哲学家莱布尼茨曾说过，世界上没有两片完全相同的叶子，同样的道理，世界上没有两个完全相同的人，每一个人都是独一无二的，是什么让你独一无二，斯坦福大学的一位科学家在Science和Nature上的一篇文章也许给您带来答案。
刚刚从耶鲁大学基因组科学中心过档去斯坦福大学的Michael Snyder博士自上任便取得好成绩，近期发表2篇高水平文章，1篇Nature，1篇Science。Michael Snyder目前任斯坦福大学基因组中心和个性化医疗研究中心主任。
据介绍，每个个体的“独一无二”性的秘密并不是蕴藏在基因中，而是在于DNA序列周围的一些因子。在DNA序列周围，存在一系列关键的蛋白，名为转录因子，这些转录因子就是控制每个人独一无二的关键所在。转录因子控制着我们的外貌、发育情况甚至疾病。
与先前的研究不同的是，以往的研究往往纠结于基因本身，这个新的研究着眼于宏观的基因组。Michael Snyder教授表示，后基因组时代，我们很快就可能每个人拥有自己的基因组序列，从基因中找出人与人之间的不同却难以实现，我们研究发现，影响人与人之间差异的是与DNA序列结合的蛋白，它们深刻地影响基因的表达。
科学家们对10个人与10只猩猩的转录因子进行研究发现，基因组上有15,000个供NF-kB转录因子结合的位点，有19,000个供RNA PolII结合的位点，尽管位点有如此多，但每个人的位点结合频率却不一样。25%的Pol II结合位点和7.5%的NF-kB的结合位点引人而异。
这些结果表明，转录因子结合位点的差异给人类的个体带来很大的差异。这是每个人独一无二的根源所在。
推荐原文出处：
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,1 Sebastian M. Waszak,3, 4 Lukas Habegger,5 Joel Rozowsky,6 Minyi Shi,1,2 Alexander E. Urban,1, 7 Mi-Young Hong,1 Konrad J. Karczewski,2 Wolfgang Huber,3 Sherman M. Weissman,7 Mark B. Gerstein,5,6,8 Jan 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.
Nature doi:10.1038/nature08934
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.
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 and FLO8, 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.
