. MUDr. Petr Němec, Ph.D.

Střevní příprava před kolonoskopií
Autoři: MUDr. Klára Kmochová, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#