Mapping of Craniofacial Traits in Outbred Mice Identifies Major Developmental Genes Involved in Shape Determination

1. Hallgrimsson B, Mio W, Marcucio RS, Spritz R (2014) Let's Face It—Complex Traits Are Just Not That Simple. PLoS Genet 10: e1004724. doi: 10.1371/journal.pgen.1004724 25375250

2. Lamichhaney S, Berglund J, Almen MS, Maqbool K, Grabherr M, et al. (2015) Evolution of Darwin/'s finches and their beaks revealed by genome sequencing. Nature 518: 371–375. doi: 10.1038/nature14181 25686609

3. Abzhanov A, Protas M, Grant BR, Grant PR, Tabin CJ (2004) Bmp4 and morphological variation of beaks in Darwin's finches. Science 305: 1462–1465. 15353802

4. Abzhanov A, Kuo WP, Hartmann C, Grant BR, Grant PR, et al. (2006) The calmodulin pathway and evolution of elongated beak morphology in Darwin's finches. Nature 442: 563–567. 16885984

5. Albertson RC, Streelman JT, Kocher TD (2003) Directional selection has shaped the oral jaws of Lake Malawi cichlid fishes. Proc Natl Acad Sci U S A 100: 5252–5257. 12704237

6. Albertson RC, Streelman JT, Kocher TD, Yelick PC (2005) Integration and evolution of the cichlid mandible: The molecular basis of alternate feeding strategies. Proc Natl Acad Sci U S A 102: 16287–16292. 16251275

7. Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, et al. (2010) A Simple Genetic Architecture Underlies Morphological Variation in Dogs. PLoS Biol 8: e1000451. doi: 10.1371/journal.pbio.1000451 20711490

8. Schoenebeck JJ, Hutchinson SA, Byers A, Beale HC, Carrington B, et al. (2012) Variation of BMP3 Contributes to Dog Breed Skull Diversity. PLoS Genet 8: e1002849. doi: 10.1371/journal.pgen.1002849 22876193

9. Schoenebeck JJ, Ostrander EA (2013) The Genetics of Canine Skull Shape Variation. Genetics 193: 317–+. doi: 10.1534/genetics.112.145284 23396475

10. Maga AM, Navarro N, Cunningham ML, Cox TC (2015) Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico. Front Physiol 6: 92. doi: 10.3389/fphys.2015.00092 25859222

11. Attanasio C, Nord AS, Zhu Y, Blow MJ, Li Z, et al. (2013) Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers. Science 342: 1241006. doi: 10.1126/science.1241006 24159046

12. Pallares LF, Harr B, Turner LM, Tautz D (2014) Use of a natural hybrid zone for genomewide association mapping of craniofacial traits in the house mouse. Molecular Ecology 23: 5756–5770. doi: 10.1111/mec.12968 25319559

13. Klingenberg CP, Leamy LJ, Cheverud JM (2004) Integration and modularity of quantitative trait locus effects on geometric shape in the mouse mandible. Genetics 166: 1909–1921. 15126408

14. Leamy LJ, Routman EJ, Cheverud JM (1997) A Search for Quantitative Trait Loci Affecting Asymmetry of Mandibular Characters in Mice. Evolution 51: 957–969.

15. Burgio G, Baylac M, Heyer E, Montagutelli X (2009) Genetic analysis of skull shape variation and morphological integration in the mouse using interspecific recombinant congenic strains between C57BL/6 and mice of the mus spretus species. Evolution 63: 2668–2686. doi: 10.1111/j.1558-5646.2009.00737.x 19490077

16. Boell L, Gregorova S, Forejt J, Tautz D (2011) A comparative assessment of mandible shape in a consomic strain panel of the house mouse (Mus musculus)—implications for epistasis and evolvability of quantitative traits. BMC Evol Biol 11: 309. doi: 10.1186/1471-2148-11-309 22011306

17. Boehringer S, van der Lijn F, Liu F, Gunther M, Sinigerova S, et al. (2011) Genetic determination of human facial morphology: links between cleft-lips and normal variation. Eur J Hum Genet 19: 1192–1197. doi: 10.1038/ejhg.2011.110 21694738

18. Liu F, van der Lijn F, Schurmann C, Zhu G, Chakravarty MM, et al. (2012) A genome-wide association study identifies five loci influencing facial morphology in Europeans. PLoS Genet 8: e1002932. doi: 10.1371/journal.pgen.1002932 23028347

19. Paternoster L, Zhurov AI, Toma AM, Kemp JP, St Pourcain B, et al. (2012) Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position. Am J Hum Genet 90: 478–485. doi: 10.1016/j.ajhg.2011.12.021 22341974

20. Claes P, Liberton DK, Daniels K, Rosana KM, Quillen EE, et al. (2014) Modeling 3D Facial Shape from DNA. PLoS Genet 10: e1004224. doi: 10.1371/journal.pgen.1004224 24651127

21. Klingenberg CP (2010) Evolution and development of shape: integrating quantitative approaches. Nat Rev Genet 11: 623–635. doi: 10.1038/nrg2829 20697423

22. Atchley WR, Hall BK (1991) A model for development and evolution of complex morphological structures. Biol Rev 66: 101–157. 1863686

23. Klingenberg CP, Navarro N (2012) Development of the mouse mandible. In: Macholán M, Baird SJE, Munclinger P, Pialek J, editors. Evolution of the House Mouse. 1st ed ed. Cambridge: Cambridge University Press. pp. 135–149.

24. Klingenberg CP, Leamy LJ, Routman EJ, Cheverud JM (2001) Genetic architecture of mandible shape in mice: effects of quantitative trait loci analyzed by geometric morphometrics. Genetics 157: 785–802. 11156997

25. Leamy LJ, Klingenberg CP, Sherratt E, Wolf JB, Cheverud JM (2008) A search for quantitative trait loci exhibiting imprinting effects on mouse mandible size and shape. Heredity 101: 518–526. doi: 10.1038/hdy.2008.79 18685568

26. Nunes MDS, Arif S, Schlotterer C, McGregor AP (2013) A Perspective on Micro-Evo-Devo: Progress and Potential. Genetics 195: 625–634. doi: 10.1534/genetics.113.156463 24190920

27. Yalcin B, Nicod J, Bhomra A, Davidson S, Cleak C, et al. (2010) Commercially Available Outbred Mice for Genome-Wide Association Studies. PLoS Genet 6: e1001085. doi: 10.1371/journal.pgen.1001085 20838427

28. Parker CC, Palmer AA (2011) Dark Matter: Are Mice the Solution to Missing Heritability? Frontiers in Genetics 2: 32. doi: 10.3389/fgene.2011.00032 22303328

29. Aldinger KA, Sokoloff G Fau—Rosenberg DM, Rosenberg Dm Fau—Palmer AA, Palmer Aa Fau—Millen KJ, Millen KJ Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies.

30. Chia R, Achilli F, Festing MF, Fisher EM (2005) The origins and uses of mouse outbred stocks. Nat Genet 37: 1181–1186. 16254564

31. Rice MC, O'Brien SJ (1980) Genetic variance of laboratory outbred Swiss mice. Nature 283: 157–161. 7350540

32. Wray NR, Yang J, Hayes BJ, Price AL, Goddard ME, et al. (2013) Pitfalls of predicting complex traits from SNPs. Nature reviews Genetics 14: 507–515. doi: 10.1038/nrg3457 23774735

33. Wongdee K, Pandaranandaka J, Teerapornpuntakit J, Tudpor K, Thongbunchoo J, et al. (2008) Osteoblasts express claudins and tight junction-associated proteins. Histochem Cell Biol 130: 79–90. doi: 10.1007/s00418-008-0419-6 18365232

34. Alshbool FZ, Mohan S (2014) Emerging multifunctional roles of Claudin tight junction proteins in bone. Endocrinology 155: 2363–2376. doi: 10.1210/en.2014-1173 24758302

35. Linares GR, Brommage R, Powell DR, Xing W, Chen ST, et al. (2012) Claudin 18 is a novel negative regulator of bone resorption and osteoclast differentiation. J Bone Miner Res 27: 1553–1565. doi: 10.1002/jbmr.1600 22437732

36. Chen F, Guo R, Itoh S, Moreno L, Rosenthal E, et al. (2014) First mouse model for combined osteogenesis imperfecta and Ehlers-Danlos syndrome. J Bone Miner Res 29: 1412–1423. doi: 10.1002/jbmr.2177 24443344

37. Basel D, Steiner RD (2009) Osteogenesis imperfecta: recent findings shed new light on this once well-understood condition. Genet Med 11: 375–385. doi: 10.1097/GIM.0b013e3181a1ff7b 19533842

38. Cheung MS, Arponen H, Roughley P, Azouz ME, Glorieux FH, et al. (2011) Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants. J Bone Miner Res 26: 405–413. doi: 10.1002/jbmr.220 20721936

39. Duverger O, Isaac J, Zah A, Hwang J, Berdal A, et al. (2013) In vivo impact of Dlx3 conditional inactivation in neural crest-derived craniofacial bones. J Cell Physiol 228: 654–664. doi: 10.1002/jcp.24175 22886599

40. Isaac J, Erthal J, Gordon J, Duverger O, Sun HW, et al. (2014) DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo. Cell Death Differ 21: 1365–1376. doi: 10.1038/cdd.2014.82 24948010

41. Depew MJ, Simpson CA, Morasso M, Rubenstein JL (2005) Reassessing the Dlx code: the genetic regulation of branchial arch skeletal pattern and development. J Anat 207: 501–561. 16313391

42. Price JA, Bowden DW, Wright JT, Pettenati MJ, Hart TC (1998) Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum Mol Genet 7: 563–569. 9467018

43. Rice R, Rice DPC, Olsen BR, Thesleff I (2003) Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4. Developmental Biology 262: 75–87. 14512019

44. Sun J, Ishii M, Ting MC, Maxson R (2013) Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2. Development 140: 1034–1044. doi: 10.1242/dev.085225 23344708

45. Mirzayans F, Lavy R, Penner-Chea J, Berry FB (2012) Initiation of Early Osteoblast Differentiation Events through the Direct Transcriptional Regulation of Msx2 by FOXC1. PLoS ONE 7.

46. Inman KE, Purcell P, Kume T, Trainor PA (2013) Interaction between Foxc1 and Fgf8 during mammalian jaw patterning and in the pathogenesis of syngnathia. PLoS Genet 9: e1003949. doi: 10.1371/journal.pgen.1003949 24385915

47. Kume T, Deng KY, Winfrey V, Gould DB, Walter MA, et al. (1998) The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 93: 985–996. 9635428

48. Mears AJ, Jordan T, Mirzayans F, Dubois S, Kume T, et al. (1998) Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 63: 1316–1328. 9792859

49. Heude E, Bellessort B, Fontaine A, Hamazaki M, Treier AC, et al. (2015) Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome. Hum Mol Genet 24: 1670–1681. doi: 10.1093/hmg/ddu579 25416281

50. Shi F, Ding S, Zhao S, Han M, Zhuang Y, et al. (2014) A piggyBac insertion disrupts Foxl2 expression that mimics BPES syndrome in mice. Hum Mol Genet 23: 3792–3800. doi: 10.1093/hmg/ddu092 24565867

51. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, et al. (2001) The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27: 159–166. 11175783

52. Itoh M, Yoshida Y, Nishida K, Narimatsu M, Hibi M, et al. (2000) Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Mol Cell Biol 20: 3695–3704. 10779359

53. Weng TJ, Mao FF, Wang YL, Sun Q, Li RX, et al. (2010) Osteoblastic molecular scaffold Gab1 is required for maintaining bone homeostasis. J Cell Sci 123: 682–689. doi: 10.1242/jcs.058396 20124419

54. Ferron M, Boudiffa M, Arsenault M, Rached M, Pata M, et al. (2011) Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Cell Metab 14: 466–477. doi: 10.1016/j.cmet.2011.08.013 21982707

55. Vacher J (2013) Inpp4b is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis. Ann N Y Acad Sci 1280: 52–54. doi: 10.1111/nyas.12014 23551105

56. Zhao H, Ross FP, Teitelbaum SL (2005) Unoccupied alpha(v)beta3 integrin regulates osteoclast apoptosis by transmitting a positive death signal. Mol Endocrinol 19: 771–780. 15591537

57. Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95: 507–519. 9827803

58. Aksoy I, Giudice V, Delahaye E, Wianny F, Aubry M, et al. (2014) Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in embryonic stem cells. Nat Commun 5: 3719. doi: 10.1038/ncomms4719 24770696

59. Zhang B, Zhang Z, Xia S, Xing C, Ci X, et al. (2013) KLF5 activates microRNA 200 transcription to maintain epithelial characteristics and prevent induced epithelial-mesenchymal transition in epithelial cells. Mol Cell Biol 33: 4919–4935. doi: 10.1128/MCB.00787-13 24126055

60. Chen Z, Couble ML, Mouterfi N, Magloire H, Bleicher F (2009) Spatial and temporal expression of KLF4 and KLF5 during murine tooth development. Arch Oral Biol 54: 403–411. doi: 10.1016/j.archoralbio.2009.02.003 19268913

61. Sur I, Rozell B, Jaks V, Bergstrom A, Toftgard R (2006) Epidermal and craniofacial defects in mice overexpressing Klf5 in the basal layer of the epidermis. J Cell Sci 119: 3593–3601. 16912082

62. Dai JX, Johnson RL, Ding YQ (2009) Manifold functions of the Nail-Patella Syndrome gene Lmx1b in vertebrate development. Dev Growth Differ 51: 241–250. doi: 10.1111/j.1440-169X.2008.01083.x 19222527

63. Chen H, Ovchinnikov D, Pressman CL, Aulehla A, Lun Y, et al. (1998) Multiple calvarial defects in lmx1b mutant mice. Dev Genet 22: 314–320. 9664684

64. Sutton AL, Zhang X, Ellison TI, Macdonald PN (2005) The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation. Mol Endocrinol 19: 2234–2244. 15890672

65. Meester-Smoor MA, Vermeij M, van Helmond MJ, Molijn AC, van Wely KH, et al. (2005) Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton. Mol Cell Biol 25: 4229–4236. 15870292

66. Zhang X, Dowd DR, Moore MC, Kranenburg TA, Meester-Smoor MA, et al. (2009) Meningioma 1 is required for appropriate osteoblast proliferation, motility, differentiation, and function. J Biol Chem 284: 18174–18183. doi: 10.1074/jbc.M109.001354 19386590

67. Davidson TB, Sanchez-Lara PA, Randolph LM, Krieger MD, Wu SQ, et al. (2012) Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature. BMC Med Genet 13: 19. doi: 10.1186/1471-2350-13-19 22436304

68. Breckpot J, Anderlid B-M, Alanay Y, Blyth M, Brahimi A, et al. (2015) Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate. Eur J Hum Genet.

69. Peake NJ, Hobbs AJ, Pingguan-Murphy B, Salter DM, Berenbaum F, et al. (2014) Role of C-type natriuretic peptide signalling in maintaining cartilage and bone function. Osteoarthritis Cartilage 22: 1800–1807. doi: 10.1016/j.joca.2014.07.018 25086404

70. Pejchalova K, Krejci P, Wilcox WR (2007) C-natriuretic peptide: an important regulator of cartilage. Mol Genet Metab 92: 210–215. 17681481

71. Jaubert J, Jaubert F, Martin N, Washburn LL, Lee BK, et al. (1999) Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proc Natl Acad Sci U S A 96: 10278–10283. 10468599

72. Pavlos NJ, Xu J, Papadimitriou JM, Zheng MH (2001) Molecular cloning of the mouse homologue of Rab3c. J Mol Endocrinol 27: 117–122. 11573517

73. Abu-Amer Y, Teitelbaum SL, Chappel JC, Schlesinger P, Ross FP (1999) Expression and Regulation of RAB3 Proteins in Osteoclasts and Their Precursors. Journal of Bone and Mineral Research 14: 1855–1860. 10571685

74. Nomura-Furuwatari C, Wakitani S, Hashimoto Y, Imai Y, Ohta Y, et al. (2008) Expression profiles of phosphodiesterase 4D splicing variants in osteoblastic cells. J Bone Miner Metab 26: 152–158. doi: 10.1007/s00774-007-0803-7 18301971

75. Wakabayashi S, Tsutsumimoto T, Kawasaki S, Kinoshita T, Horiuchi H, et al. (2002) Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J Bone Miner Res 17: 249–256. 11811555

76. Kaname T, Ki C-S, Niikawa N, Baillie GS, Day JP, et al. (2014) Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cellular Signalling 26: 2446–2459. doi: 10.1016/j.cellsig.2014.07.025 25064455

77. Reneland RH, Mah S, Kammerer S, Hoyal CR, Marnellos G, et al. (2005) Association between a variation in the phosphodiesterase 4D gene and bone mineral density. BMC Med Genet 6: 9. 15752431

78. Bögel G, Gujdár A, Geiszt M, Lányi Á, Fekete A, et al. (2012) Frank-ter Haar Syndrome Protein Tks4 Regulates Epidermal Growth Factor-dependent Cell Migration. J Biol Chem 287: 31321–31329. doi: 10.1074/jbc.M111.324897 22829589

79. Mao M, Thedens DR, Chang B, Harris BS, Zheng QY, et al. (2009) The podosomal-adaptor protein SH3PXD2B is essential for normal postnatal development. Mamm Genome 20: 462–475. doi: 10.1007/s00335-009-9210-9 19669234

80. Buschman MD, Bromann PA, Cejudo-Martin P, Wen F, Pass I, et al. (2009) The Novel Adaptor Protein Tks4 (SH3PXD2B) Is Required for Functional Podosome Formation. Mol Biol Cell 20: 1302–1311. doi: 10.1091/mbc.E08-09-0949 19144821

81. Yang B, Tian C, Zhang ZG, Han FC, Azem R, et al. (2011) Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media. PLoS ONE 6: e22622. doi: 10.1371/journal.pone.0022622 21818352

82. Iqbal Z, Cejudo-Martin P, Brouwer Ad, Zwaag Bvd, Ruiz-Lozano P, et al. (2010) Disruption of the Podosome Adaptor Protein TKS4 (SH3PXD2B) Causes the Skeletal Dysplasia, Eye, and Cardiac Abnormalities of Frank-Ter Haar Syndrome. The American Journal of Human Genetics 86: 254–261. doi: 10.1016/j.ajhg.2010.01.009 20137777

83. Wilson GR, Sunley J, Smith KR, Pope K, Bromhead CJ, et al. (2014) Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome. Eur J Hum Genet 22: 741–747. doi: 10.1038/ejhg.2013.229 24105366

84. Singh MK, Petry M, Haenig B, Lescher B, Leitges M, et al. (2005) The T-box transcription factor Tbx15 is required for skeletal development. Mech Dev 122: 131–144. 15652702

85. Candille SI, Raamsdonk CDV, Chen C, Kuijper S, Chen-Tsai Y, et al. (2004) Dorsoventral Patterning of the Mouse Coat by Tbx15. PLoS Biol 2: e3. 14737183

86. Curry GA (1959) Genetical and Developmental Studies on Droopy-eared Mice. J Embryol exp Morph 7: 39–65. 13654621

87. Lausch E, Hermanns P, Farin HF, Alanay Y, Unger S, et al. (2008) TBX15 Mutations Cause Craniofacial Dysmorphism, Hypoplasia of Scapula and Pelvis, and Short Stature in Cousin Syndrome. The American Journal of Human Genetics 83: 649–655. doi: 10.1016/j.ajhg.2008.10.011 19068278

88. Boell L (2013) Lines of least resistance and genetic architecture of house mouse (Mus musculus) mandible shape. Evolution & Development 15: 197–204.

89. Leamy LJ, Pomp D, Eisen EJ, Cheverud JM (2000) Quantitative trait loci for directional but not fluctuating asymmetry of mandible characters in mice. Genet Res Camb 76: 27–40.

90. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42: 565–569. doi: 10.1038/ng.608 20562875

91. Bérénos C, Ellis PA, Pilkington JG, Lee SH, Gratten J, et al. (2015) Heterogeneity of genetic architecture of body size traits in a free-living population. Molecular Ecology: n/a-n/a.

92. Boell L, Pallares LF, Brodski C, Chen Y, Christian JL, et al. (2013) Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation. Development Genes and Evolution 223: 279–287. doi: 10.1007/s00427-013-0443-y 23563729

93. Lekanne Deprez RH, Riegman PH, Groen NA, Warringa UL, van Biezen NA, et al. (1995) Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma. Oncogene 10: 1521–1528. 7731706

94. Tautz D, Domazet-Loso T (2011) The evolutionary origin of orphan genes. Nat Rev Genet 12: 692–702. doi: 10.1038/nrg3053 21878963

95. Rockman MV (2012) The QTN program and the alleles that matter for evolution: all that's gold does not glitter. Evolution 66: 1–17. doi: 10.1111/j.1558-5646.2011.01486.x 22220860

96. Donnelly P (2008) Progress and challenges in genome-wide association studies in humans. Nature 456: 728–731. doi: 10.1038/nature07631 19079049

97. Wood AR, Esko T, Yang J, Vedantam S, Pers TH, et al. (2014) Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 46: 1173–1186. doi: 10.1038/ng.3097 25282103

98. Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, et al. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: 832–838. doi: 10.1038/nature09410 20881960

99. Visscher PM (2008) Sizing up human height variation. Nat Genet 40: 489–490. doi: 10.1038/ng0508-489 18443579

100. Bromiley PA, Schunke AC, Ragheb H, Thacker NA, Tautz D (2014) Semi-automatic landmark point annotation for geometric morphometrics. Frontiers in Zoology 11.

101. Schunke A, Bromiley P, Tautz D, Thacker N (2012) TINA manual landmarking tool: software for the precise digitization of 3D landmarks. Frontiers in Zoology 9: 6. doi: 10.1186/1742-9994-9-6 22480150

102. Klingenberg CP (2011) MorphoJ: an integrated software package for geometric morphometrics. Molecular Ecology Resources 11: 353–357. doi: 10.1111/j.1755-0998.2010.02924.x 21429143

103. Klingenberg CP, Barluenga M, Meyer A (2002) Shape analysis of symmetric structures: quantifying variation among individuals and asymmetry. Evolution 56: 1909–1920. 12449478

104. Zelditch ML, Swiderski DL, Sheets HD (2012) Geometric Morphometrics for Biologists: A Primer. New York, USA: Elsevier Academic Press.

105. Elshire RJ, Glaubitz JC, Sun Q, Poland JA, Kawamoto K, et al. (2011) A Robust, Simple Genotyping-by-Sequencing (GBS) Approach for High Diversity Species. PLoS ONE 6: e19379. doi: 10.1371/journal.pone.0019379 21573248

106. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760. doi: 10.1093/bioinformatics/btp324 19451168

107. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20: 1297–1303. doi: 10.1101/gr.107524.110 20644199

108. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, et al. (2013) From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics 11: 11 10 11–11 10 33.

109. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, et al. (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43: 491–498. doi: 10.1038/ng.806 21478889

110. Keane TM, Goodstadt L, Danecek P, White MA, Wong K, et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477: 289–294. doi: 10.1038/nature10413 21921910

111. Howie BN, Donnelly P, Marchini J (2009) A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies. PLoS Genet 5: e1000529. doi: 10.1371/journal.pgen.1000529 19543373

112. Zhou X, Stephens M (2012) Genome-wide efficient mixed-model analysis for association studies. Nat Genet 44: 821–824. doi: 10.1038/ng.2310 22706312

113. Listgarten J, Lippert C, Kadie CM, Davidson RI, Eskin E, et al. (2012) Improved linear mixed models for genome-wide association studies. Nat Meth 9: 525–526.

114. Cheng R, Parker CC, Abney M, Palmer AA (2013) Practical Considerations Regarding the Use of Genotype and Pedigree Data to Model Relatedness in the Context of Genome-Wide Association Studies. G3: Genes|Genomes|Genetics 3: 1861–1867. doi: 10.1534/g3.113.007948 23979941

115. Yang J, Zaitlen NA, Goddard ME, Visscher PM, Price AL (2014) Advantages and pitfalls in the application of mixed-model association methods. Nat Genet 46: 100–106. doi: 10.1038/ng.2876 24473328

116. Parker CC, Carbonetto P, Sokoloff G, Park YJ, Abney M, et al. (2014) High-Resolution Genetic Mapping of Complex Traits from a Combined Analysis of F2 and Advanced Intercross Mice. Genetics 198: 103–116. doi: 10.1534/genetics.114.167056 25236452

117. Abney M (2015) Permutation testing in the presence of polygenic variation. Genet Epidemiol 39: 249–258. doi: 10.1002/gepi.21893 25758362

118. Abney M, Ober C, McPeek MS (2002) Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites. Am J Hum Genet 70: 920–934. 11880950

119. Eppig JT, Blake JA, Bult CJ, Kadin JA, Richardson JE (2012) The Mouse Genome Database (MGD): comprehensive resource for genetics and genomics of the laboratory mouse. Nucleic Acids Res 40: D881–886. doi: 10.1093/nar/gkr974 22075990

120. Klingenberg CP (2003) Quantitative genetics of geometric shape: Heritability and the pitfalls of the univariate approach. Evolution 57: 191–195. 12643582

121. Klingenberg CP, Monteiro LR (2005) Distances and Directions in Multidimensional Shape Spaces: Implications for Morphometric Applications. Syst Biol 54: 678–688. 16126663

122. Monteiro LR, Diniz JAF, dos Reis SF, Araujo ED (2002) Geometric estimates of heritability in biological shape. Evolution 56: 563–572. 11989686

123. Monteiro LR, Diniz-Filho JAF, Dos Reis SF, AraÚJo ED (2003) Shape Distances in General Linear Models: Are They Really at Odds with the Goals of Morphometrics? A Reply to Klingenberg. Evolution 57: 196–199. 12643583