Snyder Lab

Publications

All Publications (772)

Featured Publications (79)

Journal Articles (705)

Conference Proceedings (17)

Stanford W. Ascherman, MD, FACS, Professor in Genetics

Publications

  • An integrative ENCODE resource for cancer genomics. Nature communications Zhang, J., Lee, D., Dhiman, V., Jiang, P., Xu, J., McGillivray, P., Yang, H., Liu, J., Meyerson, W., Clarke, D., Gu, M., Li, S., Lou, S., Xu, J., Lochovsky, L., Ung, M., Ma, L., Yu, S., Cao, Q., Harmanci, A., Yan, K., Sethi, A., Gursoy, G., Schoenberg, M. R., Rozowsky, J., Warrell, J., Emani, P., Yang, Y. T., Galeev, T., Kong, X., Liu, S., Li, X., Krishnan, J., Feng, Y., Rivera-Mulia, J. C., Adrian, J., Broach, J. R., Bolt, M., Moran, J., Fitzgerald, D., Dileep, V., Liu, T., Mei, S., Sasaki, T., Trevilla-Garcia, C., Wang, S., Wang, Y., Zang, C., Wang, D., Klein, R. J., Snyder, M., Gilbert, D. M., Yip, K., Cheng, C., Yue, F., Liu, X. S., White, K. P., Gerstein, M. 2020; 11 (1): 3696

    Abstract

    ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.

    View details for DOI 10.1038/s41467-020-14743-w

    View details for PubMedID 32728046

  • Perspectives on ENCODE. Nature ENCODE Project Consortium, Snyder, M. P., Gingeras, T. R., Moore, J. E., Weng, Z., Gerstein, M. B., Ren, B., Hardison, R. C., Stamatoyannopoulos, J. A., Graveley, B. R., Feingold, E. A., Pazin, M. J., Pagan, M., Gilchrist, D. A., Hitz, B. C., Cherry, J. M., Bernstein, B. E., Mendenhall, E. M., Zerbino, D. R., Frankish, A., Flicek, P., Myers, R. M., Abascal, F., Acosta, R., Addleman, N. J., Adrian, J., Afzal, V., Aken, B., Akiyama, J. A., Jammal, O. A., Amrhein, H., Anderson, S. M., Andrews, G. R., Antoshechkin, I., Ardlie, K. G., Armstrong, J., Astley, M., Banerjee, B., Barkal, A. A., Barnes, I. H., Barozzi, I., Barrell, D., Barson, G., Bates, D., Baymuradov, U. K., Bazile, C., Beer, M. A., Beik, S., Bender, M. A., Bennett, R., Bouvrette, L. P., Bernstein, B. E., Berry, A., Bhaskar, A., Bignell, A., Blue, S. M., Bodine, D. M., Boix, C., Boley, N., Borrman, T., Borsari, B., Boyle, A. P., Brandsmeier, L. A., Breschi, A., Bresnick, E. H., Brooks, J. A., Buckley, M., Burge, C. B., Byron, R., Cahill, E., Cai, L., Cao, L., Carty, M., Castanon, R. G., Castillo, A., Chaib, H., Chan, E. T., Chee, D. R., Chee, S., Chen, H., Chen, H., Chen, J., Chen, S., Cherry, J. M., Chhetri, S. B., Choudhary, J. S., Chrast, J., Chung, D., Clarke, D., Cody, N. A., Coppola, C. J., Coursen, J., D'Ippolito, A. M., Dalton, S., Danyko, C., Davidson, C., Davila-Velderrain, J., Davis, C. A., Dekker, J., Deran, A., DeSalvo, G., Despacio-Reyes, G., Dewey, C. N., Dickel, D. E., Diegel, M., Diekhans, M., Dileep, V., Ding, B., Djebali, S., Dobin, A., Dominguez, D., Donaldson, S., Drenkow, J., Dreszer, T. R., Drier, Y., Duff, M. O., Dunn, D., Eastman, C., Ecker, J. R., Edwards, M. D., El-Ali, N., Elhajjajy, S. I., Elkins, K., Emili, A., Epstein, C. B., Evans, R. C., Ezkurdia, I., Fan, K., Farnham, P. J., Farrell, N., Feingold, E. A., Ferreira, A., Fisher-Aylor, K., Fitzgerald, S., Flicek, P., Foo, C. S., Fortier, K., Frankish, A., Freese, P., Fu, S., Fu, X., Fu, Y., Fukuda-Yuzawa, Y., Fulciniti, M., Funnell, A. P., Gabdank, I., Galeev, T., Gao, M., Giron, C. G., Garvin, T. H., Gelboin-Burkhart, C. A., Georgolopoulos, G., Gerstein, M. B., Giardine, B. M., Gifford, D. K., Gilbert, D. M., Gilchrist, D. A., Gillespie, S., Gingeras, T. R., Gong, P., Gonzalez, A., Gonzalez, J. M., Good, P., Goren, A., Gorkin, D. U., Graveley, B. R., Gray, M., Greenblatt, J. F., Griffiths, E., Groudine, M. T., Grubert, F., Gu, M., Guigo, R., Guo, H., Guo, Y., Guo, Y., Gursoy, G., Gutierrez-Arcelus, M., Halow, J., Hardison, R. C., Hardy, M., Hariharan, M., Harmanci, A., Harrington, A., Harrow, J. L., Hashimoto, T. B., Hasz, R. D., Hatan, M., Haugen, E., Hayes, J. E., He, P., He, Y., Heidari, N., Hendrickson, D., Heuston, E. F., Hilton, J. A., Hitz, B. C., Hochman, A., Holgren, C., Hou, L., Hou, S., Hsiao, Y. E., Hsu, S., Huang, H., Hubbard, T. J., Huey, J., Hughes, T. R., Hunt, T., Ibarrientos, S., Issner, R., Iwata, M., Izuogu, O., Jaakkola, T., Jameel, N., Jansen, C., Jiang, L., Jiang, P., Johnson, A., Johnson, R., Jungreis, I., Kadaba, M., Kasowski, M., Kasparian, M., Kato, M., Kaul, R., Kawli, T., Kay, M., Keen, J. C., Keles, S., Keller, C. A., Kelley, D., Kellis, M., Kheradpour, P., Kim, D. S., Kirilusha, A., Klein, R. J., Knoechel, B., Kuan, S., Kulik, M. J., Kumar, S., Kundaje, A., Kutyavin, T., Lagarde, J., Lajoie, B. R., Lambert, N. J., Lazar, J., Lee, A. Y., Lee, D., Lee, E., Lee, J. W., Lee, K., Leslie, C. S., Levy, S., Li, B., Li, H., Li, N., Li, X., Li, Y. I., Li, Y., Li, Y., Li, Y., Lian, J., Libbrecht, M. W., Lin, S., Lin, Y., Liu, D., Liu, J., Liu, P., Liu, T., Liu, X. S., Liu, Y., Liu, Y., Long, M., Lou, S., Loveland, J., Lu, A., Lu, Y., Lecuyer, E., Ma, L., Mackiewicz, M., Mannion, B. J., Mannstadt, M., Manthravadi, D., Marinov, G. K., Martin, F. J., Mattei, E., McCue, K., McEown, M., McVicker, G., Meadows, S. K., Meissner, A., Mendenhall, E. M., Messer, C. L., Meuleman, W., Meyer, C., Miller, S., Milton, M. G., Mishra, T., Moore, D. E., Moore, H. M., Moore, J. E., Moore, S. H., Moran, J., Mortazavi, A., Mudge, J. M., Munshi, N., Murad, R., Myers, R. M., Nandakumar, V., Nandi, P., Narasimha, A. M., Narayanan, A. K., Naughton, H., Navarro, F. C., Navas, P., Nazarovs, J., Nelson, J., Neph, S., Neri, F. J., Nery, J. R., Nesmith, A. R., Newberry, J. S., Newberry, K. M., Ngo, V., Nguyen, R., Nguyen, T. B., Nguyen, T., Nishida, A., Noble, W. S., Novak, C. S., Novoa, E. M., Nunez, B., O'Donnell, C. W., Olson, S., Onate, K. C., Otterman, E., Ozadam, H., Pagan, M., Palden, T., Pan, X., Park, Y., Partridge, E. C., Paten, B., Pauli-Behn, F., Pazin, M. J., Pei, B., Pennacchio, L. A., Perez, A. R., Perry, E. H., Pervouchine, D. D., Phalke, N. N., Pham, Q., Phanstiel, D. H., Plajzer-Frick, I., Pratt, G. A., Pratt, H. E., Preissl, S., Pritchard, J. K., Pritykin, Y., Purcaro, M. J., Qin, Q., Quinones-Valdez, G., Rabano, I., Radovani, E., Raj, A., Rajagopal, N., Ram, O., Ramirez, L., Ramirez, R. N., Rausch, D., Raychaudhuri, S., Raymond, J., Razavi, R., Reddy, T. E., Reimonn, T. M., Ren, B., Reymond, A., Reynolds, A., Rhie, S. K., Rinn, J., Rivera, M., Rivera-Mulia, J. C., Roberts, B., Rodriguez, J. M., Rozowsky, J., Ryan, R., Rynes, E., Salins, D. N., Sandstrom, R., Sasaki, T., Sathe, S., Savic, D., Scavelli, A., Scheiman, J., Schlaffner, C., Schloss, J. A., Schmitges, F. W., See, L. H., Sethi, A., Setty, M., Shafer, A., Shan, S., Sharon, E., Shen, Q., Shen, Y., Sherwood, R. I., Shi, M., Shin, S., Shoresh, N., Siebenthall, K., Sisu, C., Slifer, T., Sloan, C. A., Smith, A., Snetkova, V., Snyder, M. P., Spacek, D. V., Srinivasan, S., Srivas, R., Stamatoyannopoulos, G., Stamatoyannopoulos, J. A., Stanton, R., Steffan, D., Stehling-Sun, S., Strattan, J. S., Su, A., Sundararaman, B., Suner, M., Syed, T., Szynkarek, M., Tanaka, F. Y., Tenen, D., Teng, M., Thomas, J. A., Toffey, D., Tress, M. L., Trout, D. E., Trynka, G., Tsuji, J., Upchurch, S. A., Ursu, O., Uszczynska-Ratajczak, B., Uziel, M. C., Valencia, A., Biber, B. V., van der Velde, A. G., Van Nostrand, E. L., Vaydylevich, Y., Vazquez, J., Victorsen, A., Vielmetter, J., Vierstra, J., Visel, A., Vlasova, A., Vockley, C. M., Volpi, S., Vong, S., Wang, H., Wang, M., Wang, Q., Wang, R., Wang, T., Wang, W., Wang, X., Wang, Y., Watson, N. K., Wei, X., Wei, Z., Weisser, H., Weissman, S. M., Welch, R., Welikson, R. E., Weng, Z., Westra, H., Whitaker, J. W., White, C., White, K. P., Wildberg, A., Williams, B. A., Wine, D., Witt, H. N., Wold, B., Wolf, M., Wright, J., Xiao, R., Xiao, X., Xu, J., Xu, J., Yan, K., Yan, Y., Yang, H., Yang, X., Yang, Y., Yardimci, G. G., Yee, B. A., Yeo, G. W., Young, T., Yu, T., Yue, F., Zaleski, C., Zang, C., Zeng, H., Zeng, W., Zerbino, D. R., Zhai, J., Zhan, L., Zhan, Y., Zhang, B., Zhang, J., Zhang, J., Zhang, K., Zhang, L., Zhang, P., Zhang, Q., Zhang, X., Zhang, Y., Zhang, Z., Zhao, Y., Zheng, Y., Zhong, G., Zhou, X., Zhu, Y., Zimmerman, J. 2020; 583 (7818): 693–98

    Abstract

    The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

    View details for DOI 10.1038/s41586-020-2449-8

    View details for PubMedID 32728248

  • Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women. Cell Liang, L., Rasmussen, M. H., Piening, B., Shen, X., Chen, S., Rost, H., Snyder, J. K., Tibshirani, R., Skotte, L., Lee, N. C., Contrepois, K., Feenstra, B., Zackriah, H., Snyder, M., Melbye, M. 2020; 181 (7): 1680

    Abstract

    Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R= 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.

    View details for DOI 10.1016/j.cell.2020.05.002

    View details for PubMedID 32589958

  • Systematic identification of silencers in human cells. Nature genetics Pang, B., Snyder, M. P. 2020

    Abstract

    The majority of the human genome does not encode proteins. Many of these noncoding regions contain important regulatory sequences that control gene expression. To date, most studies have focused on activators such as enhancers, but regions that repress gene expression-silencers-have not been systematically studied. We have developed a system that identifies silencer regions in a genome-wide fashion on the basis of silencer-mediated transcriptional repression of caspase9. We found that silencers are widely distributed and may function in a tissue-specific fashion. These silencers harbor unique epigenetic signatures and are associated with specific transcription factors. Silencers also act at multiple genes, and at the level of chromosomal domains and long-range interactions. Deletion of silencer regions linked to the drug transporter genes ABCC2 and ABCG2 caused chemo-resistance. Overall, our study demonstrates that tissue-specific silencing is widespread throughout the human genome and probably contributes substantially to the regulation of gene expression and human biology.

    View details for DOI 10.1038/s41588-020-0578-5

    View details for PubMedID 32094911

  • Molecular Choreography of Acute Exercise. Cell Contrepois, K., Wu, S., Moneghetti, K. J., Hornburg, D., Ahadi, S., Tsai, M. S., Metwally, A. A., Wei, E., Lee-McMullen, B., Quijada, J. V., Chen, S., Christle, J. W., Ellenberger, M., Balliu, B., Taylor, S., Durrant, M. G., Knowles, D. A., Choudhry, H., Ashland, M., Bahmani, A., Enslen, B., Amsallem, M., Kobayashi, Y., Avina, M., Perelman, D., Schüssler-Fiorenza Rose, S. M., Zhou, W., Ashley, E. A., Montgomery, S. B., Chaib, H., Haddad, F., Snyder, M. P. 2020; 181 (5): 1112–30.e16

    Abstract

    Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

    View details for DOI 10.1016/j.cell.2020.04.043

    View details for PubMedID 32470399

  • Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nature medicine Ahadi, S., Zhou, W., Schussler-Fiorenza Rose, S. M., Sailani, M. R., Contrepois, K., Avina, M., Ashland, M., Brunet, A., Snyder, M. 2020; 26 (1): 83–90

    Abstract

    The molecular changes that occur with aging are not well understood1-4. Here, we performed longitudinal and deep multiomics profiling of 106 healthy individuals from 29 to 75 years of age and examined how different types of 'omic' measurements, including transcripts, proteins, metabolites, cytokines, microbes and clinical laboratory values, correlate with age. We identified both known and new markers that associated with age, as well as distinct molecular patterns of aging in insulin-resistant as compared to insulin-sensitive individuals. In a longitudinal setting, we identified personal aging markers whose levels changed over a short time frame of 2-3 years. Further, we defined different types of aging patterns in different individuals, termed 'ageotypes', on the basis of the types of molecular pathways that changed over time in a given individual. Ageotypes may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history, that may ultimately be useful in monitoring and intervening in the aging process.

    View details for DOI 10.1038/s41591-019-0719-5

    View details for PubMedID 31932806

  • A Quantitative Proteome Map of the Human Body. Cell Jiang, L., Wang, M., Lin, S., Jian, R., Li, X., Chan, J., Dong, G., Fang, H., Robinson, A. E., Snyder, M. P. 2020

    Abstract

    Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from over 12,000 genes across 32 normal human tissues. Tissue-specific or tissue-enriched proteins were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode tissue-specific proteins. Discordance of RNA and protein enrichment revealed potential sites of synthesis and action of secreted proteins. The tissue-specific distribution of proteins also provides an in-depth view of complex biological events that require the interplay of multiple tissues. Most importantly, our study demonstrated that protein tissue-enrichment information can explain phenotypes of genetic diseases, which cannot be obtained by transcript information alone. Overall, our results demonstrate how understanding protein levels can provide insights into regulation, secretome, metabolism, and human diseases.

    View details for DOI 10.1016/j.cell.2020.08.036

    View details for PubMedID 32916130

  • Candidate variants in TUB are associated with familial tremor. PLoS genetics Sailani, M. R., Jahanbani, F., Abbott, C. W., Lee, H., Zia, A., Rego, S., Winkelmann, J., Hopfner, F., Khan, T. N., Katsanis, N., Müller, S. H., Berg, D., Lyman, K. M., Mychajliw, C., Deuschl, G., Bernstein, J. A., Kuhlenbäumer, G., Snyder, M. P. 2020; 16 (9): e1009010

    Abstract

    Essential tremor (ET) is the most common adult-onset movement disorder. In the present study, we performed whole exome sequencing of a large ET-affected family (10 affected and 6 un-affected family members) and identified a TUB p.V431I variant (rs75594955) segregating in a manner consistent with autosomal-dominant inheritance. Subsequent targeted re-sequencing of TUB in 820 unrelated individuals with sporadic ET and 630 controls revealed significant enrichment of rare nonsynonymous TUB variants (e.g. rs75594955: p.V431I, rs1241709665: p.Ile20Phe, rs55648406: p.Arg49Gln) in the ET cohort (SKAT-O test p-value = 6.20e-08). TUB encodes a transcription factor predominantly expressed in neuronal cells and has been previously implicated in obesity. ChIP-seq analyses of the TUB transcription factor across different regions of the mouse brain revealed that TUB regulates the pathways responsible for neurotransmitter production as well thyroid hormone signaling. Together, these results support the association of rare variants in TUB with ET.

    View details for DOI 10.1371/journal.pgen.1009010

    View details for PubMedID 32956375

  • Landscape of cohesin-mediated chromatin loops in the human genome. Nature Grubert, F., Srivas, R., Spacek, D. V., Kasowski, M., Ruiz-Velasco, M., Sinnott-Armstrong, N., Greenside, P., Narasimha, A., Liu, Q., Geller, B., Sanghi, A., Kulik, M., Sa, S., Rabinovitch, M., Kundaje, A., Dalton, S., Zaugg, J. B., Snyder, M. 2020; 583 (7818): 737–43

    Abstract

    Physical interactions between distal regulatory elements have a key role in regulating gene expression, but the extent to which these interactions vary between cell types and contribute to cell-type-specific gene expression remains unclear. Here, to address these questions as part of phase III of the Encyclopedia of DNA Elements (ENCODE), we mapped cohesin-mediated chromatin loops, using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET), and analysed gene expression in 24 diverse human cell types, including core ENCODE cell lines. Twenty-eight per cent of all chromatin loops vary across cell types; these variations modestly correlate with changes in gene expression and are effective at grouping cell types according to their tissue of origin. The connectivity of genes corresponds to different functional classes, with housekeeping genes having few contacts, and dosage-sensitive genes being more connected to enhancer elements. This atlas of chromatin loops complements the diverse maps of regulatory architecture that comprise the ENCODE Encyclopedia, and will help to support emerging analyses of genome structure and function.

    View details for DOI 10.1038/s41586-020-2151-x

    View details for PubMedID 32728247

  • Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature Moore, J. E., Purcaro, M. J., Pratt, H. E., Epstein, C. B., Shoresh, N., Adrian, J., Kawli, T., Davis, C. A., Dobin, A., Kaul, R., Halow, J., Van Nostrand, E. L., Freese, P., Gorkin, D. U., Shen, Y., He, Y., Mackiewicz, M., Pauli-Behn, F., Williams, B. A., Mortazavi, A., Keller, C. A., Zhang, X. O., Elhajjajy, S. I., Huey, J., Dickel, D. E., Snetkova, V., Wei, X., Wang, X., Rivera-Mulia, J. C., Rozowsky, J., Zhang, J., Chhetri, S. B., Zhang, J., Victorsen, A., White, K. P., Visel, A., Yeo, G. W., Burge, C. B., Lécuyer, E., Gilbert, D. M., Dekker, J., Rinn, J., Mendenhall, E. M., Ecker, J. R., Kellis, M., Klein, R. J., Noble, W. S., Kundaje, A., Guigó, R., Farnham, P. J., Cherry, J. M., Myers, R. M., Ren, B., Graveley, B. R., Gerstein, M. B., Pennacchio, L. A., Snyder, M. P., Bernstein, B. E., Wold, B., Hardison, R. C., Gingeras, T. R., Stamatoyannopoulos, J. A., Weng, Z. 2020; 583 (7818): 699–710

    Abstract

    The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

    View details for DOI 10.1038/s41586-020-2493-4

    View details for PubMedID 32728249

  • Deep longitudinal multiomics profiling reveals two biological seasonal patterns in California. Nature communications Sailani, M. R., Metwally, A. A., Zhou, W., Rose, S. M., Ahadi, S., Contrepois, K., Mishra, T., Zhang, M. J., Kidziński, Ł., Chu, T. J., Snyder, M. P. 2020; 11 (1): 4933

    Abstract

    The influence of seasons on biological processes is poorly understood. In order to identify biological seasonal patterns based on diverse molecular data, rather than calendar dates, we performed a deep longitudinal multiomics profiling of 105 individuals over 4 years. Here, we report more than 1000 seasonal variations in omics analytes and clinical measures. The different molecules group into two major seasonal patterns which correlate with peaks in late spring and late fall/early winter in California. The two patterns are enriched for molecules involved in human biological processes such as inflammation, immunity, cardiovascular health, as well as neurological and psychiatric conditions. Lastly, we identify molecules and microbes that demonstrate different seasonal patterns in insulin sensitive and insulin resistant individuals. The results of our study have important implications in healthcare and highlight the value of considering seasonality when assessing population wide health risk and management.

    View details for DOI 10.1038/s41467-020-18758-1

    View details for PubMedID 33004787

  • Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing. Molecular & cellular proteomics : MCP Mitsunaga, E. M., Snyder, M. P. 2019

    Abstract

    Human antibody response studies are largely restricted to periods of high immune activity (e.g., vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.

    View details for DOI 10.1074/mcp.RA119.001633

    View details for PubMedID 31767621

  • The human body at cellular resolution: the NIH Human Biomolecular Atlas Program NATURE Snyder, M. P., Lin, S., Posgai, A., Atkinson, M., Regev, A., Rood, J., Rozenblatt-Rosen, O., Gaffney, L., Hupalowska, A., Satija, R., Gehlenborg, N., Shendure, J., Laskin, J., Harbury, P., Nystrom, N. A., Silverstein, J. C., Bar-Joseph, Z., Zhang, K., Borner, K., Lin, Y., Conroy, R., Procaccini, D., Roy, A. L., Pillai, A., Brown, M., Galis, Z. S., Cai, L., Shendure, J., Trapnell, C., Lin, S., Jackson, D., Snyder, M. P., Nolan, G., Greenleaf, W., Lin, Y., Plevritis, S., Ahadi, S., Nevins, S. A., Lee, H., Schuerch, C., Black, S., Venkataraaman, V., Esplin, E., Horning, A., Bahmani, A., Zhang, K., Sun, X., Jain, S., Hagood, J., Pryhuber, G., Kharchenko, P., Atkinson, M., Bodenmiller, B., Brusko, T., Clare-Salzler, M., Nick, H., Otto, K., Posgai, A., Wasserfall, C., Jorgensen, M., Brusko, M., Maffioletti, S., Caprioli, R. M., Spraggins, J. M., Gutierrez, D., Patterson, N., Neumann, E. K., Harris, R., deCaestecker, M., Fogo, A. B., van de Plas, R., Lau, K., Cai, L., Yuan, G., Zhu, Q., Dries, R., Yin, P., Saka, S. K., Kishi, J. Y., Wang, Y., Goldaracena, I., Laskin, J., Ye, D., Burnum-Johnson, K. E., Piehowski, P. D., Ansong, C., Zhu, Y., Harbury, P., Desai, T., Mulye, J., Chou, P., Nagendran, M., Bar-Joseph, Z., Teichmann, S. A., Paten, B., Murphy, R. F., Ma, J., Kiselev, V., Kingsford, C., Ricarte, A., Keays, M., Akoju, S. A., Ruffalo, M., Gehlenborg, N., Kharchenko, P., Vella, M., McCallum, C., Borner, K., Cross, L. E., Friedman, S. H., Heiland, R., Herr, B., Macklin, P., Quardokus, E. M., Record, L., Sluka, J. P., Weber, G. M., Nystrom, N. A., Silverstein, J. C., Blood, P. D., Ropelewski, A. J., Shirey, W. E., Scibek, R. M., Mabee, P., Lenhardt, W., Robasky, K., Michailidis, S., Satija, R., Marioni, J., Regev, A., Butler, A., Stuart, T., Fisher, E., Ghazanfar, S., Rood, J., Gaffney, L., Eraslan, G., Biancalani, T., Vaishnav, E. D., Conroy, R., Procaccini, D., Roy, A., Pillai, A., Brown, M., Galis, Z., Srinivas, P., Pawlyk, A., Sechi, S., Wilder, E., Anderson, J., HuBMAP Consortium 2019; 574 (7777): 187–92

    Abstract

    Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions.

    View details for DOI 10.1038/s41586-019-1629-x

    View details for Web of Science ID 000489784200035

    View details for PubMedID 31597973

    View details for PubMedCentralID PMC6800388

  • HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding. Molecular cell Gruber, J. J., Geller, B., Lipchik, A. M., Chen, J., Salahudeen, A. A., Ram, A. N., Ford, J. M., Kuo, C. J., Snyder, M. P. 2019

    Abstract

    The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation, and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feedforward circuit whereby HAT1 captures acetyl groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types.

    View details for DOI 10.1016/j.molcel.2019.05.034

    View details for PubMedID 31278053

  • The Integrative Human Microbiome Project NATURE Proctor, L. M., Creasy, H. H., Fettweis, J. M., Lloyd-Price, J., Mahurkar, A., Zhou, W., Buck, G. A., Snyder, M. P., Strauss, J. F., Weinstock, G. M., White, O., Huttenhower, C., Integrative HMP iHMP Res Network 2019; 569 (7758): 641–48

    Abstract

    The NIH Human Microbiome Project (HMP) has been carried out over ten years and two phases to provide resources, methods, and discoveries that link interactions between humans and their microbiomes to health-related outcomes. The recently completed second phase, the Integrative Human Microbiome Project, comprised studies of dynamic changes in the microbiome and host under three conditions: pregnancy and preterm birth; inflammatory bowel diseases; and stressors that affect individuals with prediabetes. The associated research begins to elucidate mechanisms of host-microbiome interactions under these conditions, provides unique data resources (at the HMP Data Coordination Center), and represents a paradigm for future multi-omic studies of the human microbiome.

    View details for DOI 10.1038/s41586-019-1238-8

    View details for Web of Science ID 000470144100031

    View details for PubMedID 31142853

  • A longitudinal big data approach for precision health NATURE MEDICINE Rose, S., Contrepois, K., Moneghetti, K. J., Zhou, W., Mishra, T., Mataraso, S., Dagan-Rosenfeld, O., Ganz, A. B., Dunn, J., Hornburg, D., Rego, S., Perelman, D., Ahadi, S., Sailani, M., Zhou, Y., Leopold, S. R., Chen, J., Ashland, M., Christle, J. W., Avina, M., Limcaoco, P., Ruiz, C., Tan, M., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E., McLaughlin, T. L., Haddad, F., Snyder, M. P. 2019; 25 (5): 792-+
  • Longitudinal multi-omics of host-microbe dynamics in prediabetes. Nature Zhou, W., Sailani, M. R., Contrepois, K., Zhou, Y., Ahadi, S., Leopold, S. R., Zhang, M. J., Rao, V., Avina, M., Mishra, T., Johnson, J., Lee-McMullen, B., Chen, S., Metwally, A. A., Tran, T. D., Nguyen, H., Zhou, X., Albright, B., Hong, B., Petersen, L., Bautista, E., Hanson, B., Chen, L., Spakowicz, D., Bahmani, A., Salins, D., Leopold, B., Ashland, M., Dagan-Rosenfeld, O., Rego, S., Limcaoco, P., Colbert, E., Allister, C., Perelman, D., Craig, C., Wei, E., Chaib, H., Hornburg, D., Dunn, J., Liang, L., Rose, S. M., Kukurba, K., Piening, B., Rost, H., Tse, D., McLaughlin, T., Sodergren, E., Weinstock, G. M., Snyder, M. 2019; 569 (7758): 663–71

    Abstract

    Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2Dbetter, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

    View details for DOI 10.1038/s41586-019-1236-x

    View details for PubMedID 31142858

  • The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight SCIENCE Garrett-Bakelman, F. E., Darshi, M., Green, S. J., Gur, R. C., Lin, L., Macias, B. R., McKenna, M. J., Meydan, C., Mishra, T., Nasrini, J., Piening, B. D., Rizzardi, L. F., Sharma, K., Siamwala, J. H., Taylor, L., Vitaterna, M., Afkarian, M., Afshinnekoo, E., Ahadi, S., Ambati, A., Arya, M., Bezdan, D., Callahan, C. M., Chen, S., Choi, A. K., Chlipala, G. E., Contrepois, K., Covington, M., Crucian, B. E., De Vivo, I., Dinges, D. F., Ebert, D. J., Feinberg, J. I., Gandara, J. A., George, K. A., Goutsias, J., Grills, G. S., Hargens, A. R., Heer, M., Hillary, R. P., Hoofnagle, A. N., Hook, V. H., Jenkinson, G., Jiang, P., Keshavarzian, A., Laurie, S. S., Lee-McMullen, B., Lumpkins, S. B., MacKay, M., Maienschein-Cline, M. G., Melnick, A. M., Moore, T. M., Nakahira, K., Patel, H. H., Pietrzyk, R., Rao, V., Saito, R., Salins, D. N., Schilling, J. M., Sears, D. D., Sheridan, C. K., Stenger, M. B., Tryggvadottir, R., Urban, A. E., Vaisar, T., Van Espen, B., Zhang, J., Ziegler, M. G., Zwart, S. R., Charles, J. B., Kundrot, C. E., Scott, G. I., Bailey, S. M., Basner, M., Feinberg, A. P., Lee, S. C., Mason, C. E., Mignot, E., Rana, B. K., Smith, S. M., Snyder, M. P., Turek, F. W. 2019; 364 (6436): 144-+
  • Gene-Environment Interaction in the Era of Precision Medicine CELL Li, J., Li, X., Zhang, S., Snyder, M. 2019; 177 (1): 38–44
  • A longitudinal big data approach for precision health. Nature medicine Schüssler-Fiorenza Rose, S. M., Contrepois, K., Moneghetti, K. J., Zhou, W., Mishra, T., Mataraso, S., Dagan-Rosenfeld, O., Ganz, A. B., Dunn, J., Hornburg, D., Rego, S., Perelman, D., Ahadi, S., Sailani, M. R., Zhou, Y., Leopold, S. R., Chen, J., Ashland, M., Christle, J. W., Avina, M., Limcaoco, P., Ruiz, C., Tan, M., Butte, A. J., Weinstock, G. M., Slavich, G. M., Sodergren, E., McLaughlin, T. L., Haddad, F., Snyder, M. P. 2019; 25 (5): 792–804

    Abstract

    Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

    View details for PubMedID 31068711

  • Chromatin Remodeling in Response to BRCA2-Crisis. Cell reports Gruber, J. J., Chen, J., Geller, B., Jäger, N., Lipchik, A. M., Wang, G., Kurian, A. W., Ford, J. M., Snyder, M. P. 2019; 28 (8): 2182–93.e6

    Abstract

    Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function ("BRCA2-crisis"), which may contribute to disease. Here, we establish an in vitro model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.

    View details for DOI 10.1016/j.celrep.2019.07.057

    View details for PubMedID 31433991

  • The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science (New York, N.Y.) Garrett-Bakelman, F. E., Darshi, M., Green, S. J., Gur, R. C., Lin, L., Macias, B. R., McKenna, M. J., Meydan, C., Mishra, T., Nasrini, J., Piening, B. D., Rizzardi, L. F., Sharma, K., Siamwala, J. H., Taylor, L., Vitaterna, M. H., Afkarian, M., Afshinnekoo, E., Ahadi, S., Ambati, A., Arya, M., Bezdan, D., Callahan, C. M., Chen, S., Choi, A. M., Chlipala, G. E., Contrepois, K., Covington, M., Crucian, B. E., De Vivo, I., Dinges, D. F., Ebert, D. J., Feinberg, J. I., Gandara, J. A., George, K. A., Goutsias, J., Grills, G. S., Hargens, A. R., Heer, M., Hillary, R. P., Hoofnagle, A. N., Hook, V. Y., Jenkinson, G., Jiang, P., Keshavarzian, A., Laurie, S. S., Lee-McMullen, B., Lumpkins, S. B., MacKay, M., Maienschein-Cline, M. G., Melnick, A. M., Moore, T. M., Nakahira, K., Patel, H. H., Pietrzyk, R., Rao, V., Saito, R., Salins, D. N., Schilling, J. M., Sears, D. D., Sheridan, C. K., Stenger, M. B., Tryggvadottir, R., Urban, A. E., Vaisar, T., Van Espen, B., Zhang, J., Ziegler, M. G., Zwart, S. R., Charles, J. B., Kundrot, C. E., Scott, G. B., Bailey, S. M., Basner, M., Feinberg, A. P., Lee, S. M., Mason, C. E., Mignot, E., Rana, B. K., Smith, S. M., Snyder, M. P., Turek, F. W. 2019; 364 (6436)

    Abstract

    To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.

    View details for PubMedID 30975860

  • High-Resolution Bisulfite-Sequencing of Peripheral Blood DNA Methylation in Early-Onset and Familial Risk Breast Cancer Patients. Clinical cancer research : an official journal of the American Association for Cancer Research Chen, J., Haanpää, M. K., Gruber, J. J., Jäger, N., Ford, J. M., Snyder, M. P. 2019

    Abstract

    Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer, such as BRCA1 and BRCA2, account for less than 25% of familial cases of breast cancer. Recently, specific epigenetic modifications at BRCA1 have been shown to promote hereditary breast cancer, but the broader potential for epigenetic contribution to hereditary breast cancer is not yet well understood.We examined DNA methylation through deep bisulfite sequencing of CpG islands and known promoter or regulatory regions in peripheral blood DNA from 99 familial or early-onset breast or ovarian cancer patients, 6 unaffected BRCA-mutation carriers, and 49 unaffected controls.In 9% of patients, we observed altered methylation in the promoter regions of genes known to be involved in cancer including hypermethylation at the tumor suppressor PTEN and hypomethylation at the proto-oncogene TEX14 These alterations occur in the form of allelic methylation that span up to hundreds of base-pairs in length.Our observations suggest a broader role for DNA methylation in early-onset, familial risk breast cancer. Further studies are warranted to clarify these mechanisms and the benefits of DNA methylation screening for early risk prediction of familial cancers.

    View details for DOI 10.1158/1078-0432.CCR-18-2423

    View details for PubMedID 31175093

  • Metformin Affects Heme Function as a Possible Mechanism of Action. G3 (Bethesda, Md.) Li, X., Wang, X., Snyder, M. P. 2018

    Abstract

    Metformin elicits pleiotropic effects that are beneficial for treating diabetes, and as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30-50%; the heme-targeting drug artemisinin operates at a greater potency. Significantly, metformin prevents oxidation of heme in three protein scaffolds, cytochrome c, myoglobin and hemoglobin, with Kd values < 3 mM suggesting a dual oxidation and reduction role in the regulation of heme redox transition. Since heme- and porphyrin-like groups operate in diverse enzymes that control important metabolic processes, we suggest that metformin acts, at least in part, through stabilizing appropriate redox states in heme and other porphyrin-containing groups to control cellular metabolism.

    View details for PubMedID 30554148

  • High Frequency Actionable Pathogenic Exome Variants in an Average-Risk Cohort. Cold Spring Harbor molecular case studies Rego, S., Dagan-Rosenfeld, O., Zhou, W., Sailani, M. R., Limcaoco, P., Colbert, E., Avina, M., Wheeler, J., Craig, C., Salins, D., Rost, H. L., Dunn, J., McLaughlin, T., Steinmetz, L. M., Bernstein, J. A., Snyder, M. P. 2018

    Abstract

    Exome sequencing is increasingly utilized in both clinical and non-clinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study. We analyzed exomes by identifying rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We then used American College of Medical Genetics (ACMG) guidelines for the classification of rare sequence variants. Additionally, we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes. Five had phenotypes or family histories associated with their genetic variants. The frequency of actionable variants is higher than that reported in most previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 63 participants (90%) had additional non-actionable findings, including 60 who were found to be carriers for recessive diseases and 21 who have increased Alzheimer's disease risk due to heterozygous or homozygous APOE e4 alleles (18 participants had both). Our results suggest that exome sequencing may have considerable more utility for health management in the general population than previously thought.

    View details for PubMedID 30487145

  • Longitudinal personal DNA methylome dynamics in a human with a chronic condition. Nature medicine Chen, R., Xia, L., Tu, K., Duan, M., Kukurba, K., Li-Pook-Than, J., Xie, D., Snyder, M. 2018

    Abstract

    Epigenomics regulates gene expression and is as important as genomics in precision personal health, as it is heavily influenced by environment and lifestyle. We profiled whole-genome DNA methylation and the corresponding transcriptome of peripheral blood mononuclear cells collected from a human volunteer over a period of 36 months, generating 28 methylome and 57 transcriptome datasets. We found that DNA methylomic changes are associated with infrequent glucose level alteration, whereas the transcriptome underwent dynamic changes during events such as viral infections. Most DNA meta-methylome changes occurred 80-90days before clinically detectable glucose elevation. Analysis of the deep personal methylome dataset revealed an unprecedented number of allelic differentially methylated regions that remain stable longitudinally and are preferentially associated with allele-specific gene regulation. Our results revealed that changes in different types of 'omics' data associate with different physiological aspects of this individual: DNA methylation with chronic conditions and transcriptome with acute events.

    View details for PubMedID 30397358

  • Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring. Cell Jiang, C., Wang, X., Li, X., Inlora, J., Wang, T., Liu, Q., Snyder, M. 2018; 175 (1): 277

    Abstract

    Human health is dependent upon environmental exposures, yet the diversity and variation in exposures are poorly understood. We developed a sensitive method to monitor personal airborne biological and chemical exposures and followed the personal exposomes of 15 individuals for up to 890days and over 66 distinct geographical locations. We found that individuals are potentially exposed to thousands of pan-domain species and chemical compounds, including insecticides and carcinogens. Personal biological and chemical exposomes are highly dynamic and vary spatiotemporally, even for individuals located in the same general geographical region.Integrated analysis of biological and chemical exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets, and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.

    View details for PubMedID 30241608

  • Decoding the Genomics of Abdominal Aortic Aneurysm. Cell Li, J., Pan, C., Zhang, S., Spin, J. M., Deng, A., Leung, L. L., Dalman, R. L., Tsao, P. S., Snyder, M. 2018; 174 (6): 1361

    Abstract

    A key aspect of genomic medicine is to make individualized clinical decisions from personal genomes. We developed a machine-learning framework to integrate personal genomes and electronic health record (EHR) data and used this framework to study abdominal aortic aneurysm (AAA), a prevalent irreversible cardiovascular disease with unclear etiology. Performing whole-genome sequencing on AAA patients and controls, we demonstrated its predictive precision solely from personal genomes. By modeling personal genomes with EHRs, this framework quantitatively assessed the effectiveness of adjusting personal lifestyles given personal genome baselines, demonstrating its utility as a personal health management tool. We showed that this new framework agnostically identified genetic components involved in AAA, which were subsequently validated in human aortic tissues and in murine models. Our study presents a new framework for disease genome analysis, which can be used for both health management and understanding the biological architecture of complex diseases. VIDEO ABSTRACT.

    View details for PubMedID 30193110

  • Glucotypes reveal new patterns of glucose dysregulation. PLoS biology Hall, H., Perelman, D., Breschi, A., Limcaoco, P., Kellogg, R., McLaughlin, T., Snyder, M. 2018; 16 (7): e2005143

    Abstract

    Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called "glucotypes" that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.

    View details for PubMedID 30040822

  • Natural Selection Has Differentiated the Progesterone Receptor among Human Populations. American journal of human genetics Li, J., Hong, X., Mesiano, S., Muglia, L. J., Wang, X., Snyder, M., Stevenson, D. K., Shaw, G. M. 2018

    Abstract

    The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.

    View details for PubMedID 29937092

  • Systematic Protein Prioritization for Targeted Proteomics Studies through Literature Mining JOURNAL OF PROTEOME RESEARCH Yu, K., Lee, T., Wan, C., Chen, Y., Re, C., Kou, S. C., Chiang, J., Kohane, I. S., Snyder, M. 2018; 17 (4): 1383–96

    Abstract

    There are more than 3.7 million published articles on the biological functions or disease implications of proteins, constituting an important resource of proteomics knowledge. However, it is difficult to summarize the millions of proteomics findings in the literature manually and quantify their relevance to the biology and diseases of interest. We developed a fully automated bioinformatics framework to identify and prioritize proteins associated with any biological entity. We used the 22 targeted areas of the Biology/Disease-driven (B/D)-Human Proteome Project (HPP) as examples, prioritized the relevant proteins through their Protein Universal Reference Publication-Originated Search Engine (PURPOSE) scores, validated the relevance of the score by comparing the protein prioritization results with a curated database, computed the scores of proteins across the topics of B/D-HPP, and characterized the top proteins in the common model organisms. We further extended the bioinformatics workflow to identify the relevant proteins in all organ systems and human diseases and deployed a cloud-based tool to prioritize proteins related to any custom search terms in real time. Our tool can facilitate the prioritization of proteins for any organ system or disease of interest and can contribute to the development of targeted proteomic studies for precision medicine.

    View details for PubMedID 29505266

  • Microfluidic isoform sequencing shows widespread splicing coordination in the human transcriptome GENOME RESEARCH Tilgner, H., Jahanbani, F., Gupta, I., Collier, P., Wei, E., Rasmussen, M., Snyder, M. 2018; 28 (2): 231–42

    Abstract

    Understanding transcriptome complexity is crucial for understanding human biology and disease. Technologies such as Synthetic long-read RNA sequencing (SLR-RNA-seq) delivered 5 million isoforms and allowed assessing splicing coordination. Pacific Biosciences and Oxford Nanopore increase throughput also but require high input amounts or amplification. Our new droplet-based method, sparse isoform sequencing (spISO-seq), sequences 100k-200k partitions of 10-200 molecules at a time, enabling analysis of 10-100 million RNA molecules. SpISO-seq requires less than 1 ng of input cDNA, limiting or removing the need for prior amplification with its associated biases. Adjusting the number of reads devoted to each molecule reduces sequencing lanes and cost, with little loss in detection power. The increased number of molecules expands our understanding of isoform complexity. In addition to confirming our previously published cases of splicing coordination (e.g., BIN1), the greater depth reveals many new cases, such as MAPT Coordination of internal exons is found to be extensive among protein coding genes: 23.5%-59.3% (95% confidence interval) of highly expressed genes with distant alternative exons exhibit coordination, showcasing the need for long-read transcriptomics. However, coordination is less frequent for noncoding sequences, suggesting a larger role of splicing coordination in shaping proteins. Groups of genes with coordination are involved in protein-protein interactions with each other, raising the possibility that coordination facilitates complex formation and/or function. We also find new splicing coordination types, involving initial and terminal exons. Our results provide a more comprehensive understanding of the human transcriptome and a general, cost-effective method to analyze it.

    View details for PubMedID 29196558

    View details for PubMedCentralID PMC5793787

  • A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth SCIENTIFIC REPORTS Rappoport, N., Toung, J., Hadley, D., Wong, R. J., Fujioka, K., Reuter, J., Abbott, C. W., Oh, S., Hu, D., Eng, C., Huntsman, S., Bodian, D. L., Niederhuber, J. E., Hong, X., Zhang, G., Sikora-Wohfeld, W., Gignoux, C. R., Wang, H., Oehlert, J., Jelliffe-Pawlowski, L. L., Gould, J. B., Darmstadt, G. L., Wang, X., Bustamante, C. D., Snyder, M. P., Ziv, E., Patsopoulos, N. A., Muglia, L. J., Burchard, E., Shaw, G. M., O'Brodovich, H. M., Stevenson, D. K., Butte, A. J., Sirota, M. 2018; 8: 226

    Abstract

    Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

    View details for PubMedID 29317701

  • Integrative Personal Omics Profiles during Periods of Weight Gain and Loss. Cell systems Piening, B. D., Zhou, W., Contrepois, K., Röst, H., Gu Urban, G. J., Mishra, T., Hanson, B. M., Bautista, E. J., Leopold, S., Yeh, C. Y., Spakowicz, D., Banerjee, I., Chen, C., Kukurba, K., Perelman, D., Craig, C., Colbert, E., Salins, D., Rego, S., Lee, S., Zhang, C., Wheeler, J., Sailani, M. R., Liang, L., Abbott, C., Gerstein, M., Mardinoglu, A., Smith, U., Rubin, D. L., Pitteri, S., Sodergren, E., McLaughlin, T. L., Weinstock, G. M., Snyder, M. P. 2018

    Abstract

    Advances in omics technologies now allow an unprecedented level of phenotyping for human diseases, including obesity, in which individual responses to excess weight are heterogeneous and unpredictable. To aid the development of better understanding of these phenotypes, we performed a controlled longitudinal weight perturbation study combining multiple omics strategies (genomics, transcriptomics, multiple proteomics assays, metabolomics, and microbiomics) during periods of weight gain and loss in humans. Results demonstrated that: (1) weight gain is associated with the activation of strong inflammatory and hypertrophic cardiomyopathy signatures in blood; (2) although weight loss reverses some changes, a number of signatures persist, indicative of long-term physiologic changes; (3) we observed omics signatures associated with insulin resistance that may serve as novel diagnostics; (4) specific biomolecules were highly individualized and stable in response to perturbations, potentially representing stable personalized markers. Most data are available open access and serve as a valuable resource for the community.

    View details for PubMedID 29361466

  • Association of Omics Features with Histopathology Patterns in Lung Adenocarcinoma CELL SYSTEMS Yu, K., Berry, G. J., Rubin, D. L., Re, C., Altman, R. B., Snyder, M. 2017; 5 (6): 620-+

    Abstract

    Adenocarcinoma accounts for more than 40% of lung malignancy, and microscopic pathology evaluation is indispensable for its diagnosis. However, how histopathology findings relate to molecular abnormalities remains largely unknown. Here, we obtained H&E-stained whole-slide histopathology images, pathology reports, RNA sequencing, and proteomics data of 538 lung adenocarcinoma patients from The Cancer Genome Atlas and used these to identify molecular pathways associated with histopathology patterns. We report cell-cycle regulation and nucleotide binding pathways underpinning tumor cell dedifferentiation, and we predicted histology grade using transcriptomics and proteomics signatures (area under curve >0.80). We built an integrative histopathology-transcriptomics model to generate better prognostic predictions for stage I patients (p = 0.0182 ± 0.0021) compared with gene expression or histopathology studies alone, and the results were replicated in an independent cohort (p = 0.0220 ± 0.0070). These results motivate the integration of histopathology and omics data to investigate molecular mechanisms of pathology findings and enhance clinical prognostic prediction.

    View details for PubMedID 29153840

    View details for PubMedCentralID PMC5746468

  • Plasma sterols and depressive symptom severity in a population-based cohort PLOS ONE Cenik, B., Cenik, C., Snyder, M. P., Brown, E. 2017; 12 (9): e0184382

    Abstract

    Convergent evidence strongly suggests major depressive disorder is heterogeneous in its etiology and clinical characteristics. Depression biomarkers hold potential for identifying etiological subtypes, improving diagnostic accuracy, predicting treatment response, and personalization of treatment. Human plasma contains numerous sterols that have not been systematically studied. Changes in cholesterol concentrations have been implicated in suicide and depression, suggesting plasma sterols may be depression biomarkers. Here, we investigated associations between plasma levels of 34 sterols (measured by mass spectrometry) and scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) scale in 3117 adult participants in the Dallas Heart Study, an ethnically diverse, population-based cohort. We built a random forest model using feature selection from a pool of 43 variables including demographics, general health indicators, and sterol concentrations. This model comprised 19 variables, 13 of which were sterol concentrations, and explained 15.5% of the variation in depressive symptoms. Desmosterol concentrations below the fifth percentile (1.9 ng/mL, OR 1.9, 95% CI 1.2-2.9) were significantly associated with depressive symptoms of at least moderate severity (QIDS-SR16 score ≥10.5). This is the first study reporting a novel association between plasma concentrations cholesterol precursors and depressive symptom severity.

    View details for PubMedID 28886149

  • Fetal de novo mutations and preterm birth. PLoS genetics Li, J., Oehlert, J., Snyder, M., Stevenson, D. K., Shaw, G. M. 2017; 13 (4)

    Abstract

    Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.

    View details for DOI 10.1371/journal.pgen.1006689

    View details for PubMedID 28388617

  • De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease GENOME MEDICINE Takahashi, S., Andreoletti, G., Chen, R., Munehira, Y., Batra, A., Afzal, N. A., Beattie, R. M., Bernstein, J. A., Ennis, S., Snyder, M. 2017; 9

    Abstract

    Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood.We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles.In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Biochemical assays revealed that all six rare HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD, and also expand our understanding of the roles of HSP70s in human disease.

    View details for DOI 10.1186/s13073-016-0394-9

    View details for PubMedID 28126021

  • Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information. PLoS biology Li, X., Dunn, J., Salins, D., Zhou, G., Zhou, W., Schüssler-Fiorenza Rose, S. M., Perelman, D., Colbert, E., Runge, R., Rego, S., Sonecha, R., Datta, S., McLaughlin, T., Snyder, M. P. 2017; 15 (1)

    Abstract

    A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography.

    View details for DOI 10.1371/journal.pbio.2001402

    View details for PubMedID 28081144

  • Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development. Molecular cell Phanstiel, D. H., Van Bortle, K., Spacek, D., Hess, G. T., Shamim, M. S., Machol, I., Love, M. I., Aiden, E. L., Bassik, M. C., Snyder, M. P. 2017; 67 (6): 1037–48.e6

    Abstract

    The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops in human monocytes and differentiated macrophages. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer activation of preformed loops together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for activator protein 1 (AP-1)-binding events, suggesting that multi-loop activation hubs involving cell-type-specific transcription factors represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription.

    View details for PubMedID 28890333

  • Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers. Cell stem cell Gu, M., Shao, N., Sa, S., Li, D., Termglinchan, V., Ameen, M., Karakikes, I., Sosa, G., Grubert, F., Lee, J., Cao, A., Taylor, S., Ma, Y., Zhao, Z., Chappell, J., Hamid, R., Austin, E. D., Gold, J. D., Wu, J. C., Snyder, M. P., Rabinovitch, M. 2016

    Abstract

    In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration, and angiogenesis compared to UMC-iPSC-ECs and control cells. The "rescued" phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and was independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.

    View details for DOI 10.1016/j.stem.2016.08.019

    View details for PubMedID 28017794

  • Simul-seq: combined DNA and RNA sequencing for whole-genome and transcriptome profiling. Nature methods Reuter, J. A., Spacek, D. V., Pai, R. K., Snyder, M. P. 2016; 13 (11): 953-958

    Abstract

    Paired DNA and RNA profiling is increasingly employed in genomics research to uncover molecular mechanisms of disease and to explore personal genotype and phenotype correlations. Here, we introduce Simul-seq, a technique for the production of high-quality whole-genome and transcriptome sequencing libraries from small quantities of cells or tissues. We apply the method to laser-capture-microdissected esophageal adenocarcinoma tissue, revealing a highly aneuploid tumor genome with extensive blocks of increased homozygosity and corresponding increases in allele-specific expression. Among this widespread allele-specific expression, we identify germline polymorphisms that are associated with response to cancer therapies. We further leverage this integrative data to uncover expressed mutations in several known cancer genes as well as a recurrent mutation in the motor domain of KIF3B that significantly affects kinesin-microtubule interactions. Simul-seq provides a new streamlined approach for generating comprehensive genome and transcriptome profiles from limited quantities of clinically relevant samples.

    View details for DOI 10.1038/nmeth.4028

    View details for PubMedID 27723755

  • Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations NATURE GENETICS Araya, C. L., Cenik, C., Reuters, J. A., Kiss, G., Pande, V. S., Snyder, M. P., Greenleaf, W. J. 2016; 48 (2): 117-125

    Abstract

    Cancer sequencing studies have primarily identified cancer driver genes by the accumulation of protein-altering mutations. An improved method would be annotation independent, sensitive to unknown distributions of functions within proteins and inclusive of noncoding drivers. We employed density-based clustering methods in 21 tumor types to detect variably sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and noncoding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼15% of specific tumor types. SMRs demonstrate spatial clustering of alterations in molecular domains and at interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated across tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest that mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally agnostic driver identification.

    View details for DOI 10.1038/ng.3471

    View details for Web of Science ID 000369043900008

  • Synthetic long-read sequencing reveals intraspecies diversity in the human microbiome. Nature biotechnology Kuleshov, V., Jiang, C., Zhou, W., Jahanbani, F., Batzoglou, S., Snyder, M. 2016; 34 (1): 64-69

    Abstract

    Identifying bacterial strains in metagenome and microbiome samples using computational analyses of short-read sequences remains a difficult problem. Here, we present an analysis of a human gut microbiome using TruSeq synthetic long reads combined with computational tools for metagenomic long-read assembly, variant calling and haplotyping (Nanoscope and Lens). Our analysis identifies 178 bacterial species, of which 51 were not found using shotgun reads alone. We recover bacterial contigs that comprise multiple operons, including 22 contigs of >1 Mbp. Furthermore, we observe extensive intraspecies variation within microbial strains in the form of haplotypes that span up to hundreds of Kbp. Incorporation of synthetic long-read sequencing technology with standard short-read approaches enables more precise and comprehensive analyses of metagenomic samples.

    View details for DOI 10.1038/nbt.3416

    View details for PubMedID 26655498

    View details for PubMedCentralID PMC4884093

  • Yeast longevity promoted by reversing aging-associated decline in heavy isotope content. NPJ aging and mechanisms of disease Li, X., Snyder, M. P. 2016; 2: 16004

    Abstract

    Dysregulation of metabolism develops with organismal aging. Both genetic and environmental manipulations promote longevity by effectively diverting various metabolic processes against aging. How these processes converge on the metabolome is not clear. Here we report that the heavy isotopic forms of common elements, a universal feature of metabolites, decline in yeast cells undergoing chronological aging. Supplementation of deuterium, a heavy hydrogen isotope, through heavy water (D2O) uptake extends yeast chronological lifespan (CLS) by up to 85% with minimal effects on growth. The CLS extension by D2O bypasses several known genetic regulators, but is abrogated by calorie restriction and mitochondrial deficiency. Heavy water substantially suppresses endogenous generation of reactive oxygen species (ROS) and slows the pace of metabolic consumption and disposal. Protection from aging by heavy isotopes might result from kinetic modulation of biochemical reactions. Altogether, our findings reveal a novel perspective of aging and new means for promoting longevity.

    View details for PubMedID 28721263

  • Predicting non-small cell lung cancer prognosis by fully automated microscopic pathology image features. Nature communications Yu, K., Zhang, C., Berry, G. J., Altman, R. B., Ré, C., Rubin, D. L., Snyder, M. 2016; 7: 12474-?

    Abstract

    Lung cancer is the most prevalent cancer worldwide, and histopathological assessment is indispensable for its diagnosis. However, human evaluation of pathology slides cannot accurately predict patients' prognoses. In this study, we obtain 2,186 haematoxylin and eosin stained histopathology whole-slide images of lung adenocarcinoma and squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA), and 294 additional images from Stanford Tissue Microarray (TMA) Database. We extract 9,879 quantitative image features and use regularized machine-learning methods to select the top features and to distinguish shorter-term survivors from longer-term survivors with stage I adenocarcinoma (P<0.003) or squamous cell carcinoma (P=0.023) in the TCGA data set. We validate the survival prediction framework with the TMA cohort (P<0.036 for both tumour types). Our results suggest that automatically derived image features can predict the prognosis of lung cancer patients and thereby contribute to precision oncology. Our methods are extensible to histopathology images of other organs.

    View details for DOI 10.1038/ncomms12474

    View details for PubMedID 27527408

  • Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders CELL SYSTEMS Li, J., Ma, Z., Shi, M., Malty, R. H., Aoki, H., Minic, Z., Phanse, S., Jin, K., Wall, D. P., Zhang, Z., Urban, A. E., Hallmayer, J., Babu, M., Snyder, M. 2015; 1 (5): 361-374

    Abstract

    The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.

    View details for DOI 10.1016/j.cels.2015.11.002

    View details for Web of Science ID 000209926300009

    View details for PubMedCentralID PMC4776331

  • Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions CELL Grubert, F., Zaugg, J. B., Kasowski, M., Ursu, O., Spacek, D. V., Martin, A. R., Greenside, P., Srivas, R., Phanstiel, D. H., Pekowska, A., Heidari, N., Euskirchen, G., Huber, W., Pritchard, J. K., Bustamante, C. D., Steinmetz, L. M., Kundaje, A., Snyder, M. 2015; 162 (5): 1051-1065

    Abstract

    Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

    View details for DOI 10.1016/j.cell.2015.07.048

    View details for Web of Science ID 000360589900015

    View details for PubMedCentralID PMC4556133

  • Recurrent somatic mutations in regulatory regions of human cancer genomes. Nature genetics Melton, C., Reuter, J. A., Spacek, D. V., Snyder, M. 2015; 47 (7): 710-716

    Abstract

    Aberrant regulation of gene expression in cancer can promote survival and proliferation of cancer cells. Here we integrate whole-genome sequencing data from The Cancer Genome Atlas (TCGA) for 436 patients from 8 cancer subtypes with ENCODE and other regulatory annotations to identify point mutations in regulatory regions. We find evidence for positive selection of mutations in transcription factor binding sites, consistent with these sites regulating important cancer cell functions. Using a new method that adjusts for sample- and genomic locus-specific mutation rates, we identify recurrently mutated sites across individuals with cancer. Mutated regulatory sites include known sites in the TERT promoter and many new sites, including a subset in proximity to cancer-related genes. In reporter assays, two new sites display decreased enhancer activity upon mutation. These data demonstrate that many regulatory regions contain mutations under selective pressure and suggest a greater role for regulatory mutations in cancer than previously appreciated.

    View details for DOI 10.1038/ng.3332

    View details for PubMedID 26053494

    View details for PubMedCentralID PMC4485503

  • Comprehensive transcriptome analysis using synthetic long-read sequencing reveals molecular co-association of distant splicing events NATURE BIOTECHNOLOGY Tilgner, H., Jahanbani, F., Blauwkamp, T., Moshrefi, A., Jaeger, E., Chen, F., Harel, I., Bustamante, C. D., Rasmussen, M., Snyder, M. P. 2015; 33 (7): 736-742

    Abstract

    Alternative splicing shapes mammalian transcriptomes, with many RNA molecules undergoing multiple distant alternative splicing events. Comprehensive transcriptome analysis, including analysis of exon co-association in the same molecule, requires deep, long-read sequencing. Here we introduce an RNA sequencing method, synthetic long-read RNA sequencing (SLR-RNA-seq), in which small pools (≤1,000 molecules/pool, ≤1 molecule/gene for most genes) of full-length cDNAs are amplified, fragmented and short-read-sequenced. We demonstrate that these RNA sequences reconstructed from the short reads from each of the pools are mostly close to full length and contain few insertion and deletion errors. We report many previously undescribed isoforms (human brain: ∼13,800 affected genes, 14.5% of molecules; mouse brain ∼8,600 genes, 18% of molecules) and up to 165 human distant molecularly associated exon pairs (dMAPs) and distant molecularly and mutually exclusive pairs (dMEPs). Of 16 associated pairs detected in the mouse brain, 9 are conserved in human. Our results indicate conserved mechanisms that can produce distant but phased features on transcript and proteome isoforms.

    View details for DOI 10.1038/nbt.3242

    View details for Web of Science ID 000358396100029

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