European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
Big Data in Biology and Medicine
Molecular biology is now a leading example of a data intensive science, with both pragmatic and theoretical challenges being raised by data volumes and dimensionality of the data. These changes are present in both “large scale” consortia science and small scale science, and across now a broad range of applications – from human health, through to agriculture and ecosystems. All of molecular life science is feeling this effect.
As molecular techniques – from genomics through transcriptomics and metabolomics – drop in price and turn around time there is a wealth of opportunity for clinical research and in some cases, active changes clinical practice even at this early stage. The development of this work requires inter-disciplinary teams spanning basic research, bioinformatics and clinical expertise.
This shift in modality is creating a wealth of new opportunities and has some accompanying challenges. In particular there is a continued need for a robust information infrastructure for molecular biology and clinical research. This ranges from the physical aspects of dealing with data volume through to the more statistically challenging aspects of interpreting it. A particular problem is finding causal relationships in the high level of correlative data. Genetic data are particular useful in resolving these issues.
Author, The $1,000 Genome and Cracking the Genome;
Founding Editor, Nature Genetics;
Executive Editor, The CRISPR Journal
OBSERVATIONS ON THE ROAD TO THE $1000 GENOME. (working title)
Since his first book Breakthrough (co-authored with a former Thompson Twin) which covered the race to isolate the breast cancer gene, Kevin Davies, the founding editor of Nature Genetics, has enjoyed publishing and reporting on advances in genome research. His subsequent books, Cracking the Genome and The $1,000 Genome, spanned the Human Genome Project and advances in next-gen sequencing and consumer genetics. The latter led to a personal invitation to collaborate with Jim Watson on an updated version of DNA: The Story of the Genetic Revolution. In this talk, Kevin shares stories and highlights from the genome revolution, including his current fascination with CRISPR and gene editing.
Principal Scientist, Illumina
SAMPLE PREPARATION FOR NGS ON A SURFACE
NGS platforms require biological samples to be transformed into a library format prior to sequencing. This usually entails several enzymatic, sometimes mechanical, steps performed on the bench. Traditionally, these reactions have been performed in solution phase in tubes, in contrast to the sequencing reactions or clustering reactions that are performed on a surface of a flow cell. Illumina recently introduced a novel sample preparation workflow where libraries are also generated on a surface: on paramagnetic beads. In this talk, the characteristics and potential of generating sequencing on a surface will be discussed.
Medical Microbiology Research Laboratory, Norwich Medical School, University of East Anglia, Norwich, NR4 7UQ, UK
METABOLIC SIGNATURES OF HOST ADAPTAION IN SALMONELLA ENTERICA
Serotyping separates isolates of Salmonella enterica into more than 1,500 serovars. Many serovars contain isolates which have biological coherence (e.g. S. Typhi all cause enteric fever in humans), but this is not the case for all serovars. The focus here is upon isolates with the antigenic formula (O: H phase I: H phase II) 6,7:c:1,5: S. Choleraesuis, S. Paratyphi C and S. Typhisuis. This group contains strains adapted to different animal hosts and are currently typed by biochemical tests. These three closely related but very different serovars therefore represented an opportunity to investigate host adaptation within the S. enterica species. Whole genome sequencing was used to analyse a collection of Salmonella which share an antigenic formula; 6,7:c:1,5, but differ in host adaptation: S. Paratyphi C (human), S. Choleraesuis (both humans and swine) and S. Typhisuis (swine). Genes were identified which can be used for differentiating them in a diagnostic laboratory and their metabolic ability in the context of their host adaptation was compared.
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America.
THE CHROMOSOMAL ORGANIZATION OF HORIZONTAL GENE TRANSFER IN BACTERIA
Bacterial adaptation is accelerated by the acquisition of novel traits through horizontal gene transfer, but the integration of these genes affects genome organization. We analyzed 932 complete genomes of 80 bacterial species, and found that transferred genes are concentrated in only ~1% of the chromosomal regions (hotspots)1. This concentration increases with genome size and with the rate of transfer. Hotspots diversify by rapid gene turnover; their chromosomal distribution depends on local contexts (neighboring core genes), and content in mobile genetic elements. Hotspots concentrate most changes in gene repertoires, reduce the trade-off between genome diversification and organization, and should be treasure troves of strain-specific adaptive genes. Most mobile genetic elements and antibiotic resistance genes are in hotspots, but many hotspots lack recognizable mobile genetic elements and exhibit frequent homologous recombination at flanking core genes. Overrepresentation of hotspots with fewer mobile genetic elements in naturally transformable bacteria suggests that homologous recombination and horizontal gene transfer are tightly linked in genome evolution. Knowing the organizational traits of chromosomes might facilitate large-scale genetic engineering and should lead to a better understanding of the evolutionary interactions between horizontal gene transfer and genome organization.
1 Oliveira, PH; Touchon, M; Cury, J; Rocha, EPC. (2017). The chromosomal organization of horizontal gene transfer in bacteria. Nature Communications. 8, 841.
EMEA Sales Development Manager, PacBio
Single Molecule, Real-Time (SMRT®) Sequencing delivers long continuous reads (>20 kb), high consensus accuracy (up to 99.999% QV50), uniform coverage (even across high GC content regions), along with simultaneous epigenetics characterization.
Obtaining microbial genomes with high accuracy and contiguity has become faster and more affordable thanks to new multiplexing barcoding kit, pooling tool, and streamlined analysis workflow. The increased throughput of the PacBio® Sequel® System enables multiple microbes to be sequenced on a single SMRT Cell, greatly increasing throughput and reducing costs per genome assembly.
Ralph will review workflows and share example data to illustrate how the PacBio technology enables scientists to generate high-quality reference genomes, reconstruct intact genes and gene clusters, clarify the role of mobile elements in drug resistance and transmission, and assess the contribution of DNA modification to pathogenesis.
Staff Scientist, National Human Genome Research Institute
TRIOBINNING: TRIO-BASED ASSEMBLY (working title)
Reference genome projects have historically selected inbred individuals to minimize heterozygosity and simplify assembly. We challenge this dogma and present a new approach designed specifically for heterozygous genomes. “Trio binning” uses short reads from two parental genomes to partition long reads from an offspring into haplotype-specific sets prior to assembly. Each haplotype is then assembled independently, resulting in a complete diploid reconstruction. On a benchmark human trio, this method achieved high accuracy and recovered complex structural variants missed by alternative approaches. To demonstrate its effectiveness on a heterozygous genome, we sequenced an F1 cross between cattle subspecies Bos taurus taurus and Bos taurus indicus, and completely assembled both parental haplotypes with NG50 haplotig sizes >20 Mbp and 99.998% accuracy, surpassing the quality of current cattle reference genomes. We propose trio binning as a new best practice for diploid genome assembly that will enable new studies of haplotype variation and inheritance.
Director of Science at the Earlham Institute (EI) and director of the BRIDGE Colombia network of researchers across the UK and Colombia
EVOLUTION OF GENE REGULATORY NETWORKS CONTROLLING TRAITS UNDER NATURAL SELECTION IN CICHLIDS
Gene regulatory network evolution is a key driver of anatomical innovations, serving as a substrate for the evolution of phenotypic diversity and adaptation. However, little is known about the genome-wide evolution of regulatory networks (genotype) and their potential phenotypic effect across ecologically-diverse species (ecotype). In vertebrates, the phenotypic and ecotypic diversification of East African cichlids is unparalleled, implying the rapid evolution of regulatory regions and networks underlying the traits under selection during the early stages of speciation. To investigate tissue-specific evolution of gene regulatory networks along a phylogeny, we developed a framework to identify ancestral reconstructed and extant species co-expression modules and their associated regulators (cis-regulatory elements, transcription factors and miRNAs) and applied this framework to six tissues in five East African cichlids. Along the phylogeny, our analyses identified modules with tissue-specific patterns across the five cichlids species that were predicted to be regulated by diverged suites of regulators. We report striking cases of rapid network rewiring for genes known to be involved in traits under natural and/or sexual selection, such as the visual system. In regulatory regions of visual opsin genes e.g. sws1, polymorphisms in transcription factor binding sites (TFBSs) have driven network rewiring, consistent with ecological niches of different lake species. Within same lake species but between ecologically diverse groups, segregating TFBSs suggests ecotype-associated network rewiring in East African cichlid radiations. Our unique integrative approach to infer regulatory networks across multiple species allowed us to identify the rapid regulatory changes associated with traits under selection in radiating cichlids.
Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, MAHSC, Manchester, UK and Prevention Breast Cancer Unit and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust (South), Manchester, UK.
BREAST CANCER PATHOLOGY AND STAGE ARE BETTER PREDICTED BY RISK STRATIFICATION MODELS THAT INCLUDE MAMMOGRAPHIC DENSITY AND COMMON GENETIC VARIANTS
Background: There are increasing efforts to stratify breast cancer risk to enable more targeted early detection and prevention strategies that will better balance the risks and benefits of population screening programmes.
Methods: Data from a subset of 9362 of the 57,902 women in the Predicting Risk Of Cancer At Screening (PROCAS) study were examined. These women were unaffected by breast cancer at study entry and provided DNA for a polygenic risk score (PRS). The PRS was analysed along with mammographic density (density residual-DR) and standard risk factors to assess future risk of breast cancer based on tumour stage receptor expression and pathology (invasive/DCIS).
Results: For the 195 prospective incident breast cancers a predictor based on Tyrer-Cuzick, DR and PRS was informative for subsequent breast cancer overall (IQ-OR=2.25 (1.89-2.68)) with excellent calibration (0.99). The model performed particularly well in predicting higher stage (stage 2+ IQ-OR=2.69 (2.02–3.60) and ER+ BCs (ER+ IQ-OR =2.36 (1.93–2.89)). Individually DR was most predictive for HER2+ and stage 2+ cancers but did not discriminate as well between poor and extremely good prognosis BC as either Tyrer-Cuzick or the PRS. In contrast the PRS gave the highest OR for incident stage 2+ cancers, (IQR-OR=1.79 (95% CI 1.30-2.46)). None of the three prediction measures, individually or in combination, were good predictors of ER negative breast cancer.
Conclusions: A combined approach using Tyrer-Cuzick, DR and PRS provides accurate risk stratification, particularly for poor prognosis cancers. This provides support for reducing the screening interval in high-risk women and increasing the screening interval in low-risk women defined by this model.
Product Specialist, Agilent Technologies
THE AGILENT NGS WORKFLOW
Agilent presents it’s NGS workflow, from sample to data interpretation. Including the latest library preparation offering; SureSelect XT HS and SureSelect XT Low Input, that is suitable for limited samples such as FFPE. We will be introducing our latest software platform; Alissa Align and Call, the next evolution of Agilent’s Alissa Clinical informatics solution. Agilent will also be showing a sneak preview of our upcoming automation platform.
Cryptosporidium Reference Unit, Public Health Wales Microbiology and Health Protection, Singleton Hospital, Swansea, UK
Swansea University Medical School, Singleton Park, Swansea
Aberystwyth University, Penglais Hill, Aberystwyth
CRYPTOSPORIDIUM GENOMICS: WHERE HAVE WE COME FROM AND WHERE ARE WE GOING?
Cryptosporidium is a protozoan parasite that causes diarrhoeal disease in pre-weaned ruminant livestock and prolonged gastroenteritis (cryptosporidiosis) in humans, especially young children. Symptoms can last 2-3 weeks, but are self-limiting in immuno-competent hosts, immuno-compromise can lead to severe, sometimes life-threatening disease. Most human disease in the UK is caused by C. parvum(zoonotic) or C. hominis(anthroponotic).
Routine stool diagnostics are based on either microscopy of stained smears, detection of antigens by enzyme immunoassays or DNA by PCR for presence/absence of the genus. Although species-level genotyping is undertaken on positive stools referred to the Cryptosporidium Reference Unit, there is no standardised multilocus subtyping scheme for C. parvumand C. hominis, and Sanger sequencing the gp60 gene is used to characterise isolates especially in outbreaks.
The number of Cryptosporidiumreference genomes released so far is limited and the diversity within and between Cryptosporidiumspecies is still being discovered. The generation of new reference genomes requires either passage of clinical isolates through animals to collect sufficient oocysts or the use of whole genome amplification for subsequent genomic DNA recovery and sequence analysis. Either way, pre-preparation before DNA extraction is critical.
Nethertheless, the number of available genomes is increasing and improving our understanding of the biology, pathology and evolution of this parasite. At the conference I will describe some of the work undertakento support public health applications of Cryptosporidiumgenomics.
Senior Lecturer, Rowett Institute, University of Aberdeen
THE HUMAN GUT MICROBIOME: MYTHS AND TRUTHS
Thousands of different microbial species are capable of colonising the human intestines, and it has been estimated that these microbes encode more than 10 million unique genes. Under normal circumstances our resident GI tract microbes are considered to play a number of key roles in the maintenance of human health. Conversely, alterations in microbiota composition and activities have been linked to a wide range of diseases. As a result, academic, clinical, public and commercial interest in the microbiota has increased exponentially over the last decade. There is now a concerted effort, involving researchers around the world, to better understand the microbiota, and to manipulate it for therapeutic purposes.
Much of the recent progress has been underpinned by technological advances in areas such as DNA sequencing approaches. While these approaches are hugely powerful, they have inherent limitations and biases. There have been a number of encouraging advances, but much work remains to be carried out before we truly understand the role the microbiota plays, and how we might reproducibly alter it in beneficial ways.
A key challenge for the field is to try and communicate exciting advances, while cutting through the hype that sometimes surrounds this burgeoning area of research. In my talk I will give an overview of current knowledge, and attempt to dispel some persistent and common myths surrounding the human gut microbiota.
Dr Lesley Hoyles, Nottingham Trent University
TOWARDS UNDERSTANDING THE ROLE OF THE GUT MICROBIOME IN FATTY LIVER DISEASE
Non-alcoholic fatty liver disease (NAFLD) refers to a group of conditions in which there is excess lipid accumulation (steatosis) in the liver of those who drink little to no alcohol. It is the most common cause of chronic liver disease, increasing in worldwide prevalence in line with the obesity epidemic, and is closely associated with metabolic syndrome. Animal studies have shown the microbiome contributes to the steatosis phenome, but human data are more limited regarding the role of the microbiome in disease onset/progression. Using an integrated systems biology approach it was possible to evaluate the contribution of the gut microbiome to the molecular phenome of steatosis. Various -omic (metagenomic, transcriptomic, metabolomic) and clinical data were collected for 56 non-diabetic, morbidly obese (BMI >35) women who elected for bariatric surgery. Histological examination of liver biopsies was used to grade steatosis. In common with other diseases, microbial gene richness was anti-correlated with steatosis. Even though only subtle compositional changes were observed in the faecal microbiota, increased abundance of Gram-negative Proteobacteriaand microbial processing of dietary lipids and amino acids, as well as endotoxin-related processes related to Proteobacteria, were correlated with steatosis. Involvement of Proteobacteriain steatosis was reflected in the hepatic transcriptome, in which immune responses associated with non-specific (Gram-negative, viral) microbial infections were activated. Plasma levels of the microbiome-associated metabolite phenylacetic acid (PAA) were associated with steatosis. Treatment of primary human hepatocytes with PAA and feeding the metabolite to mice led to lipid accumulation in liver cells. The steatosis phenotype was transferred upon transplantation of faeces from steatosis patients to mice. Taken together, these results demonstrate the microbiome makes a significant contribution to the steatosis phenome. There is disruption of the gut–liver axis in steatosis, which can be detected in the gut microbiome, hepatic transcriptome and metabolome.
Group Leader, Max Planck Institute for Biology of Ageing, Cologne, Germany
THE GENOMIC PHYLOGENY OF AFRICAN KILLIFISHES REVEALS PERVASIVE GENOME-WIDE RELAXATION OF SELECTION UPON ADAPTATION TO ANNUAL ENVIRONMENTS
African killifishes have evolved in a wide range of environments, from rain forest to arid savanna woodlands, characterised by intermittent water availability. However, the genomic events underlying adaptations to this range of environments are largely unknown. To study the evolutionary genomic events underlying adaptations to environments with different degrees of annual precipitation and temperatures, we sequenced the genome of 45 African killifish species from different habitats, generating four de novo genome assemblies and annotations. Independent adaptations to annual environments are characterised by convergent positive selection and by extensive genome-wide relaxation of selective constraints, leading to significant increase in genome size and to excess of functional sequence divergence at highly conserved genes. Genomic resequencing in 235 individuals from two annual species, in populations ranging from dry to wet environments, revealed that individuals from dry environments have smaller effective populations size, have undergone more severe bottlenecks, leading to high frequency of deleterious mutations. Loss of selective constraints in species evolved in annual environments led to the accumulations of novel mutations at conserved sites in key ageing-modulating genes, including TOR, InsR, Ampk and Foxo3. Mitochondrially-encoded genes show significant accumulation of novel functional gene variants in all but one gene, showing that relaxation of selection pervades nuclear and mitochondrial genome evolution in species evolved in annual environments. We demonstrate that relaxation of selection is a major evolutionary force that moulds genome evolution in species evolving under annual environments, providing a fundamental mechanism to explain life history trait evolution.
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
A SINGLE-CELL RESOLUTION ROADMAP FROM MOUSE GASTRULATION TO EARLY ORGANOGENESIS
The generation of cellular diversity is a hallmark of all metazoan life. Across the animal kingdom, gastrulation represents the key developmental stage at which embryonic pluripotent cells diversify into the lineage-specific precursor cells that will generate the adult organism. Despite its fundamental importance, our understanding of mammalian gastrulation has remained far from complete because the limiting cell numbers in early embryos preclude conventional molecular analysis. I will discuss our recently generated transcriptional profiles for ~90,000 single cells from mouse embryos collected at nine sequential time-points ranging from 6.5 to 8.5 days post-fertilisation. We have used this new dataset to reconstruct a molecular roadmap of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex molecular and cellular events involved in the convergence of visceral and primitive streak-derived endoderm. I will also outline how this work can serve as a vital baseline for understanding the effects of developmental gene mutations, as well as a critical step for the optimisation of in vitrodifferentiation protocols for regenerative medicine.
Wellcome Sanger Institute, Hinxton, CB10 1SA, UK
A MALARIA CELL ATLAS: UNDERSTANDING TRANSCRIPTIONAL VARIATION ACROSS THE PLASMODIUM LIFE-CYCLE USING SINGLE-CELL RNA-SEQ
Virginia Howick, Andrew Russell, Adam Ried, Tom Metcalf, Oliver Billker, Arthur Talman, Mara Lawniczak
Single-cell RNA-sequencing is revolutionizing our understanding of parasite populations. Using this technology, we are now able to understand how a unicellular parasite coordinates gene expression throughout its life-cycle and in response to environmental stimuli. Here we present the initial effort in a Malaria Cell Atlas, which currently consists of single-cell transcriptomes covering the entire Plasmodium berghei life-cycle, including stages in both mosquito and mammalian hosts. Using these data, we are able to finely map the developmental trajectory of the parasite across the life-cycle and have identified differentially expressed and highly variable genes across host environment and parasite phases (invasive, replicative, and sexual stages). We are currently adapting these methods to characterize the vector and host response at a single-cell level with the goal of profiling all cellular players involved in interplay leading to transmission and pathogenesis.
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT
Centre for Trophoblast Research, University of Cambridge, CB2 3EG
Wellcome Trust Sanger Institute, Cambridge CB10 1SA
SINGLE CELL EPIGENOME LANDSCAPE OF DEVELOPMENT AND AGEING
Wolf Reik 1,2,3 , Ferdinand von Meyenn 1 , Melanie Eckersley-Maslin 1 , Stephen Clark 1 , Thomas Stubbs 1 ,
Hisham Mohammed 1 , Rebecca Berrens 1 , Fatima Santos 1 & Wendy Dean 1
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3A T
2Centre for Trophoblast Research, University of Cambridge, CB2 3EG
3Wellcome Trust Sanger Institute, Cambridge CB10 1SA
Epigenetic information is relatively stable in somatic cells but is reprogrammed on a genome wide level
in germ cells and early embryos. Epigenetic reprogramming appears to be conserved in mammals
including humans. This reprogramming is essential for imprinting, and important for the return to naïve
pluripotency including the generation of iPS cells, the erasure of epimutations, and perhaps for the
control of transposons in the germ line. Following reprogramming, epigenetic marking occurs during
lineage commitment in the embryo in order to ensure the stability of the differentiated state in adult
tissues. Signalling and cell interactions that occur during these sensitive periods in development may
have an impact on the epigenome with potentially long lasting effects. The epigenome changes in a
potentially programmed fashion during the ageing process; this epigenetic ageing clock seems to be
conserved in mammals.
Our recent work addresses the mechanisms and consequences of global epigenetic reprogramming in
the germ line, and the role of passive and active mechanisms of DNA demethylation. Using single cell
multi-epigenomics techniques, we are beginning to chart the epigenetic and transcriptional dynamics and
heterogeneity during the exit from pluripotency, symmetry breaking, and initial cell fate decisions leading
up to gastrulation. We are also interested in the potentially programmed degradation of epigenetic
information during the ageing process and how this might be coordinated across tissues and individual
Research Associate, Haniffa lab, Institute of Cellular Medicine, Medical School, Newcastle University
DISCOVERING THE DIVERSITY OF HUMAN SKIN IMMUNE CELLS USING SINGLE-CELL RNA-SEQ
Modern sequencing technologies allow single-cell transcriptome measurements of thousands of cells from a tissue sample. This has revolutionised our understanding of cellular heterogeneity within human tissues. In this presentation, I will outline our approach to deconstruct the cellular composition of human skin using single-cell RNA sequencing. Using a droplet-encapsulation platform to analyse ~100 000 skin cells from three adult donors, we demonstrate the cellular composition and functional organisation of healthy human skin.
Jordi Paps; University of Essex & University of Oxford; firstname.lastname@example.org
RECONSTRUCTION OF THE FIRST ANIMAL GENOME REVELAS A BURST OF GENOMIC NOVELTY
Understanding the emergence the Animal Kingdom is one of the major challenges of modern evolutionary biology. Many genomic changes took place along the evolutionary lineage that gave rise to the Metazoa. Recent research has revealed the role that co-option of old genes played during this transition, but the contribution of genomic novelty has not been fully assessed. Using extensive genome comparisons between metazoans and multiple outgroups we infer the minimal protein-coding genome of the first animal, in addition to other eukaryotic ancestors, and estimate the proportion of novelties in these ancient genomes. Contrary to the prevailing view, this uncovers an unprecedented increase in the extent of genomic novelty during the origin of metazoans, and identifies 25 groups of metazoan-specific genes that are essential across the Animal Kingdom. We argue that internal genomic changes were as important as external factors in the emergence of animals.
Associate Professor, School of Life Sciences and Future Foods Beacon, University of Nottingham.
THE PERVASIVE POPULATION GENOMIC IMPACTS OF GENOME DUPLICATION, GENE FLOW AND SELECTION
The outcrossing relatives Arabidopsis arenosa and Arabidopsis lyrata are increasingly the subjects of population genomic studies of adaptive evolution. These works provide case studies for how population genomics can be applied to targeted questions, from understanding the basis of adaptation to whole genome duplication (WGD) to the genomic basis of adaptation to extreme environments, including toxic mines and high salinity soils. I present an overview of our studies that allows for a large-scale investigation of within- and between-population evolutionary dynamics in this model genus.
We individually resequenced ~600 A. arenosa genomes from 70 diploid and autopolyploid populations, allowing the dating and ordering of successive selective sweeps as lineages follow distinct evolutionary trajectories and diversify across Europe. We integrate these data with 120 A. lyrata and Arabidopsis halleri genomes for a genus-wide view of the genomic basis of diverse adaptations. In A. arenosa, we observe that the population genomic consequences of WGD are pervasive: following WGD there is evidence of a reduced efficacy of purifying selection, with an increase in non-synonymous polymorphisms, and patterns of linkage disequilibrium differ dramatically between ploidies. Autotetraploid diversity is further enriched via local introgression from distantly related diploid populations to the extent that the signal of tetraploid monophyly is largely erased, except at discrete loci resistant to interploidy introgression. Examples of such barrier loci encode alleles that mediate adaptation to WGD. In addition, the tetraploids specifically exchange compelling candidate alleles for interspecies adaptive gene flow with autotetraploid A. lyrata. We hypothesise that the combined effects of initial masking of deleterious mutations, a higher proportion of adaptive substitutions and rampant interploidy (and interspecies) introgression likely all conspire to shape the evolutionary potential of these young autopolyploids.
Group Leader, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh
IDENTIFYING CASUAL VARIANTS IN COMPLEX DISEASE THAT ALTER TRANSCRIPTIONAL FACTOR BINDING
Neil Clark, Giuseppe Gallone, Olympia Gianfrancesco, Chris P Ponting
Genome-wide association studies have linked genetic variation with a very large number of traits and diseases. What we do not know, however, in most cases, is which specific DNA variant is causal for the change in trait or in disease susceptibility. If we are to understand complex traits mechanistically then we need to identify such variants. Our approach differs from most in asking whether any DNA variants that alter the affinity of a transcription factor are causally responsible for a change in any trait. Consequently, we start with the molecular mechanism and determine for which trait this mechanism explains its variation. In our first application of this approach we have used published vitamin D receptor-binding data to identify >10 single nucleotide variants as causal of trait variation.
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
DECODING CELL-CELL INTERACTIONS AT THE MATERNAL-FETAL INTERFACE USING SINGLE CELL TRANSCRIPTOMICS
During the early weeks of human pregnancy, the fetal placenta implants into the uterine mucosa (decidua) where placental trophoblast cells intermingle and communicate with maternal cells. Here, we profile transcriptomes of ~50,000 single cells from this unique microenvironment, sampling matched first trimester maternal blood and decidua, and fetal cells from the placenta itself. We define the cellular composition of human decidua, revealing five distinct subsets of decidual fibroblasts with differing growth factors and hormone production profiles, and show that fibroblast states definetwo distinct decidual layers. Among decidual NK cells, we resolve three subsets, each with a different immunomodulatory and chemokine profile. We develop a repository of ligand-receptor pairs (www.CellPhoneDB.org) and a statistical tool to predict the probability of cell-cell interactions via these pairs, highlighting specific interactions between decidual NK cells and invading fetal extravillous trophoblast cells, maternal immune and stromal cells. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.