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Science Journals — AAAS RESEARCH | REPORTS 11. R. Sorjamaa et al., Atmos. Chem. Phys. 4, 2107–2117 21. K. Broekhuizen, P. P. Kumar, J. P. D. Abbatt, Geophys. Res. ACKNOWLEDGMENTS Lett. 31 (2004). , L01107 (2004). This work is supported by the Office of Science Early Career Atmos. Chem. Phys. et al Atmos. Environ. – 12. S. Ekström, B. Nozière, H. C. Hansson, 9, 22. K. E. H. Hartz ., 40,605 617 Research Program, through the Office of Energy Research, – 973 980 (2009). (2006). Office of Basic Energy Science of the U.S. Department of Energy Nature J. Aerosol Sci. 13. M. C. Facchini, M. Mircea, S. Fuzzi, R. J. Charlson, 401, 23. M. Hori, S. Ohta, N. Murao, S. Yamagata, 34, under contract no. DE-AC02-05CH11231. The continuous-flow – – 257 259 (1999). 419 448 (2003). streamwise thermal gradient chamber was originally developed Nat. Commun. J. Phys. Chem. A 14. B. Nozière, C. Baduel, J.-L. Jaffrezo, 5, 3335 24. A. Kristensson, T. Rosenørn, M. Bilde, 114, by Patrick Chuang and Anthanasios Nenes with support from – (2014). 379 386 (2010). NASA’s Atmospheric Radiation Measurement program. 15. Materials and methods and supporting analysis of the 25. M. Kuwata, W. Shao, R. Lebouteiller, S. T. Martin, Atmos. Chem. Phys. – experimental data are available as supplementary materials on 13, 5309 5324 (2013). SUPPLEMENTARY MATERIALS Science Online. 26. M. D. Petters et al., Tellus B Chem. Phys. Meterol. 58, 196–205 www.sciencemag.org/content/351/6280/1447/suppl/DC1 16. M. L. Shulman, M. C. Jacobson, R. J. Carlson, R. E. Synovec, (2006). Materials and Methods T. E. Young, Geophys. Res. Lett. 23, 277–280 (1996). 27. H. Wex et al., Atmos. Chem. Phys. 9, 3987–3997 (2009). Supplementary Text 17. S. Henning et al., Atmos. Chem. Phys. 5, 575–582 (2005). 28. C. R. Ruehl, K. R. Wilson, J. Phys. Chem. A 118, 3952–3966 Figs. S1 to S7 18. G. Jura, W. D. Harkins, J. Am. Chem. Soc. 68, 1941–1952 (2014). Tables S1 to S3 (1946). 29. G. C. Roberts, A. Nenes, Aerosol Sci. Technol. 39, 206–221 References (31–39) 19. R. H. Moore et al., J. Geophys. Res. Atmos. 117, D00V12 (2012). (2005). 20. E. Hammer et al., Atmos. Chem. Phys. 14,10517–10533 30.K.C.Young,A.J.Warren,J. Atmos. Sci. 49,1138–1143 18 September 2015; accepted 18 February 2016 (2014). (1992). 10.1126/science.aad4889 PROTEIN EVOLUTION most known Mendelian disease mutations in TFs occur in homeodomain proteins. We analyzed homeodomain-DNA cocrystal structures in the Pro- tein Data Bank to assemble a composite protein- Survey of variation in human DNA “contact map” (fig. S1). As anticipated, residues that contact DNA bases or phosphate backbone, transcription factors reveals or that immediately neighbor base-contacting res- idues, are enriched among Mendelian disease mu- prevalent DNA binding changes tations (P < 0.005, permutation test). In contrast, individuals in the population are depleted for 1,2,3,4 1 1 1,2 variants at base- or backbone-contacting positions Luis A. Barrera, Anastasia Vedenko, * Jesse V. Kurland, * Julia M. Rogers, (P = 0.0134 or 0.0312, respectively, permutation Stephen S. Gisselbrecht,1 Elizabeth J. Rossin,3,5,6 Jaie Woodard,1,2 Luca Mariani,1 test) (Fig. 1C). This highlights the value of con- on April 3, 2016 Kian Hong Kock,1,7 Sachi Inukai,1 Trevor Siggers,1† Leila Shokri,1 Raluca Gordân,1‡ sidering protein-DNA contacts in predicting the Nidhi Sahni,8,9,10§ Chris Cotsapas,5,6|| Tong Hao,8,9,10 Song Yi,8,9,10 Manolis Kellis,4,6 5,6,11 8,9,10 8,9,10 1,2,3,6,7,8,12 impact of variants. Mark J. Daly, Marc Vidal, David E. Hill, Martha L. Bulyk ¶ On the basis of these results, we expanded our approach to other TF families. For each variant Sequencing of exomes and genomes has revealed abundant genetic variation affecting the we considered multiple criteria, including (i) po- coding sequences of human transcription factors (TFs), but the consequences of such sition of the residue relative to the protein-DNA variation remain largely unexplored. We developed a computational, structure-based interface in homologous cocrystal structures (fig. approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity Downloaded from across 41 reference and 117 variant alleles found in individuals of diverse ancestries and 1Division of Genetics, Department of Medicine, Brigham and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding Women’s Hospital and Harvard Medical School, Boston, MA 2 affinity or specificity and identified thousands of rare alleles likely to alter the DNA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. 3Harvard- binding activity of human sequence-specific TFs. Our results suggest that most MIT Division of Health Sciences and Technology, Harvard individuals have unique repertoires of TF DNA binding activities, which may contribute Medical School, Boston, MA 02115, USA. 4Computer Science to phenotypic variation. and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 5Analytic and Translational Genetics Unit, Department of Medicine, xome sequencing studies have identified S2) from genotype data for 64,706 individuals Massachusetts General Hospital and Harvard Medical School, 6 many nonsynonymous single-nucleotide encompassing African, Asian, and European an- Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. 7Program in Biological and polymorphisms (nsSNPs) in transcription cestries (Fig. 1A) (1, 2, 7). We also identified 4552 Biomedical Sciences, Harvard University, Cambridge, MA factors (TFs) (1). Genetic variants that alter unique nonsense mutations that result in partial 02138, USA. 8Center for Cancer Systems Biology (CCSB), E Dana-Farber Cancer Institute, Boston, MA 02215, USA. transcript expression levels have been as- or full DBD truncation (table S3). 9 sociated with human disease risk and are wide- We found a median of 60 heterozygous and 20 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. 10Department of Genetics, 2 3 11 spread in human populations ( , ). Numerous homozygous DBDPs (Fig. 1B) per genome. We Harvard Medical School, Boston, MA 02115, USA. Center for Mendelian diseases are attributable to mutations found a significant depletion (odds ratio = 3.7, Human Genetics Research and Center for Computational and in TFs (4). Missense SNPs that change the amino P = 0.005, Fisher’s exact test) of DBDPs among Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. 12Department of Pathology, Brigham and acid sequence of TF DNA binding domains (DBDs) TFs with known Mendelian disease mutations ’ 6 8 Women s Hospital and Harvard Medical School, Boston, MA might disrupt their DNA binding activities and ( , ), suggesting that DBDPs in disease-associated 02115, USA. thus have detrimental effects on their gene reg- TFs have phenotypic consequences. *These authors contributed equally to this work. †Present address: ulatory functions. Despite their medical impor- We developed a computational approach (6)to Department of Biology, Boston University, Boston, MA 02215, USA. ‡ tance, the consequences of coding variation in evaluate missense substitutions in TF DBDs for Present address: Departments of Biostatistics and Bioinformatics, Computer Science, and Molecular Genetics and Microbiology, DBDs for TF function have remained largely their impact on DNA binding activity. Existing Institute for Genome Sciences and Policy, Duke University, unexplored. methods for predicting the impact of missense Durham, NC 27708, USA. §Present address: Department of We identified 53,384 unique DBD polymor- mutations (9, 10) do not adequately consider the Systems Biology, The University of Texas MD Anderson Cancer phisms (DBDPs) (table S1) (here, defined as mis- roles of residues in protein-DNA interactions, Center, Houston, TX 77030, USA. ||Present address: Department of Neurology and Department of Genetics, Yale School of Medicine, sense variants) in a curated, high-confidence set which we reasoned should improve predictions. New Haven, CT 06520, USA. ¶Corresponding author. E-mail: of 1254 sequence-specific human TFs (5, 6)(table We first focused on homeodomain DBDs, as [email protected] 1450 25 MARCH 2016 • VOL 351 ISSUE 6280 sciencemag.org SCIENCE RESEARCH | REPORTS ExAC 0.08 Type Reference 1kG 0.06 Heterozygous Project Homozygous nsSNP 0.04 4,008 39,386 Mendelian 696 2,291 Type of alleles 36 0.02 020406080 5,736 Relative frequency Number of alleles 0.00 1,231 ESP6500 20 40 60 80 100 DBDPs per individual Fig. 1. Evaluation of coding variation in TF DBDs. (A)Numberof I II III unique DBDPs in 1kG (Phase 3), ESP 6500, or ExAC v0.2 individuals. (B) Histograms of unique DBDPs per individual in either homozy- gous or heterozygous states. (C) Number of Mendelian mutations, 20 20 * and nsSNPs found in ExAC, across all homeodomain TFs annotated * by their position and type of DNA contact associated with each 10 10 * Mean position. “I,”“II,” and “III” refer to a helices; III is the DNA-recognition Mendelian mutations helix. Adjacent bar graphs depict mean number of variants for each 0 00 Mean.AC position type; enrichment (*) or depletion (**) relative to non–DNA- 0 1102030405010 contacting residues (P < 0.05, permutation test); error bars rep- 10 pfam.domain.position 20 N resent 1 SEM, = 332 Mendelian mutations, 1300 nsSNPs, and 11 20 30 base-contacting, 12 phosphate-backbone–contacting, 5 neighboring- DBDPs 30 40 * – – – * DNA contacting, and 30 non DNA contacting positions. (D)Allele 40 * * types assayed by PBMs. Mutations per 11020304050 position type Residue type: Position Backbone-contacting Next to base-contacting Base-contacting Not DNA-contacting NR1H4 Specificity change No change Affinity change 0.5 * 0.50 0.50 Allele R2 = 0.76 Matching R2 = 0.98 150 0.4 CRX R90W 0.3 6-mer CRX ref.
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