Annual Scientific Report 2015

The Birney group used methods developed by the Stegle
group to explore links between molecular events in a
variety of normal and diseased human samples, and
collaborated with MRI researchers and cardiologists at
Imperial College, UK to detail the molecular structure
and physiology of the human heart.
In 2015 the Stegle, Marioni and Teichmann groups
devised new ways to tease out the heterogeneity of gene
expression between single cells (Buettner et al., Nature
Biotechnology 2015). The new protocol clarifies the
true differences and similarities between cells, helping
scientists better understand cancer cells, differentiation
processes and the pathogenesis of diseases.
The Marioni group developed and validated a highthroughput
method to identify the precise spatial origin
of cells assayed using scRNA-seq (Achim, Pettit et al.,
Nature Biotechnology 2015). This approach compares
complete mRNA ‘fingerprints’ of a cell with geneexpression
profiles derived from a gene-expression atlas.
Gene expression regulation and culture conditions
are both critical for maintaining the pluripotency of
mouse embryonic stem cells (mESCs) in vitro. Using
the single-cell RNA-seq (scRNA-seq) approach, the
Marioni and Teichmann groups investigated the
transcriptome profiles of mESCs in different culture
conditions (Kolodziejczyk et al., Cell Stem Cell 2015) and
showed that globally, expression in specific sets of genes
varies systematically. The study brought to light new
pluripotency network genes, demonstrating the value of
scRNA-seq for future discovery.
A new approach to cell signalling developed by the
Beltrao group (Wagih et al., Nature Methods 2016)
combines protein phosphorylation and interactionnetwork
data to predict sequence determinants for
kinase recognition. The group used the method to
predict the specificity of hundreds of human kinases,
which helps clarify how protein kinases identify their
target substrates.
The Enright group collaborated with the Furlong group
at EMBL Heidelberg and the O’Carroll group at the
University of Edinburgh to compile a catalogue of long
non-coding RNAs (lncRNAs) expressed through the
murine germline. They used this incredibly detailed
atlas of transcription to identify a set of lncRNAs
whose functions may be extremely important to the
maintenance of the germline and genomic integrity.
Ewan Birney coordinated an independent, international
consortium that tested and evaluated the MinION, a
handheld DNA-sequencing device developed by Oxford
Nanopore. Reflecting a rapid innovation environment,
the data from these evaluations was made freely
available for re-analysis on a dedicated F1000Research
channel. The device opens up new possibilities for
using sequencing technology in the field, for example in
tracking disease outbreaks, testing packaged food or the
trafficking of protected species.
Development
The Stegle group developed new statistical methods
to study the consequence of structural variants in the
human genome on gene-expression levels. With the
Korbel team at EMBL Heidelberg, they surveyed these
effects at a genome-wide scale using the data from the
final release of the most extensive catalogue of structural
variations, the 1000 Genomes Project (Sudmant et
al., Science 2015). The group found that structural
variations – more than SNPs – are often likely to have
functional consequences. This knowledge helps focus
research into the genetic causes of a given condition.
In 2015 the Bertone group, with colleagues at the
Wellcome Trust–MRC Stem Cell Institute, published a
map of gene expression in mouse and primate embryos
that defines the common origins of pluripotency
in mammalian development. (Marmoset Genome
Sequencing and Analysis Consortium, Developmental
Cell 2015). The group analysed the complex network of
gene regulation that supports pluripotency, examining
how this network comes together and later collapses
as cells exit the pluripotent state to become specialised
cell types. The findings have implications for optimising
methods to reprogram cells to pluripotency, or to
improve human embryo culture.
Understanding ageing and disease
The Saez-Rodriguez group developed a novel method to
build logic signalling networks from phospho-proteomic
data generated in MS shotgun data and, with colleagues
at Barts and the London School of Medicine and
Dentistry, used it to study the effect of drugs on breast
cancer cells (Terfve et al., Nature Communications
2015). The method reconstructs pathways robustly,
allowing researchers to ask more precise questions
about how drugs affect proteins and pathways.
In their work on ageing, the Thornton group, building
on the results of their GWAS study for Drosophila
lifespan (Ivanov et al., Journals of Gerontology 2015),
collaborated with the Institute of Healthy Ageing
at UCL to test the effect of manipulating 10 of the
Drosophila genes most significantly associated with
lifespan. Preliminary results suggest that a proportion
of the genes significantly reduced lifespan, and overexpression
of one significantly increased lifespan as
compared to control.
In a series of computational studies (Tyagi et al.,
Frontiers in Immunology 2015), the Thornton group
established molecular similarities between parasite
proteins and allergens that affect the nature of immune
response, and predicted regions of parasite proteins
that potentially share similarity with the IgE-binding
regions of the allergens. Their findings, part of an
interdisciplinary collaboration with the University
of Cambridge, the University of Edinburgh and the
Ugandan Ministry of Health, have implications for the
prediction of likely allergens and the design of molecules
to treat allergy.
2015 EMBL-EBI Annual Scientific Report 35