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Evolution of Regulatory Landscapes in Chordates

Periodic Reporting for period 1 - EVOREL (Evolution of Regulatory Landscapes in Chordates)

Reporting period: 2016-01-01 to 2017-12-31

Genomes are the richest data source to understand human biology, disease and past evolutionary history. As in the geological record, multiple evolutionary strata are contained in our DNA, from recent changes which appeared after the divergence from our extinct Neanderthal relatives, to extremely ancient genes operating basic cellular functions shared even with bacterial species. In this Russian doll-like pattern, we can recognize the nested layers of genomic traits that we specifically share with other primates, vertebrates, chordates, metazoans, etc, allowing a better understanding of our genotype-phenotype map and the unique combination of novel and ancestral traits that define our species. However, before the project EVOREL, these questions had been studied by focusing almost exclusively on the evolution of protein coding genes, but not the regulatory elements controlling their expression, severely limiting the understanding of our own genetic makeup as vertebrates. Thus, the aim of EVOREL was to fill this gap and understand the evolution and origin of specific genomic features that regulate the genes of vertebrates and are responsible for our characteristic morphology.
All chordates share a fundamental bodyplan that was greatly elaborated in vertebrates. Vertebrates also evolved highly distinctive genomes, sculpted by two whole genome duplications (WGD) that generated extra gene copies for every gene in the genome and the acquisition of unique genomic traits. To investigate the evolution of these features and genome regulation in vertebrates, we needed to identify and characterize the gene regulatory elements of a close animal relative of vertebrates that would allow us to perform meaningful genomic comparisons. To that end, we chose the cephalochordate amphioxus, a slow-evolving non-vertebrate chordate that shares many anatomical and genomic features with vertebrates and whose genome has not undergone WGDs. By comparing amphioxus regulatory elements with those of vertebrates, our aim was to identify the core genomic regulatory landscape organization that we and other vertebrates share and that underlie the novel and conserved features that characterize our body plan. This way we wanted to make ground breaking advances in our understanding of how the regulatory architecture of our genome was assembled during evolution, providing new insights on how gene regulatory organization has impacted gene expression and, ultimately, unveiling the deep evolutionary roots of the human regulatory architecture.
To achieve the aims of the project, we have identified and characterized genome-wide gene regulatory elements in the amphioxus genome. To that end, we applied multiple cutting-edge functional genomics techniques for the first time in this animal species. This allowed us to identify and study amphioxus gene regulatory elements in a genome-wide manner, including enhancers, promoters, open chromatin regions and 3D chromatin architecture and the expression profiles of every amphioxus gene. By comparing these amphioxus regulatory elements and gene expression profiles with those of vertebrates, we have revealed a high conservation of gene expression and its underlying gene regulatory logic between these two chordate lineages, especially in certain organs and tissues such as the brain, the liver, the gut and the muscle. We also found a strong increase in the complexity of vertebrate gene regulatory landscapes, specially among genes retained in several copies after the two vertebrate WGDs. Finally, we unraveled that many of these extra gene copies generated by the WGDs specialized and restricted their expression and functions, in particular to the brain. Altogether, EVOREL has changed previous assumptions on the evolutionary impact of WGDs and regulatory evolution in general. Furthermore, our data have paved the way for a better understanding of the regulatory principles underlying key vertebrate innovations.
EVOREL results are in the process of being published as an open access manuscript in a high impact scientific journal. Furthermore our findings have been presented in several national and international meetings and invited talks in several research institutions across the world. Finally, all the primary data generated during this work will be publicly available, so other investigators can use them and benefit from them to advance in their research.
Before this project, very little was known about how the regulatory architecture of our genome was assembled during evolution, especially from a macroevolutionary perspective, i.e. at the origin of the vertebrate lineage. EVOREL has completely changed this picture challenging previous assumptions on the evolutionary impact of WGDs and regulatory evolution in general, providing a better understanding on how gene regulatory organization has impacted animal evolution.
To achieve these scientific results, we have pioneered the use of highly innovative functional genomics techniques in a non-model laboratory species, amphioxus, for the first time. This has allowed us to generate a huge amount of functional genomics sequencing data that will be extremely useful for many other investigators and research projects in the future and that is about be available as an open resource upon the forthcoming publication of our results in a scientific journal.
Furthermore, we have developed new bioinformatics methods to compare regulatory information across deep evolutionary distances, such as those mediating between vertebrates and the cephalochordate amphioxus, which will be very useful to other researchers.
Thus, our project will open new research avenues in the comparative genomics, evolution of gene regulation and evodevo fields.
EVOREL Graphical Abstract