摘要

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10−8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10−3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.

关键词

Human;GWAS;images;gene regulation;European;face;genome-wide association study

授权许可

© 2019, Xiong et al
http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

通讯作者

推荐引用方式

Ziyi Xiong,Gabriela Dankova,Laurence J Howe,Myoung Keun Lee,Pirro G Hysi,Markus A de Jong,Gu Zhu,Kaustubh Adhikari,Dan Li,Yi Li,Bo Pan,Eleanor Feingold,Mary L Marazita,John R Shaffer,Kerrie McAloney,Shu-Hua Xu,Li Jin,Sijia Wang,Femke MS de Vrij,Bas Lendemeijer,Stephen Richmond,Alexei Zhurov,Sarah Lewis,Gemma C Sharp,Lavinia Paternoster,Holly Thompson,Rolando Gonzalez-Jose,Maria Catira Bortolini,Samuel Canizales-Quinteros,Carla Gallo,Giovanni Poletti,Gabriel Bedoya,Francisco Rothhammer,André G Uitterlinden,M Arfan Ikram,Eppo Wolvius,Steven A Kushner,Tamar EC Nijsten,Robert-Jan TS Palstra,Stefan Boehringer,Sarah E Medland,Kun Tang,Andres Ruiz-Linares,Nicholas G Martin,Timothy D Spector,Evie Stergiakouli,Seth M Weinberg,Fan Liu,Manfred Kayser. Novel genetic loci affecting facial shape variation in humans. eLife ,Vol.8(2019)

您觉得这篇文章对您有帮助吗？

分享和收藏

参考文献

[1]	J Lonsdale, J Thomas, M Salvatore, R Phillips. et al.(2013). The Genotype-Tissue expression (GTEx) project. Nature Genetics.45:580-585. DOI: 10.6084/m9.figshare.10298396.
[2]	A Hofman, S Darwish Murad, CM van Duijn, OH Franco. et al.(2013). The Rotterdam study: 2014 objectives and design update. European Journal of Epidemiology.28:889-926. DOI: 10.6084/m9.figshare.10298396.
[3]	KU Ludwig, E Mangold, S Herms, S Nowak. et al.(2012). Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nature Genetics.44:968-971. DOI: 10.6084/m9.figshare.10298396.
[4]	N Gunhanlar, G Shpak, M van der Kroeg, LA Gouty-Colomer. et al.(2018). A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells. Molecular Psychiatry.23:1336-1344. DOI: 10.6084/m9.figshare.10298396.
[5]	E Mangold, KU Ludwig, S Birnbaum, C Baluardo. et al.(2010). Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nature Genetics.42:24-26. DOI: 10.6084/m9.figshare.10298396.
[6]	A Visconti, DL Duffy, F Liu, G Zhu. et al.(2018). Genome-wide association study in 176,678 europeans reveals genetic loci for tanning response to sun exposure. Nature Communications.9. DOI: 10.6084/m9.figshare.10298396.
[7]	J Guo, X Mei, K Tang. (2013). Automatic landmark annotation and dense correspondence registration for 3D human facial images. BMC Bioinformatics.14. DOI: 10.6084/m9.figshare.10298396.
[8]	KU Ludwig, AC Böhmer, J Bowes, M Nikolic. et al.(2017). Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only. Human Molecular Genetics.26:829-842. DOI: 10.6084/m9.figshare.10298396.
[9]	SF Grant, K Wang, H Zhang, W Glaberson. et al.(2009). A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. The Journal of Pediatrics.155:909-913. DOI: 10.6084/m9.figshare.10298396.
[10]	M Visser, RJ Palstra, M Kayser. (2014). Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene. Human Molecular Genetics.23:5750-5762. DOI: 10.6084/m9.figshare.10298396.
[11]	M Visser, M Kayser, RJ Palstra. (2012). HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Research.22:446-455. DOI: 10.6084/m9.figshare.10298396.
[12]	EJ Leslie, JC Carlson, JR Shaffer, A Butali. et al.(2017). Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Human Genetics.136:275-286. DOI: 10.6084/m9.figshare.10298396.
[13]	X Zhou, M Stephens. (2014). Efficient multivariate linear mixed model algorithms for genome-wide association studies. Nature Methods.11:407-409. DOI: 10.6084/m9.figshare.10298396.
[14]	Y Field, EA Boyle, N Telis, Z Gao. et al.(2016). Detection of human adaptation during the past 2000 years. Science.354:760-764. DOI: 10.6084/m9.figshare.10298396.
[15]	F Liu, F van der Lijn, C Schurmann, G Zhu. et al.(2012). A genome-wide association study identifies five loci influencing facial morphology in europeans. PLOS Genetics.8. DOI: 10.6084/m9.figshare.10298396.
[16]	. (2011). Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nature Genetics.43:561-564. DOI: 10.6084/m9.figshare.10298396.
[17]	A Fraser, C Macdonald-Wallis, K Tilling, A Boyd. et al.(2013). Cohort profile: the avon longitudinal study of parents and children: alspac mothers cohort. International Journal of Epidemiology.42:97-110. DOI: 10.6084/m9.figshare.10298396.
[18]	J Li, L Ji. (2005). Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity.95:221-227. DOI: 10.6084/m9.figshare.10298396.
[19]	J Golding, M Pembrey, R Jones. (2001). ALSPAC--the avon longitudinal Study of parents and children. I. study methodology. Paediatric and Perinatal Epidemiology.15:74-87. DOI: 10.6084/m9.figshare.10298396.
[20]	AM Toma, A Zhurov, R Playle, E Ong. et al.(2009). Reproducibility of facial soft tissue landmarks on 3D laser-scanned facial images. Orthodontics & Craniofacial Research.12:33-42. DOI: 10.6084/m9.figshare.10298396.
[21]	HA Thomason, MJ Dixon, J Dixon. (2008). Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and shh signaling. Developmental Biology.321:273-282. DOI: 10.6084/m9.figshare.10298396.
[22]	YG Kamberov, S Wang, J Tan, P Gerbault. et al.(2013). Modeling recent human evolution in mice by expression of a selected EDAR variant. Cell.152:691-702. DOI: 10.6084/m9.figshare.10298396.
[23]	A Siepel, G Bejerano, JS Pedersen, AS Hinrichs. et al.(2005). Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Research.15:1034-1050. DOI: 10.6084/m9.figshare.10298396.
[24]	S Joss, U Kini, R Fisher, S Mundlos. et al.(2011). The face of ulnar mammary syndrome?. European Journal of Medical Genetics.54:301-305. DOI: 10.6084/m9.figshare.10298396.
[25]	PG Hysi, AM Valdes, F Liu, NA Furlotte. et al.(2018). Genome-wide association meta-analysis of individuals of european ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. Nature Genetics.50:652-656. DOI: 10.6084/m9.figshare.10298396.
[26]	MK Singh, M Petry, B Haenig, B Lescher. et al.(2005). The T-box transcription factor Tbx15 is required for skeletal development. Mechanisms of Development.122:131-144. DOI: 10.6084/m9.figshare.10298396.
[27]	J Tan, Y Yang, K Tang, PC Sabeti. et al.(2013). The adaptive variant EDARV370A is associated with straight hair in east asians. Human Genetics.132:1187-1191. DOI: 10.6084/m9.figshare.10298396.
[28]	Y Sun, Y Huang, A Yin, Y Pan. et al.(2015). Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate. Nature Communications.6. DOI: 10.6084/m9.figshare.10298396.
[29]	GR Abecasis, A Auton, LD Brooks, MA DePristo. et al.(2012). An integrated map of genetic variation from 1,092 human genomes. Nature.491:56-65. DOI: 10.6084/m9.figshare.10298396.
[30]	K Adhikari, G Reales, AJ Smith, E Konka. et al.(2015). A genome-wide association study identifies multiple loci for variation in human ear morphology. Nature Communications.6. DOI: 10.6084/m9.figshare.10298396.
[31]	CC Hui, AL Joyner. (1993). A mouse model of greig cephalo–polysyndactyly syndrome: the extra–toesJ mutation contains an intragenic deletion of the Gli3 gene. Nature Genetics.3:241-246. DOI: 10.6084/m9.figshare.10298396.
[32]	KE Holsinger, BS Weir. (2009). Genetics in geographically structured populations: defining, estimating and interpreting F(ST). Nature Reviews Genetics.10:639-650. DOI: 10.6084/m9.figshare.10298396.
[33]	BN Howie, P Donnelly, J Marchini. (2009). A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLOS Genetics.5. DOI: 10.6084/m9.figshare.10298396.
[34]	W Satoh, M Matsuyama, H Takemura, S Aizawa. et al.(2008). Sfrp1, Sfrp2, and Sfrp5 regulate the wnt/beta-catenin and the planar cell polarity pathways during early trunk formation in mouse. Genesis.46:92-103. DOI: 10.6084/m9.figshare.10298396.
[35]	GC Schwabe, B Trepczik, K Süring, N Brieske. et al.(2004). knockout mouse as a model for the developmental pathology of autosomal recessive robinow syndrome. Developmental Dynamics.229:400-410. DOI: 10.6084/m9.figshare.10298396.
[36]	JR Shaffer, E Orlova, MK Lee, EJ Leslie. et al.(2016). Genome-Wide association study reveals multiple loci influencing normal human facial morphology. PLOS Genetics.12. DOI: 10.6084/m9.figshare.10298396.
[37]	M Kayser, F Liu, AC Janssens, F Rivadeneira. et al.(2008). Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. The American Journal of Human Genetics.82:411-423. DOI: 10.6084/m9.figshare.10298396.
[38]	MA de Jong, A Wollstein, C Ruff, D Dunaway. et al.(2016). An automatic 3D facial landmarking algorithm using 2D gabor wavelets. IEEE Transactions on Image Processing.25:580-588. DOI: 10.6084/m9.figshare.10298396.
[39]	CH Kau, A Zhurov, R Scheer, S Bouwman. et al.(2004). The feasibility of measuring three-dimensional facial morphology in children. Orthodontics and Craniofacial Research.7:198-204. DOI: 10.6084/m9.figshare.10298396.
[40]	JT Kost, MP McDermott. (2002). Combining dependent P-values. Statistics & Probability Letters.60:183-190. DOI: 10.6084/m9.figshare.10298396.
[41]	D Welter, J MacArthur, J Morales, T Burdett. et al.(2014). The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Research.42:D1001-D1006. DOI: 10.6084/m9.figshare.10298396.
[42]	AR Wood, T Esko, J Yang, S Vedantam. et al.(2014). Defining the role of common variation in the genomic and biological architecture of adult human height. Nature Genetics.46:1173-1186. DOI: 10.6084/m9.figshare.10298396.
[43]	R Kimura, T Yamaguchi, M Takeda, O Kondo. et al.(2009). A common variation in EDAR is a genetic determinant of shovel-shaped incisors. The American Journal of Human Genetics.85:528-535. DOI: 10.6084/m9.figshare.10298396.
[44]	G Sachse, C Church, M Stewart, H Cater. et al.(2018). FTO demethylase activity is essential for normal bone growth and bone mineralization in mice. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease.1864:843-850. DOI: 10.6084/m9.figshare.10298396.
[45]	PC Sabeti, DE Reich, JM Higgins, HZ Levine. et al.(2002). Detecting recent positive selection in the human genome from haplotype structure. Nature.419:832-837. DOI: 10.6084/m9.figshare.10298396.
[46]	TH Beaty, I Ruczinski, JC Murray, ML Marazita. et al.(2011). Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genetic Epidemiology.42:469-478. DOI: 10.6084/m9.figshare.10298396.
[47]	A Ruiz-Linares, K Adhikari, V Acuña-Alonzo, M Quinto-Sanchez. et al.(2014). Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals. PLOS Genetics.10. DOI: 10.6084/m9.figshare.10298396.
[48]	S Birnbaum, KU Ludwig, H Reutter, S Herms. et al.(2009). Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nature Genetics.41:473-477. DOI: 10.6084/m9.figshare.10298396.
[49]	JS Weiner. (1954). Nose shape and climate. American Journal of Physical Anthropology.12:615-618. DOI: 10.6084/m9.figshare.10298396.
[50]	TH Beaty, JC Murray, ML Marazita, RG Munger. et al.(2010). A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nature Genetics.42:525-529. DOI: 10.6084/m9.figshare.10298396.
[51]	DR Cordero, S Brugmann, Y Chu, R Bajpai. et al.(2011). Cranial neural crest cells on the move: their roles in craniofacial development. American Journal of Medical Genetics Part A.155:270-279. DOI: 10.6084/m9.figshare.10298396.
[52]	JB Cole, M Manyama, E Kimwaga, J Mathayo. et al.(2016). Genomewide association study of african children identifies association of SCHIP1 and PDE8A with facial size and shape. PLOS Genetics.12. DOI: 10.6084/m9.figshare.10298396.
[53]	H Lango Allen, K Estrada, G Lettre, SI Berndt. et al.(2010). Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature.467:832-838. DOI: 10.6084/m9.figshare.10298396.
[54]	LH Chadwick. (2012). The NIH roadmap epigenomics program data resource. Epigenomics.4:317-324. DOI: 10.6084/m9.figshare.10298396.
[55]	P Claes, J Roosenboom, JD White, T Swigut. et al.(2018). Genome-wide mapping of global-to-local genetic effects on human facial shape. Nature Genetics.50:414-423. DOI: 10.6084/m9.figshare.10298396.
[56]	BF Voight, S Kudaravalli, X Wen, JK Pritchard. et al.(2006). A map of recent positive selection in the human genome. PLOS Biology.4. DOI: 10.6084/m9.figshare.10298396.
[57]	SM Weinberg, ZD Raffensperger, MJ Kesterke, CL Heike. et al.(2016). The 3D facial norms database: part 1. A Web-Based craniofacial anthropometric and image repository for the clinical and research community. The Cleft Palate-Craniofacial Journal.53:185-197. DOI: 10.6084/m9.figshare.10298396.
[58]	G Lee, H Kim, Y Elkabetz, G Al Shamy. et al.(2007). Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nature Biotechnology.25:1468-1475. DOI: 10.6084/m9.figshare.10298396.
[59]	MK Lee, JR Shaffer, EJ Leslie, E Orlova. et al.(2017). Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2. PLOS ONE.12. DOI: 10.6084/m9.figshare.10298396.
[60]	P Royston. (1995). Remark AS R94: a remark on algorithm AS 181: the W-test for normality. Journal of the Royal Statistical Society.44:547-551. DOI: 10.6084/m9.figshare.10298396.
[61]	JH Ward. (1963). Hierarchical grouping to optimize an objective function. Journal of the American Statistical Association.58:236-244. DOI: 10.6084/m9.figshare.10298396.
[62]	BL Aken, S Ayling, D Barrell, L Clarke. et al.(2016). The ensembl gene annotation system. Database.2016. DOI: 10.6084/m9.figshare.10298396.
[63]	S Purcell, B Neale, K Todd-Brown, L Thomas. et al.(2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics.81:559-575. DOI: 10.6084/m9.figshare.10298396.
[64]	L Qiao, Y Yang, P Fu, S Hu. et al.(2018). Genome-wide variants of eurasian facial shape differentiation and a prospective model of DNA based face prediction. Journal of Genetics and Genomics.45:419-432. DOI: 10.6084/m9.figshare.10298396.
[65]	A Auton, LD Brooks, RM Durbin, EP Garrison. et al.(2015). A global reference for human genetic variation. Nature.526:68-74. DOI: 10.6084/m9.figshare.10298396.
[66]	RJ Pruim, RP Welch, S Sanna, TM Teslovich. et al.(2010). LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics.26:2336-2337. DOI: 10.6084/m9.figshare.10298396.
[67]	M Visser, RJ Palstra, M Kayser. (2015). Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter. Human Molecular Genetics.24:2649-2661. DOI: 10.6084/m9.figshare.10298396.
[68]	M Bamshad, RC Lin, DJ Law, WC Watkins. et al.(1997). Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nature Genetics.16:311-315. DOI: 10.6084/m9.figshare.10298396.
[69]	K Adhikari, M Fuentes-Guajardo, M Quinto-Sánchez, J Mendoza-Revilla. et al.(2016). A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation. Nature Communications.7. DOI: 10.6084/m9.figshare.10298396.
[70]	S Cha, JE Lim, AY Park, JH Do. et al.(2018). Identification of five novel genetic loci related to facial morphology by genome-wide association studies. BMC Genomics.19. DOI: 10.6084/m9.figshare.10298396.
[71]	S Feng, D Liu, X Zhan, MK Wing. et al.(2014). RAREMETAL: fast and powerful meta-analysis for rare variants. Bioinformatics.30:2828-2829. DOI: 10.6084/m9.figshare.10298396.
[72]	X Zhou, M Stephens. (2012). Genome-wide efficient mixed-model analysis for association studies. Nature Genetics.44:821-824. DOI: 10.6084/m9.figshare.10298396.
[73]	SL Prescott, R Srinivasan, MC Marchetto, I Grishina. et al.(2015). Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest. Cell.163:68-83. DOI: 10.6084/m9.figshare.10298396.
[74]	H Zeng, AN Hoover, A Liu. (2010). PCP effector gene inturned is an important regulator of cilia formation and embryonic development in mammals. Developmental Biology.339:418-428. DOI: 10.6084/m9.figshare.10298396.
[75]	L Paternoster, AI Zhurov, AM Toma, JP Kemp. et al.(2012). Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position. The American Journal of Human Genetics.90:478-485. DOI: 10.6084/m9.figshare.10298396.
[76]	A Zalc, R Rattenbach, F Auradé, B Cadot. et al.(2015). Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects. Developmental Cell.33:56-66. DOI: 10.6084/m9.figshare.10298396.
[77]	SB Carroll. (2008). Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell.134:25-36. DOI: 10.6084/m9.figshare.10298396.
[78]	JK Pickrell, T Berisa, JZ Liu, L Ségurel. et al.(2016). Detection and interpretation of shared genetic influences on 42 human traits. Nature Genetics.48:709-717. DOI: 10.6084/m9.figshare.10298396.
[79]	O Canela-Xandri, K Rawlik, A Tenesa. (2018). An atlas of genetic associations in UK biobank. Nature Genetics.50:1593-1599. DOI: 10.6084/m9.figshare.10298396.
[80]	Y Yu, X Zuo, M He, J Gao. et al.(2017). Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity. Nature Communications.8. DOI: 10.6084/m9.figshare.10298396.
[81]	. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature.489:57-74. DOI: 10.6084/m9.figshare.10298396.
[82]	JG Buchan, RS Gray, JM Gansner, DM Alvarado. et al.(2014). Kinesin family member 6 (kif6) is necessary for spine development in zebrafish. Developmental Dynamics.243:1646-1657. DOI: 10.6084/m9.figshare.10298396.
[83]	E Dupin, JM Coelho-Aguiar. (2013). Isolation and differentiation properties of neural crest stem cells. Cytometry Part A.83A:38-47. DOI: 10.6084/m9.figshare.10298396.
[84]	AL Bruel, B Franco, Y Duffourd, J Thevenon. et al.(2017). Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. Journal of Medical Genetics.54:371-380. DOI: 10.6084/m9.figshare.10298396.
[85]	M Delous, L Baala, R Salomon, C Laclef. et al.(2007). The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nature Genetics.39:875-881. DOI: 10.6084/m9.figshare.10298396.
[86]	J Djordjevic, AI Zhurov, S Richmond. (2016). Genetic and environmental contributions to facial morphological variation: a 3D Population-Based twin study. PLOS ONE.11. DOI: 10.6084/m9.figshare.10298396.
[87]	ML Noback, K Harvati, F Spoor. (2011). Climate-related variation of the human nasal cavity. American Journal of Physical Anthropology.145:599-614. DOI: 10.6084/m9.figshare.10298396.
[88]	J O'Connell, D Gurdasani, O Delaneau, N Pirastu. et al.(2014). A general approach for haplotype phasing across the full spectrum of relatedness. PLOS Genetics.10. DOI: 10.6084/m9.figshare.10298396.
[89]	G Yu, LG Wang, Y Han, QY He. et al.(2012). clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS: A Journal of Integrative Biology.16:284-287. DOI: 10.6084/m9.figshare.10298396.
[90]	J Yang, SH Lee, ME Goddard, PM Visscher. et al.(2011). GCTA: a tool for genome-wide complex trait analysis. The American Journal of Human Genetics.88:76-82. DOI: 10.6084/m9.figshare.10298396.
[91]	GA Wray. (2007). The evolutionary significance of cis-regulatory mutations. Nature Reviews Genetics.8:206-216. DOI: 10.6084/m9.figshare.10298396.
[92]	SJ Morrison, PM White, C Zock, DJ Anderson. et al.(1999). Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell.96:737-749. DOI: 10.6084/m9.figshare.10298396.
[93]	ME Bronner, NM LeDouarin. (2012). Development and evolution of the neural crest: an overview. Developmental Biology.366:2-9. DOI: 10.6084/m9.figshare.10298396.
[94]	BC Bjork, A Turbe-Doan, M Prysak, BJ Herron. et al.(2010). Prdm16 is required for normal palatogenesis in mice. Human Molecular Genetics.19:774-789. DOI: 10.6084/m9.figshare.10298396.
[95]	O Delaneau, J Marchini, J-F Zagury. (2012). A linear complexity phasing method for thousands of genomes. Nature Methods.9:179-181. DOI: 10.6084/m9.figshare.10298396.
[96]	A Boyd, J Golding, J Macleod, DA Lawlor. et al.(2013). Cohort profile: the 'children of the 90s'--the index offspring of the Avon Longitudinal Study of Parents and Children. International Journal of Epidemiology.42:111-127. DOI: 10.6084/m9.figshare.10298396.
[97]	MA de Jong, P Hysi, T Spector, W Niessen. et al.(2018). Ensemble landmarking of 3D facial surface scans. Scientific Reports.8. DOI: 10.6084/m9.figshare.10298396.