Projects
in the Bejerano Lab aim at better
understanding vertebrate gene regulation. Driven by recent
developments in the field, we raise testable hypotheses. We then exploit
existing computational tools, as well as write many unique tools
ourselves, to make use of a powerful in-house compute cluster, to sift
the ever growing expanses of public domain data. Novel
insights are then validated in our own lab, or those of close
collaborators. We are currently
recruiting for the following
projects and more:
Ultraconserved Elements and Human Disease
Ultraconservation describes the perfect
conservation of genomic regions between related species across large
evolutionary distances. As
co-discoverer of this phenomenon, the Bejerano Lab is particularly
interested in studying its many facets - its origins, the different
functions these regions play, the reasons for and mechanisms behind
their extreme
conservation, and particularly how they relate to human disease. We are
currently estimating the power of selection on
ultraconserved sequences in healthy individuals, expanding our research
to the study of non-coding polymorphisms and positional effects in
individuals affected by hereditary developmental diseases.
The Vertebrate Cis-Regulatory Code
Recently, many ultraconserved regions have been shown in the lab
to act as
distal gene regulatory elements. Little is understood about these
enhancers, repressors and insulators.
The flexibility exhibited by individual binding sites to
fluctuate in
sequence space, even turn-over while conserving the overall function of
a regulatory element, stands in stark contrast to the
immutable nature of ultraconserved regions and the deep conservation of
many thousands of putative regulatory elements found predominantly near
genes involved in organism development. We aim to understand how these
regions encode their functions, how they synergize to create tightly
regulated gene expression domains, and how variation in them gives rise
to novel traits and deleterious phenotypes.
In doing so we are setting up several close collaborations:
- With the Kingsley
Lab at Stanford, we study the molecular basis for the
evolution of novel traits in vertebrates, using the recently sequenced
stickleback genome.
- With the Myers
Lab at Stanford, we aim to validate and study putative
regulatory elements in different functional contexts.
- With the Rubenstein
Lab at UCSF, we study the mammalian forebrain, as a model for
understanding a developmental pathway.
- With the Feldheim
Lab at UCSC, we study ephrins and ephrin receptors, as a
model for families of paralogous genes exhibiting tight, yet diverse
patterns of expression during development.
- We are also involved in work led by the Miller Lab at PSU,
to reconstruct ancestral primate and mammalian genomes, using extant species.
The Vertebrate-Invertebrate "Great Divide"
Most protein-coding gene families and some structural RNA genes can
easily
be traced between vertebrates and invertebrates. In fact, some
of these
families are surprisingly old. The picture is dramatically different for
gene regulatory regions. Essentially none of these can be traced
between sequenced vertebrates and invertebrates. Our lab aims to design
cis-regulatory specific metrics that cross this chasm,
drawing inspiration from a handful of experimentally validated cases.
Genomic Co-option and Vertebrate
Evolution
The recent availability of genomic sequences and manipulation
techniques strongly suggest that the evolution of cis-regulatory
elements, more than the actual protein coding genes they
control,
may well be responsible for much of the observed morphological
diversity in multi-cellular organisms. While some regulatory regions
may be functionally conserved between the phyla (see above)
many others arose de-novo during evolution. We have recently
shown that an ancient mobile element has left behind multiple
functional copies in tetrapodal genomes, including one or more distal
enhancers. The Bejerano Lab is interested in measuring the extent of
this phenomenon, known as co-option or exaptation, in vertebrate and
human evolution in particular.
Genome Browser Based Analysis Tools
The UCSC and Ensembl genome browsers represent a tremendous effort to
integrate many heterogeneous types of biological information into one
coherent environment. While general purpose and especially micro-array
analysis tools abound, our lab focuses on developing tools that exploit
this wealth of data to study the many thousands of putative
cis-regulatory elements found across our genome. These tools address
pattern finding, pattern matching, correlations between different types
of annotations, and more. Often, the tools are also made available to the growing scientific community
interested in cis-regulation, through seamless interfacing, or even
integration, with the central repositories.
Sensitive Sequence Searching
Sequence searching methodology is quite advanced, and available
web-based search tools abound. However, due to the sheer volume of
available sequence data, public servers are forced to run at
sub-optimal settings. Leveraging on our powerful compute cluster, the
Bejerano Lab maintains and develops a uniquely sensitive
sequence
search engine. The allocation of
hundreds of CPUs to the task allows us to reveal previously hidden
homologies, both
within and between different species. The further development of this
tool involves challenges in informatics, database
research and parallel processing.
Bring Your Own Idea
Individuals with specific projects within the broad field of vertebrate genomics are welcome to
contact Gill.
