Genomics of gene regulation

The genomics of gene regulation team seek to understand the role of gene regulation in human disease and evolution. Headed by Daniel Gaffney, the group combines computational and statistical methods with high-throughput experimental techniques to understand the role played by changes in gene regulation in disease susceptibility and human evolution. We are currently involved in both the data generation and analysis of molecular phenotypes in human induced pluripotent stem cells as part of the Human Induced Pluripotent Stem Cells Initiative

All genes in the genome are regulated to control how their genetic information is turned into gene products, a process known as gene expression. Understanding this process is important because the majority of mutations that are associated with human disease and evolution are thought to affect gene expression.

The team aims to understand how genetic changes affect the level, location and timing of gene expression using a combination of experimental and computational methods. We are particularly focussed on understanding this variation in pluripotent stem cells as a model of human disease and development.

We welcome applications from prospective postdocs and PhD students. Projects are available in the areas of genomics of gene regulation, molecular evolution and on population genomics of gene regulation. All our work involves data analysis, but there is also scope for projects with a component of laboratory work. Interested applicants should send a CV to Dan (see profile page for contact details), with information on your research, publications and contact details for three references.

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Background

Since the publication of the human genome sequence the pace of discovery in human genetics has accelerated dramatically. We have begun to identify which changes in the genome are important for a variety of human diseases and which have occurred during recent human evolution. However, biological interpretation of these results is complicated because most of these changes do not occur inside known genes. In fact, many important genetic changes occur in the non-coding fraction of the genome, and are believed to affect the regulation of gene expression.

Understanding how changes in gene regulation alter observable phenotypes is important for:

  • understanding the functional basis of genetic disease
  • development of more accurate, powerful and specific diagnostics
  • interpreting the biological changes that have occurred since we diverged from our common ancestors.

Recent technological developments mean that we can now assay key molecular phenotypes, including protein-coding and noncoding RNA transcription, transcription factor binding and chromatin accessibility, genome-wide and with high accuracy.

Our group studies epigenetic and gene expression variation in human populations. Recently, we have started work in human induced pluripotent stem cells as a model system for disease and development.

Research

Gene expression and regulatory variation in human populations

Part of our group's research focuses on using naturally occurring variation as a model system that we can use to test hypotheses about gene regulation. We look for genetic variants that correlate with differences in gene expression between individuals. The genetic and epigenetic context of these changes can inform about the biology of gene regulation, and can help pinpoint likely causal disease mutations.

Annotating active regulatory elements using next-generation sequencing

Our group uses experimental methods such as DNaseI digestion, chromatin-immunoprecipitation and formaldehyde-assisted recovery of regulatory elements (FAIRE) to identify active regulatory regions, and develops computational and statistical methods for interpreting these data.

Collaborations

We collaborate closely with a number of groups both at the Sanger Institute and elsewhere. We are currently working with Ludovic Vallier's lab in Cambridge on annotating regulatory elements in a variety of cell types. We also work with Duncan Odom's groups at the Sanger Institute and Cancer Research UK: Cambridge Research Institute to develop high-throughput methods for regulatory element annotation. We have close links with Ville Mustonen and Carl Anderson's groups at the Sanger Institute.

  • Carl Anderson - Statistical genetics, The Wellome Trust Sanger Institute, Hinxton
  • Duncan Odom - Regulatory evolution in mammalian tissues, The Wellome Trust Sanger Institute, Hinxton
  • Ludovic Vallier - Gene expression variation in induced pluripotent stem cells, The Wellcome Trust Centre for Stem Cell Research, Cambridge

Selected Publications

  • Global properties and functional complexity of human gene regulatory variation.

    Gaffney DJ

    PLoS genetics 2013;9;5;e1003501

  • Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.

    Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, Ducker SJ, Day DB, Heneghan MA, Neuberger JM, Donaldson PT, Bathgate AJ, Burroughs A, Davies MH, Jones DE, Alexander GJ, Barrett JC, Sandford RN, Anderson CA, UK Primary Biliary Cirrhosis (PBC) Consortium and Wellcome Trust Case Control Consortium 3

    Nature genetics 2012;44;10;1137-41

  • DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina.

    Zullo JM, Demarco IA, Piqué-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL and Singh H

    Cell 2012;149;7;1474-87

  • DNase I sensitivity QTLs are a major determinant of human expression variation.

    Degner JF, Pai AA, Pique-Regi R, Veyrieras JB, Gaffney DJ, Pickrell JK, De Leon S, Michelini K, Lewellen N, Crawford GE, Stephens M, Gilad Y and Pritchard JK

    Nature 2012;482;7385;390-4

  • The contribution of RNA decay quantitative trait loci to inter-individual variation in steady-state gene expression levels.

    Pai AA, Cain CE, Mizrahi-Man O, De Leon S, Lewellen N, Veyrieras JB, Degner JF, Gaffney DJ, Pickrell JK, Stephens M, Pritchard JK and Gilad Y

    PLoS genetics 2012;8;10;e1003000

  • Controls of nucleosome positioning in the human genome.

    Gaffney DJ, McVicker G, Pai AA, Fondufe-Mittendorf YN, Lewellen N, Michelini K, Widom J, Gilad Y and Pritchard JK

    PLoS genetics 2012;8;11;e1003036

  • Dissecting the regulatory architecture of gene expression QTLs.

    Gaffney DJ, Veyrieras JB, Degner JF, Pique-Regi R, Pai AA, Crawford GE, Stephens M, Gilad Y and Pritchard JK

    Genome biology 2012;13;1;R7

  • Exon-specific QTLs skew the inferred distribution of expression QTLs detected using gene expression array data.

    Veyrieras JB, Gaffney DJ, Pickrell JK, Gilad Y, Stephens M and Pritchard JK

    PloS one 2012;7;2;e30629

  • False positive peaks in ChIP-seq and other sequencing-based functional assays caused by unannotated high copy number regions.

    Pickrell JK, Gaffney DJ, Gilad Y and Pritchard JK

    Bioinformatics (Oxford, England) 2011;27;15;2144-6

  • Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data.

    Pique-Regi R, Degner JF, Pai AA, Gaffney DJ, Gilad Y and Pritchard JK

    Genome research 2011;21;3;447-55

  • DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines.

    Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y and Pritchard JK

    Genome biology 2011;12;1;R10

  • Alternative splicing is frequent during early embryonic development in mouse.

    Revil T, Gaffney D, Dias C, Majewski J and Jerome-Majewska LA

    BMC genomics 2010;11;399

  • Selective constraints in experimentally defined primate regulatory regions.

    Gaffney DJ, Blekhman R and Majewski J

    PLoS genetics 2008;4;8;e1000157

  • Effect of the assignment of ancestral CpG state on the estimation of nucleotide substitution rates in mammals.

    Gaffney DJ and Keightley PD

    BMC evolutionary biology 2008;8;265

  • Genomic selective constraints in murid noncoding DNA.

    Gaffney DJ and Keightley PD

    PLoS genetics 2006;2;11;e204

  • The scale of mutational variation in the murid genome.

    Gaffney DJ and Keightley PD

    Genome research 2005;15;8;1086-94

  • Functional constraints and frequency of deleterious mutations in noncoding DNA of rodents.

    Keightley PD and Gaffney DJ

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;23;13402-6

Team

No team members listed

Group leader

Dr Daniel Gaffney Dr Daniel Gaffney
Daniel's profile

* quick link - http://q.sanger.ac.uk/w5lgrmsi