Dosage regulation, and variation in gene expression and copy number of human Y chromosome ampliconic genes


Autoři: Rahulsimham Vegesna aff001;  Marta Tomaszkiewicz aff003;  Paul Medvedev aff002;  Kateryna D. Makova aff001
Působiště autorů: Bioinformatics and Genomics Graduate Program, The Huck Institutes for the Life Sciences, Pennsylvania State University, University Park, PA, United States of America aff001;  Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United States of America aff002;  Department of Biology, Pennsylvania State University, University Park, PA, United States of America aff003;  Department of Computer Science and Engineering, Pennsylvania State University, University Park, PA, United States of America aff004;  Center for Computational Biology and Bioinformatics, Pennsylvania State University, University Park, PA, United States of America aff005;  Center for Medical Genomics, Pennsylvania State University, University Park, PA, United States of America aff006
Vyšlo v časopise: Dosage regulation, and variation in gene expression and copy number of human Y chromosome ampliconic genes. PLoS Genet 15(9): e32767. doi:10.1371/journal.pgen.1008369
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008369

Souhrn

The Y chromosome harbors nine multi-copy ampliconic gene families expressed exclusively in testis. The gene copies within each family are >99% identical to each other, which poses a major challenge in evaluating their copy number. Recent studies demonstrated high variation in Y ampliconic gene copy number among humans. However, how this variation affects expression levels in human testis remains understudied. Here we developed a novel computational tool Ampliconic Copy Number Estimator (AmpliCoNE) that utilizes read sequencing depth information to estimate Y ampliconic gene copy number per family. We applied this tool to whole-genome sequencing data of 149 men with matched testis expression data whose samples are part of the Genotype-Tissue Expression (GTEx) project. We found that the Y ampliconic gene families with low copy number in humans were deleted or pseudogenized in non-human great apes, suggesting relaxation of functional constraints. Among the Y ampliconic gene families, higher copy number leads to higher expression. Within the Y ampliconic gene families, copy number does not influence gene expression, rather a high tolerance for variation in gene expression was observed in testis of presumably healthy men. No differences in gene expression levels were found among major Y haplogroups. Age positively correlated with expression levels of the HSFY and PRY gene families in the African subhaplogroup E1b, but not in the European subhaplogroups R1b and I1. We also found that expression of five out of six Y ampliconic gene families is coordinated with that of their non-Y (i.e. X or autosomal) homologs. Indeed, five ampliconic gene families had consistently lower expression levels when compared to their non-Y homologs suggesting dosage regulation, while the HSFY family had higher expression levels than its X homolog and thus lacked dosage regulation.

Klíčová slova:

Biology and life sciences – Genetics – Gene expression – Gene regulation – Population genetics – Haplogroups – Evolutionary biology – Evolutionary genetics – Population biology – Cell biology – Chromosome biology – Chromosomes – Sex chromosomes – Y chromosomes – Meiosis – Spermatogenesis – Cell processes – Cell cycle and cell division – Physiology – Reproductive physiology – Medicine and health sciences – Research and analysis methods – Database and informatics methods – Bioinformatics – Sequence analysis – Sequence alignment – Social sciences – Sociology – Human families


Zdroje

1. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003 Jun 19;423(6942):825–37. doi: 10.1038/nature01722 12815422

2. Repping S, Skaletsky H, Lange J, Silber S, van der Veen F, Oates RD, et al. Recombination between Palindromes P5 and P1 on the Human Y Chromosome Causes Massive Deletions and Spermatogenic Failure. Am J Hum Genet. 2002;71(4):906–22. doi: 10.1086/342928 12297986

3. Ye D, Zaidi AA, Tomaszkiewicz M, Anthony K, Liebowitz C, DeGiorgio M, et al. High Levels of Copy Number Variation of Ampliconic Genes across Major Human Y Haplogroups. Genome Biol Evol. 2018 May 1;10(5):1333–50. doi: 10.1093/gbe/evy086 29718380

4. Skov L, Danish Pan Genome Consortium, Schierup MH. Analysis of 62 hybrid assembled human Y chromosomes exposes rapid structural changes and high rates of gene conversion. PLoS Genet. 2017 Aug;13(8):e1006834. doi: 10.1371/journal.pgen.1006834 28846694

5. Lucotte EA, Skov L, Jensen JM, Coll Macià M, Munch K, Schierup MH. Dynamic Copy Number Evolution of X- and Y-Linked Ampliconic Genes in Human Populations. Genetics. 2018 Jul 1;209(3):907–20. doi: 10.1534/genetics.118.300826 29769284

6. Rozen S, Skaletsky H, Marszalek JD, Minx PJ, Cordum HS, Waterston RH, et al. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature. 2003 Jun 19;423(6942):873–6. doi: 10.1038/nature01723 12815433

7. Betrán E, Demuth JP, Williford A. Why Chromosome Palindromes? Int J Evol Biol. 2012;2012(Figure 2):1–14.

8. Charlesworth B, Charlesworth D. The degeneration of Y chromosomes. Philos Trans R Soc Lond B Biol Sci. 2000;355(1403):1563–72. doi: 10.1098/rstb.2000.0717 11127901

9. Bellott DW, Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Cho T-J, et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature. 2014 Apr 24;508(7497):494–9. doi: 10.1038/nature13206 24759411

10. Charlesworth D, Charlesworth B. Sex differences in fitness and selection for centric fusions between sex-chromosomes and autosomes. Genet Res. 1980;35(02):205.

11. Giachini C, Nuti F, Turner DJ, Laface I, Xue Y, Daguin F, et al. TSPY1Copy Number Variation Influences Spermatogenesis and Shows Differences among Y Lineages. J Clin Endocrinol Metab. 2009;94(10):4016–22. doi: 10.1210/jc.2009-1029 19773397

12. Krausz C, Chianese C, Giachini C, Guarducci E, Laface I, Forti G. The Y chromosome-linked copy number variations and male fertility. J Endocrinol Invest. 2011;34(5):376–82. doi: 10.3275/7612 21422806

13. Krausz C, Giachini C, Forti G. TSPY and Male Fertility. Genes. 2010 Sep 21;1(2):308–16. doi: 10.3390/genes1020308 24710048

14. Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996;5(7):933–43. doi: 10.1093/hmg/5.7.933 8817327

15. Navarro-Costa P, Plancha CE, Gonaçlves J. Genetic dissection of the AZF regions of the human Y chromosome: Thriller or filler for male (In)fertility? BioMed Research International. 2010 Jun 30;2010.

16. Carvalho CMB, Zhang F, Lupski JR. Structural variation of the human genome: mechanisms, assays, and role in male infertility. Syst Biol Reprod Med. 2011 Feb;57(1–2):3–16. doi: 10.3109/19396368.2010.527427 21210740

17. Mallick S, Li H, Lipson M, Mathieson I, Gymrek M, Racimo F, et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature. 2016 Oct 13;538(7624):201–6. doi: 10.1038/nature18964 27654912

18. Teitz LS, Pyntikova T, Skaletsky H, Page DC. Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages. Am J Hum Genet. 2018 Aug 2;103(2):261–75. doi: 10.1016/j.ajhg.2018.07.007 30075113

19. Vinuela A, Brown AA, Buil A, Tsai P-C, Davies MN, Bell JT, et al. Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort. Human molecular genetics. 2017 Dec 8;27(4):732–41.

20. Yang J, The GTEx Consortium, Huang T, Petralia F, Long Q, Zhang B, et al. Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases. Scientific reports. 2015 Oct 19;5:15145. doi: 10.1038/srep15145 26477495

21. Handsaker RE, Van Doren V, Berman JR, Genovese G, Kashin S, Boettger LM, et al. Large multiallelic copy number variations in humans. Nat Genet. 2015 Mar;47(3):296–303. doi: 10.1038/ng.3200 25621458

22. Henrichsen CN, Chaignat E, Reymond A. Copy number variants, diseases and gene expression. Hum Mol Genet. 2009;18(R1):R1–8. doi: 10.1093/hmg/ddp011 19297395

23. Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015 May 21;161(5):1012–25. doi: 10.1016/j.cell.2015.04.004 25959774

24. Spielmann M, Lupiáñez DG, Mundlos S. Structural variation in the 3D genome. Nat Rev Genet. 2018 Jul;19(7):453–67. doi: 10.1038/s41576-018-0007-0 29692413

25. Carithers LJ, Ardlie K, Barcus M, Branton PA, Britton A, Buia SA, et al. A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. Biopreserv Biobank. 2015 Oct;13(5):311–9. doi: 10.1089/bio.2015.0032 26484571

26. Medvedev P, Stanciu M, Brudno M. Computational methods for discovering structural variation with next-generation sequencing. Nat Methods. 2009 Oct 15;6(11s):S13.

27. Sudmant PH, Kitzman JO, Antonacci F, Alkan C, Malig M, Tsalenko A, et al. Diversity of human copy number variation and multicopy genes. Science. 2010 Oct 29;330(6004):641–6. doi: 10.1126/science.1197005 21030649

28. Cortez D, Marin R, Toledo-Flores D, Froidevaux L, Liechti A, Waters PD, et al. Origins and functional evolution of Y chromosomes across mammals. Nature. 2014 Apr 24;508(7497):488–93. doi: 10.1038/nature13151 24759410

29. Oetjens MT, Shen F, Emery SB, Zou Z, Kidd JM. Y-Chromosome Structural Diversity in the Bonobo and Chimpanzee Lineages. Genome Biol Evol. 2016 Aug 3;8(7):2231–40. doi: 10.1093/gbe/evw150 27358426

30. Zook JM, Chapman B, Wang J, Mittelman D, Hofmann O, Hide W, et al. Integrating human sequence data sets provides a resource of benchmark SNP and indel genotype calls. Nat Biotechnol. 2014 Feb 16;32(3):246. doi: 10.1038/nbt.2835 24531798

31. Trombetta B, Cruciani F, Underhill PA, Sellitto D, Scozzari R. Footprints of X-to-Y gene conversion in recent human evolution. Mol Biol Evol. 2010 Mar;27(3):714–25. doi: 10.1093/molbev/msp231 19812029

32. Iwase M, Satta Y, Hirai H, Hirai Y, Takahata N. Frequent gene conversion events between the X and Y homologous chromosomal regions in primates. BMC Evol Biol. 2010 Jul 23;10:225. doi: 10.1186/1471-2148-10-225 20650009

33. Hallast P, Jobling MA. The Y chromosomes of the great apes. Hum Genet. 2017 May;136(5):511–28. doi: 10.1007/s00439-017-1769-8 28265767

34. Bhowmick BK, Satta Y, Takahata N. The origin and evolution of human ampliconic gene families and ampliconic structure. Genome Res. 2007 Apr;17(4):441–50. doi: 10.1101/gr.5734907 17185645

35. Gu L, Walters JR. Evolution of Sex Chromosome Dosage Compensation in Animals: A Beautiful Theory, Undermined by Facts and Bedeviled by Details. Genome Biol Evol. 2017 Sep 1;9(9):2461–76. doi: 10.1093/gbe/evx154 28961969

36. Lynch M, Conery JS. The evolutionary fate and consequences of duplicate genes. Science. 2000 Nov 10;290(5494):1151–5. doi: 10.1126/science.290.5494.1151 11073452

37. Yu H, Luscombe NM, Qian J, Gerstein M. Genomic analysis of gene expression relationships in transcriptional regulatory networks. Trends Genet. 2003 Aug;19(8):422–7. doi: 10.1016/S0168-9525(03)00175-6 12902159

38. Lan X, Pritchard JK. Coregulation of tandem duplicate genes slows evolution of subfunctionalization in mammals. Science. 2016 May 20;352(6288):1009–13. doi: 10.1126/science.aad8411 27199432

39. Vangompel MJW, Xu EY. The roles of the DAZ family in spermatogenesis: More than just translation? Spermatogenesis. 2011 Jan 1;1(1):36–46. doi: 10.4161/spmg.1.1.14659 22523742

40. Dorus S, Gilbert SL, Forster ML, Barndt RJ, Lahn BT. The CDY-related gene family: coordinated evolution in copy number, expression profile and protein sequence. Hum Mol Genet. 2003 Jul 15;12(14):1643–50. doi: 10.1093/hmg/ddg185 12837688

41. Ardlie KG, DeLuca DS, Segrè AV, Sullivan TJ, Young TR, Gelfand ET, et al. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science. 2015;348(6235):648–60. doi: 10.1126/science.1262110

42. Hastings PJ James R Lupski SMRAGI. Mechanisms of change in gene copy number. Nat Rev Genet. 2010;10(8):551–64.

43. Jobling MA. Copy number variation on the human Y chromosome. Cytogenet Genome Res. 2008;123(1–4):253–62. doi: 10.1159/000184715 19287162

44. Lambert S, Saintigny Y, Delacote F, Amiot F, Chaput B, Lecomte M, et al. Analysis of intrachromosomal homologous recombination in mammalian cell, using tandem repeat sequences. Mutat Res. 1999 Apr 9;433(3):159–68. doi: 10.1016/s0921-8777(99)00004-x 10343649

45. Yan Y, Yang X, Liu Y, Shen Y, Tu W, Dong Q, et al. Copy number variation of functional RBMY1 is associated with sperm motility: an azoospermia factor-linked candidate for asthenozoospermia. Hum Reprod. 2017 Jul 1;32(7):1521–31. doi: 10.1093/humrep/dex100 28498920

46. Tsuei D-J, Lee P-H, Peng H-Y, Lu H-L, Su D-S, Jeng Y-M, et al. Male germ cell-specific RNA binding protein RBMY: a new oncogene explaining male predominance in liver cancer. PLoS One. 2011 Nov 4;6(11):e26948. doi: 10.1371/journal.pone.0026948 22073224

47. Kido T, Lau Y-FC. The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells. Biochem Biophys Res Commun. 2014 Mar 28;446(1):206–11. doi: 10.1016/j.bbrc.2014.02.083 24583132

48. Gu W, Zhang F, Lupski JR. Mechanisms for human genomic rearrangements. Pathogenetics. 2008;1(1):4. doi: 10.1186/1755-8417-1-4 19014668

49. Connallon T, Clark AG. Gene duplication, gene conversion and the evolution of the Y chromosome. Genetics. 2010 Sep;186(1):277–86. doi: 10.1534/genetics.110.116756 20551442

50. Poli MN, Iriarte PF, Iudica C, Zanier JHM, Coco R. New Sequence Variations in Spermatogenesis Candidates Genes. JBRA Assist Reprod. 2015 Nov 1;19(4):216–22. doi: 10.5935/1518-0557.20150042 27203195

51. Sin H-S, Ichijima Y, Koh E, Namiki M, Namekawa SH. Human postmeiotic sex chromatin and its impact on sex chromosome evolution. Genome Res. 2012 May;22(5):827–36. doi: 10.1101/gr.135046.111 22375025

52. Larson EL, Kopania EEK, Good JM. Spermatogenesis and the Evolution of Mammalian Sex Chromosomes. Trends Genet. 2018 Sep;34(9):722–32. doi: 10.1016/j.tig.2018.06.003 30077434

53. Handel MA. The XY body: a specialized meiotic chromatin domain. Exp Cell Res. 2004 May 15;296(1):57–63. doi: 10.1016/j.yexcr.2004.03.008 15120994

54. Djureinovic D, Fagerberg L, Hallström B, Danielsson A, Lindskog C, Uhlén M, et al. The human testis-specific proteome defined by transcriptomics and antibody-based profiling. Mol Hum Reprod. 2014 Jun;20(6):476–88. doi: 10.1093/molehr/gau018 24598113

55. Harris ID, Fronczak C, Roth L, Meacham RB. Fertility and the aging male. Rev Urol. 2011;13(4):e184–90. 22232567

56. Gunes S, Hekim GNT, Arslan MA, Asci R. Effects of aging on the male reproductive system. J Assist Reprod Genet. 2016 Apr;33(4):441–54. doi: 10.1007/s10815-016-0663-y 26867640

57. Vicoso B, Bachtrog D. Progress and prospects toward our understanding of the evolution of dosage compensation. Chromosome Res. 2009;17(5):585–602. doi: 10.1007/s10577-009-9053-y 19626444

58. Straub T, Becker PB. Dosage compensation: the beginning and end of generalization. Nat Rev Genet. 2007 Jan;8(1):47–57. doi: 10.1038/nrg2013 17173057

59. Nguyen DK, Disteche CM. Dosage compensation of the active X chromosome in mammals. Nat Genet. 2005;38(1):47–53. doi: 10.1038/ng1705 16341221

60. Lahn BT, Page DC. A human sex-chromosomal gene family expressed in male germ cells and encoding variably charged proteins. Hum Mol Genet. 2000 Jan 22;9(2):311–9. doi: 10.1093/hmg/9.2.311 10607842

61. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015 Jan 23;347(6220):1260419. doi: 10.1126/science.1260419 25613900

62. Zou SW, Zhang JC, Zhang XD, Miao SY, Zong SD, Sheng Q, et al. Expression and localization of VCX/Y proteins and their possible involvement in regulation of ribosome assembly during spermatogenesis. Cell Res. 2003 Jun;13(3):171–7. doi: 10.1038/sj.cr.7290161 12862317

63. Sahlin K, Tomaszkiewicz M, Makova KD, Medvedev P. Deciphering highly similar multigene family transcripts from Iso-Seq data with IsoCon. Nat Commun. 2018 Nov 2;9(1):4601. doi: 10.1038/s41467-018-06910-x 30389934

64. Shinka T, Sato Y, Chen G, Naroda T, Kinoshita K, Unemi Y, et al. Molecular characterization of heat shock-like factor encoded on the human Y chromosome, and implications for male infertility. Biol Reprod. 2004 Jul;71(1):297–306. doi: 10.1095/biolreprod.103.023580 15044259

65. Kichine E, Rozé V, Di Cristofaro J, Taulier D, Navarro A, Streichemberger E, et al. HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation. Hum Reprod. 2012 Feb 1;27(2):615–24. doi: 10.1093/humrep/der421 22158087

66. Kinoshita K, Shinka T, Sato Y, Kurahashi H, Kowa H, Chen G, et al. Expression analysis of a mouse orthologue of HSFY, a candidate for the azoospermic factor on the human Y chromosome. J Med Invest. 2006 Feb;53(1–2):117–22. 16538004

67. Stahl PJ, Mielnik AN, Barbieri CE, Schlegel PN, Paduch DA. Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia. Asian J Androl. 2012 Sep;14(5):676–82. doi: 10.1038/aja.2012.55 22820855

68. Makova KD, Li W-H. Strong male-driven evolution of DNA sequences in humans and apes. Nature. 2002 Apr 11;416(6881):624–6. doi: 10.1038/416624a 11948348

69. Alkan C, Kidd JM, Marques-Bonet T, Aksay G, Antonacci F, Hormozdiari F, et al. Personalized copy number and segmental duplication maps using next-generation sequencing. Nat Genet. 2009 Oct;41(10):1061–7. doi: 10.1038/ng.437 19718026

70. Derrien T, Estellé J, Marco Sola S, Knowles DG, Raineri E, Guigó R, et al. Fast computation and applications of genome mappability. PLoS One. 2012 Jan 19;7(1):e30377. doi: 10.1371/journal.pone.0030377 22276185

71. Smit AFA, Hubley R, Green P. RepeatMasker Open-4.0. 2013–2015 <http://www.repeatmasker.org>.

72. Benson G. Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res. 1999;27(2):573–80. doi: 10.1093/nar/27.2.573 9862982

73. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012 Mar 4;9(4):357–9. doi: 10.1038/nmeth.1923 22388286

74. Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008 Nov 6;456(7218):53. doi: 10.1038/nature07517 18987734

75. Yoon S, Xuan Z, Makarov V, Ye K, Sebat J. Sensitive and accurate detection of copy number variants using read depth of coverage. Genome Res. 2009 Sep;19(9):1586–92. doi: 10.1101/gr.092981.109 19657104

76. Li H. wgsim-Read simulator for next generation sequencing. Github Repository. 2011 [online] http://github.com/lh3/wgsim.

77. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv preprint arXiv:1303.3997. 2013 Mar 16.

78. “Picard Toolkit.” 2019. Broad Institute, GitHub Repository. http://broadinstitute.github.io/picard/.

79. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009 Aug 15;25(16):2078–9. doi: 10.1093/bioinformatics/btp352 19505943

80. Leinonen R, Sugawara H, Shumway M, on behalf of the International Nucleotide Sequence Database Collaboration. The Sequence Read Archive. Nucleic Acids Res. 2010;39(Database):D19–21. doi: 10.1093/nar/gkq1019 21062823

81. Kent WJ. BLAT—the BLAST-like alignment tool. Genome Res. 2002 Apr;12(4):656–64. doi: 10.1101/gr.229202 11932250

82. Tomaszkiewicz M, Rangavittal S, Cechova M, Campos Sanchez R, Fescemyer HW, Harris R, et al. A time- and cost-effective strategy to sequence mammalian Y Chromosomes: an application to the de novo assembly of gorilla Y. Genome Res. 2016 Apr;26(4):530–40. doi: 10.1101/gr.199448.115 26934921

83. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The Human Genome Browser at UCSC. Genome Res. 2002;12(6):996–1006. doi: 10.1101/gr.229102 12045153

84. Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016 May;34(5):525–7. doi: 10.1038/nbt.3519 27043002

85. Soneson C, Love MI, Robinson MD. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res. 2015 Dec 30;4:1521. doi: 10.12688/f1000research.7563.2 26925227

86. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281

87. Poznik GD, David Poznik G. Identifying Y-chromosome haplogroups in arbitrarily large samples of sequenced or genotyped men. bioRxiv. 2016 Jan 1:088716.

88. Church DM, Schneider VA, Graves T, Auger K, Cunningham F, Bouk N, et al. Modernizing reference genome assemblies. PLoS Biol. 2011 Jul;9(7):e1001091. doi: 10.1371/journal.pbio.1001091 21750661

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