Person: Kellis, Manolis
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Kellis
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Manolis
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Kellis, Manolis
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Publication Long Noncoding RNAs Regulate Adipogenesis(Proceedings of the National Academy of Sciences, 2013) Sun, Lei; Goff, Loyal; Trapnell, Cole; Alexander, Ryan; Lo, Kinyui Alice; Hacisuleyman, Ezgi; Sauvageau, Martin; Tazon-Vega, Barbara; Kelley, David Roy; Hendrickson, David Gillis; Yuan, Bingbing; Kellis, Manolis; Lodish, Harvey F.; Rinn, JohnThe prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.Publication Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma(Public Library of Science, 2012) Yaspan, Brian L.; Hauser, Michael A.; Allingham, R. Rand; Olson, Lana M.; Abdrabou, Wael; Brodeur, Wendy; Budenz, Donald L.; Caprioli, Joseph; Crenshaw, Andrew; Crooks, Kristy; DelBono, Elizabeth; Doheny, Kimberly F.; Gaasterland, Douglas; Gaasterland, Terry; Laurie, Cathy; Lichter, Paul R.; Loomis, Stephanie; Liu, Yutao; Medeiros, Felipe A.; McCarty, Cathy; Mirel, Daniel; Moroi, Sayoko E.; Musch, David C.; Realini, Anthony; Rozsa, Frank W.; Schuman, Joel S.; Scott, Kathleen; Singh, Kuldev; Trager, Edward H.; VanVeldhuisen, Paul; Vollrath, Douglas; Wollstein, Gadi; Yoneyama, Sachiko; Zhang, Kang; Weinreb, Robert N.; Ernst, Jason; Masuda, Tomohiro; Zack, Don; Richards, Julia E.; Pericak-Vance, Margaret; Haines, Jonathan L.; Wiggs, Janey; Kang, Jae Hee; Fan, Baojian; Wang, Danyi; Friedman, David S.; Lee, Richard K.; Stein, Joshua D.; Kellis, Manolis; Pasquale, LouisOptic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10\(^{−18}\)), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10\(^{−11}\)). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10\(^{−12}\)) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10\(^{−10}\)). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.Publication High Depth, Whole-Genome Sequencing of Cholera Isolates from Haiti and the Dominican Republic(BioMed Central, 2012) Sealfon, Rachel; Gire, Stephen K; Ellis, Crystal Nicole; Calderwood, Stephen; Qadri, Firdausi; Hensley, Lisa; Kellis, Manolis; Ryan, Edward; Larocque, Regina; Harris, Jason; Sabeti, PardisBackground: Whole-genome sequencing is an important tool for understanding microbial evolution and identifying the emergence of functionally important variants over the course of epidemics. In October 2010, a severe cholera epidemic began in Haiti, with additional cases identified in the neighboring Dominican Republic. We used whole- genome approaches to sequence four Vibrio cholerae isolates from Haiti and the Dominican Republic and three additional V. cholerae isolates to a high depth of coverage (>2000x); four of the seven isolates were previously sequenced. Results: Using these sequence data, we examined the effect of depth of coverage and sequencing platform on genome assembly and identification of sequence variants. We found that 50x coverage is sufficient to construct a whole-genome assembly and to accurately call most variants from 100 base pair paired-end sequencing reads. Phylogenetic analysis between the newly sequenced and thirty-three previously sequenced V. cholerae isolates indicates that the Haitian and Dominican Republic isolates are closest to strains from South Asia. The Haitian and Dominican Republic isolates form a tight cluster, with only four variants unique to individual isolates. These variants are located in the CTX region, the SXT region, and the core genome. Of the 126 mutations identified that separate the Haiti-Dominican Republic cluster from the V. cholerae reference strain (N16961), 73 are non-synonymous changes, and a number of these changes cluster in specific genes and pathways. Conclusions: Sequence variant analyses of V. cholerae isolates, including multiple isolates from the Haitian outbreak, identify coverage-specific and technology-specific effects on variant detection, and provide insight into genomic change and functional evolution during an epidemic.Publication The Changing Face of Genomics(BioMed Central, 2004) Kellis, ManolisA report on the 5th annual Advances in Genome Biology and Technology (AGBT) and Automation in DNA Mapping and Sequencing (AMS) meeting, Marco Island, USA, 4-7 February 2004.Publication A Comprehensive Map of Insulator Elements for the Drosophila Genome(Public Library of Science, 2010) Nègre, Nicolas; Kheradpour, Pouya; Morrison, Carolyn A.; Henikoff, Jorja G.; Feng, Xin; Ahmad, Kami; Stein, Lincoln; Henikoff, Steven; White, Kevin P.; Brown, Christopher D.; Shah, Parantu; Russell, Steven; White, Robert A. H.; Kellis, ManolisInsulators are DNA sequences that control the interactions among genomic regulatory elements and act as chromatin boundaries. A thorough understanding of their location and function is necessary to address the complexities of metazoan gene regulation. We studied by ChIP–chip the genome-wide binding sites of 6 insulator-associated proteins—dCTCF, CP190, BEAF-32, Su(Hw), Mod(mdg4), and GAF—to obtain the first comprehensive map of insulator elements in Drosophila embryos. We identify over 14,000 putative insulators, including all classically defined insulators. We find two major classes of insulators defined by dCTCF/CP190/BEAF-32 and Su(Hw), respectively. Distributional analyses of insulators revealed that particular sub-classes of insulator elements are excluded between cis-regulatory elements and their target promoters; divide differentially expressed, alternative, and divergent promoters; act as chromatin boundaries; are associated with chromosomal breakpoints among species; and are embedded within active chromatin domains. Together, these results provide a map demarcating the boundaries of gene regulatory units and a framework for understanding insulator function during the development and evolution of Drosophila.Publication Performance and Scalability of Discriminative Metrics for Comparative Gene Identification in 12 Drosophila Genomes(Public Library of Science, 2008) Deoras, Ameya N.; Rasmussen, Matthew D.; Guigó, Roderic; Lin, Michael; Kellis, ManolisComparative genomics of multiple related species is a powerful methodology for the discovery of functional genomic elements, and its power should increase with the number of species compared. Here, we use 12 Drosophila genomes to study the power of comparative genomics metrics to distinguish between protein-coding and non-coding regions. First, we study the relative power of different comparative metrics and their relationship to single-species metrics. We find that even relatively simple multi-species metrics robustly outperform advanced single-species metrics, especially for shorter exons (≤240 nt), which are common in animal genomes. Moreover, the two capture largely independent features of protein-coding genes, with different sensitivity/specificity trade-offs, such that their combinations lead to even greater discriminatory power. In addition, we study how discovery power scales with the number and phylogenetic distance of the genomes compared. We find that species at a broad range of distances are comparably effective informants for pairwise comparative gene identification, but that these are surpassed by multi-species comparisons at similar evolutionary divergence. In particular, while pairwise discovery power plateaued at larger distances and never outperformed the most advanced single-species metrics, multi-species comparisons continued to benefit even from the most distant species with no apparent saturation. Last, we find that genes in functional categories typically considered fast-evolving can nonetheless be recovered at very high rates using comparative methods. Our results have implications for comparative genomics analyses in any species, including the human.Publication A Bayesian Approach for Fast and Accurate Gene Tree Reconstruction(Oxford University Press, 2011) Rasmussen, Matthew D.; Kellis, ManolisRecent sequencing and computing advances have enabled phylogenetic analyses to expand to both entire genomes and large clades, thus requiring more efficient and accurate methods designed specifically for the phylogenomic context. Here, we present SPIMAP, an efficient Bayesian method for reconstructing gene trees in the presence of a known species tree. We observe many improvements in reconstruction accuracy, achieved by modeling multiple aspects of evolution, including gene duplication and loss (DL) rates, speciation times, and correlated substitution rate variation across both species and loci. We have implemented and applied this method on two clades of fully sequenced species, 12 Drosophila and 16 fungal genomes as well as simulated phylogenies and find dramatic improvements in reconstruction accuracy as compared with the most popular existing methods, including those that take the species tree into account. We find that reconstruction inaccuracies of traditional phylogenetic methods overestimate the number of DL events by as much as 2–3-fold, whereas our method achieves significantly higher accuracy. We feel that the results and methods presented here will have many important implications for future investigations of gene evolution.Publication Large-scale discovery and validation of functional elements in the human genome(BioMed Central, 2005) Bernstein, Bradley; Kellis, ManolisA report on the genomics workshop 'Identification of Functional Elements in Mammalian Genomes', Cold Spring Harbor, New York, 11-13 November 2004.Publication Sequences to Systems(BioMed Central, 2010) Kellis, Manolis; Rinn, JohnA report of the seventh annual meeting on Systems Biology: Global Regulation of Gene Expression, 23-27 March 2010, Cold Spring Harbor, USA.Publication Single-Cell Transcriptomic Analysis of Alzheimer’s Disease(Springer Science and Business Media LLC, 2019-05-01) Gao, Fan; Kellis, Manolis; Mathys, Hansruedi; Davila-Velderrain, Jose; Peng, Zhuyu; Mohammadi, Shahin; Young, Jennie; Menon, Madhvi; He, Liang; Abdurrob, Fatema; Jiang, Xueqiao; Martorell, Anthony; Ransohoff, Richard; Hafler, Brian; Bennett, David; Tsai, Li-HueiAlzheimer’s disease (AD) is a pervasive neurodegenerative disorder whose molecular and cellular complexity remains poorly understood. Here, we profiled and analyzed 80,660 single-nucleus transcriptomes from prefrontal cortex of 48 individuals with varying degrees of AD pathology. We identified transcriptionally-distinct subpopulations across six major brain cell-types, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest AD-associated changes appeared early in pathological progression and were highly cell type-specific, whereas genes upregulated in late-stage were common across cell types and primarily involved in global stress response. Surprisingly, we found an overrepresentation of female cells in AD-associated subpopulations, and substantially different transcriptional responses between sexes in multiple cell types including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting a key role in AD pathophysiology. Our single-cell transcriptomic resource provides a first blueprint for interrogating the molecular underpinnings and cellular basis of AD.