Population and evolutionary genomics of gene regulation

The Population and evolutionary 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.

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 high-throughput experiments, computational and statistical analysis. We are particularly focussed on understanding this variation in pluripotent stem cells as a model of human disease and development.

[Wikimedia Commons]

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 produce the phenotype we observe is a key step in the development of:

  • more accurate, powerful and specific diagnostics
  • treatments of genetic diseases
  • our understanding the biological changes that have occurred since we split from our common ancestors.

Recent technological developments mean that we can now begin to decipher key molecular components of this process across the genome and with high accuracy, including protein-coding and noncoding RNA expression, transcription factor binding and chromatin accessibility.

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

The wet-lab in our group uses experimental methods such as DNaseI digestion, chromatin-immunoprecipitation and formaldehyde-assisted recovery of regulatory elements (FAIRE) to identify active regulatory regions. These techniques are then combined with next generation sequencing and we develop computational methods for analysing the data in our dry-lab.

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
  • Ville Mustonen - Population genomics of molecular phenotypes, The Wellome Trust Sanger Institute, Hinxton
  • Duncan Odom - Odom Lab, Cancer Research UK: Cambridge Research Institute, Cambridge
  • Duncan Odom - Regulatory evolution in mammalian tissues, The Wellome Trust Sanger Institute, Hinxton
  • Ludovic Vallier - Mechanisms controlling differentiation in pluripotent stem cells into definitive endoderm, The Wellcome Trust Centre for Stem Cell Research, Cambridge

Selected Publications

  • 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

    PUBMED: 21690102; PMC: 3137225; DOI: 10.1093/bioinformatics/btr354

  • 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

    PUBMED: 21106904; PMC: 3044858; DOI: 10.1101/gr.112623.110

  • 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

    PUBMED: 21251332; PMC: 3091299; DOI: 10.1186/gb-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

    PUBMED: 20573213; PMC: 2898759; DOI: 10.1186/1471-2164-11-399

  • Selective constraints in experimentally defined primate regulatory regions.

    Gaffney DJ, Blekhman R and Majewski J

    PLoS genetics 2008;4;8;e1000157

    PUBMED: 18704158; PMC: 2490716; DOI: 10.1371/journal.pgen.1000157

  • Genomic selective constraints in murid noncoding DNA.

    Gaffney DJ and Keightley PD

    PLoS genetics 2006;2;11;e204

    PUBMED: 17166057; PMC: 1657059; DOI: 10.1371/journal.pgen.0020204

  • The scale of mutational variation in the murid genome.

    Gaffney DJ and Keightley PD

    Genome research 2005;15;8;1086-94

    PUBMED: 16024822; PMC: 1182221; DOI: 10.1101/gr.3895005

  • 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

    PUBMED: 14597721; PMC: 263826; DOI: 10.1073/pnas.2233252100

Team

No team members listed

Group leader

Dr Daniel Gaffney Dr Daniel Gaffney
Daniel's profile

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