ScienceDaily (Mar. 18, 2010) — The key to human individuality may lie not in our genes, but in the sequences that surround and control them, according to new research by scientists at the Stanford University School of Medicine and Yale University. The interaction of those sequences with a class of key proteins, called transcription factors, can vary significantly between two people and are likely to affect our appearance, our development and even our predisposition to certain diseases, the study found.
Researchers have found that the unique, specific changes among individuals in the sequence of DNA affect the ability of "control proteins" called transcription factors to bind to the regions that control gene expression. (Credit: iStockphoto/Andrey Prokhorov)
"We are rapidly entering a time when nearly anyone can have his or her genome sequenced," said Michael Snyder, PhD, professor and chair of genetics at Stanford. "However, the bulk of the differences among individuals are not found in the genes themselves, but in regions we know relatively little about. Now we see that these differences profoundly impact protein binding and gene expression."
Snyder is the senior author of two papers -- one in Science Expressand one in Nature -- exploring these protein-binding differences in humans, chimpanzees and yeast. Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics, came to Stanford in July 2009 from Yale, where much of the work was conducted.
Genes, which carry the specific instructions necessary to make proteins do the work of the cell, vary by only about 0.025 percent across all humans. Scientists have spent decades trying to understand how these tiny differences affect who we are and what we become. In contrast, non-coding regions of the genome, which account for approximately 98 percent of our DNA, vary in their sequence by about 1 to 4 percent. But until recently, scientists had little, if any, idea what these regions do and how they contribute to the "special sauce" that makes me, me, and you, you.
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Science DOI: 10.1126/science.1183621
Variation in Transcription Factor Binding Among Humans
Maya Kasowski,1,* Fabian Grubert,1,2,* Christopher Heffelfinger,1 Manoj Hariharan,1,2 Akwasi Asabere,1Sebastian M. Waszak,3, 4 Lukas Habegger,5 Joel Rozowsky,6 Minyi Shi,1,2 Alexander E. Urban,1, 7Mi-Young Hong,1 Konrad J. Karczewski,2 Wolfgang Huber,3 Sherman M. Weissman,7 Mark B. Gerstein,5,6,8Jan O. Korbel,3, 9, Michael Snyder1,6,7,
Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee using chromatin immunoprecipitation followed by sequencing (ChIP-Seq). The binding sites of RNA Polymerase II (PolII) and a key regulator of immune responses, NFB (p65), were mapped in ten lymphoblastoid cell lines and 25% and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with SNPs and genomic structural variants (SVs) and were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between human and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding and provide insight into the genetic events responsible for these differences.
1 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
3 Genome Biology Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
4 Department of Biotechnology and Bioinformatics, Weihenstephan-Triesdorf University of Applied Sciences, 85350 Freising, Germany.
5 Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
6 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
7 Department Genetics, Yale University School of Medicine, New Haven, CT 08520, USA.
8 Department of Computer Science, Yale University, New Haven, CT 06520, USA.
9 European Molecular Biology Laboratory–European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: jan.korbel@embl.de (J.O.K.); mpsnyder@stanford.edu(M.S.)
Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee using chromatin immunoprecipitation followed by sequencing (ChIP-Seq). The binding sites of RNA Polymerase II (PolII) and a key regulator of immune responses, NFB (p65), were mapped in ten lymphoblastoid cell lines and 25% and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with SNPs and genomic structural variants (SVs) and were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between human and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding and provide insight into the genetic events responsible for these differences.
1 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
3 Genome Biology Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
4 Department of Biotechnology and Bioinformatics, Weihenstephan-Triesdorf University of Applied Sciences, 85350 Freising, Germany.
5 Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
6 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
7 Department Genetics, Yale University School of Medicine, New Haven, CT 08520, USA.
8 Department of Computer Science, Yale University, New Haven, CT 06520, USA.
9 European Molecular Biology Laboratory–European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: jan.korbel@embl.de (J.O.K.); mpsnyder@stanford.edu(M.S.)
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Genetic analysis of variation in transcription factor binding in yeast
Wei Zheng1,6, Hongyu Zhao2,3, Eugenio Mancera4, Lars M. Steinmetz4 & Michael Snyder1,5
Department of Molecular, Cellular and Developmental Biology, Yale University,
Program in Computational Biology and Bioinformatics, Yale University,
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520, USA
Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
Present address: Biostatics Resources, Keck Laboratory, Yale University, New Haven, Connecticut 06520, USA.
Correspondence to: Michael Snyder1,5 Correspondence and requests for materials should be addressed to M.S. (Email: mpsnyder@stanford.edu).
Abstract
Variation in transcriptional regulation is thought to be a major cause of phenotypic diversity1, 2. Although widespread differences in gene expression among individuals of a species have been observed3, 4, 5, 6, 7, 8, studies to examine the variability of transcription factor binding on a global scale have not been performed, and thus the extent and underlying genetic basis of transcription factor binding diversity is unknown. By mapping differences in transcription factor binding among individuals, here we present the genetic basis of such variation on a genome-wide scale. Whole-genome Ste12-binding profiles were determined using chromatin immunoprecipitation coupled with DNA sequencing in pheromone-treated cells of 43 segregants of a cross between two highly diverged yeast strains and their parental lines. We identified extensive Ste12-binding variation among individuals, and mapped underlying cis- and trans-acting loci responsible for such variation. We showed that most transcription factor binding variation is cis-linked, and that many variations are associated with polymorphisms residing in the binding motifs of Ste12 as well as those of several proposed Ste12 cofactors. We also identified two trans-factors, AMN1 andFLO8, that modulate Ste12 binding to promoters of more than ten genes under α-factor treatment. Neither of these two genes was previously known to regulate Ste12, and we suggest that they may be mediators of gene activity and phenotypic diversity. Ste12 binding strongly correlates with gene expression for more than 200 genes, indicating that binding variation is functional. Many of the variable-bound genes are involved in cell wall organization and biogenesis. Overall, these studies identified genetic regulators of molecular diversity among individuals and provide new insights into mechanisms of gene regulation.
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