Publications by authors named "Federico Gaiti"

15 Publications

  • Page 1 of 1

Pre-introduction introgression contributes to parallel differentiation and contrasting hybridization outcomes between invasive and native marine mussels.

J Evol Biol 2021 Jan 14;34(1):175-192. Epub 2020 Dec 14.

School of Biological Sciences, University of Queensland, St Lucia, Qld, Australia.

Non-native species experience novel selection pressures in introduced environments and may interbreed with native lineages. Species introductions therefore provide opportunities to investigate repeated patterns of adaptation and introgression across replicated contact zones. Here, we investigate genetic parallelism between multiple introduced populations of the invasive marine mussel, Mytilus galloprovincialis, in the absence (South Africa and California) and presence of hybridization with a native congener (Mytilus planulatus in Batemans Bay and Sydney Harbour, Australia). Repeatability in post-introduction differentiation from native-range populations varied between genetically distinct Atlantic and Mediterranean lineages, with Atlantic-derived introductions displaying high differentiation (maxF  > 0.4) and parallelism at outlier loci. Identification of long noncoding RNA transcripts (lncRNA) additionally allowed us to clarify that parallel responses are largely limited to protein-coding loci, with lncRNAs likely evolving under evolutionary constraints. Comparisons of independent hybrid zones revealed differential introgression most strongly in Batemans Bay, with an excess of M. galloprovincialis ancestry and resistance to introgression at loci differentiating parental lineages (M. planulatus and Atlantic M. galloprovincialis). Additionally, contigs putatively introgressed with divergent alleles from a closely related species, Mytilus edulis, showed stronger introgression asymmetries compared with genome-wide trends and also diverged in parallel in both Atlantic-derived introductions. These results suggest that divergent demographic histories experienced by introduced lineages, including pre-introduction introgression, influence contemporary admixture dynamics. Our findings build on previous investigations reporting contributions of historical introgression to intrinsic reproductive architectures shared between marine lineages and illustrate that interspecific introgression history can shape differentiation between colonizing populations and their hybridization with native congeners.
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http://dx.doi.org/10.1111/jeb.13746DOI Listing
January 2021

Deep conservation of the enhancer regulatory code in animals.

Science 2020 11;370(6517)

School of Biological Sciences, University of Queensland, Brisbane, Australia.

Interactions of transcription factors (TFs) with DNA regulatory sequences, known as enhancers, specify cell identity during animal development. Unlike TFs, the origin and evolution of enhancers has been difficult to trace. We drove zebrafish and mouse developmental transcription using enhancers from an evolutionarily distant marine sponge. Some of these sponge enhancers are located in highly conserved microsyntenic regions, including an enhancer in the - region. We found that enhancers in humans and mice share a suite of TF binding motifs with sponges, and that they drive gene expression patterns similar to those of sponge and endogenous enhancers in zebrafish. Our results suggest the existence of an ancient and conserved, yet flexible, genomic regulatory syntax that has been repeatedly co-opted into cell type-specific gene regulatory networks across the animal kingdom.
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http://dx.doi.org/10.1126/science.aax8137DOI Listing
November 2020

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

Nat Med 2020 07 1;26(7):1114-1124. Epub 2020 Jun 1.

New York Genome Center, New York, NY, USA.

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.
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http://dx.doi.org/10.1038/s41591-020-0915-3DOI Listing
July 2020

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Nat Genet 2020 04 23;52(4):378-387. Epub 2020 Mar 23.

New York Genome Center, New York, NY, USA.

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies and clonal hematopoiesis. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.
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http://dx.doi.org/10.1038/s41588-020-0595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216752PMC
April 2020

Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia.

Nature 2019 05 15;569(7757):576-580. Epub 2019 May 15.

New York Genome Center, New York, NY, USA.

Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer. Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy. The CLL epigenome is also an important disease-defining feature, and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations. However, previous studies using bulk sequencing methods to analyse the patterns of DNA methylation were unable to determine whether epimutations affect CLL populations homogeneously. Here, to measure the epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced-representation bisulfite sequencing to B cells from healthy donors and patients with CLL. We observed that the common clonal origin of CLL results in a consistently increased epimutation rate, with low variability in the cell-to-cell epimutation rate. By contrast, variable epimutation rates across healthy B cells reflect diverse evolutionary ages across the trajectory of B cell differentiation, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed us to reconstruct lineages at high-resolution with single-cell data, and to apply this directly to patient samples. The CLL lineage tree shape revealed earlier branching and longer branch lengths than in normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. Integration of single-cell bisulfite sequencing analysis with single-cell transcriptomes and genotyping confirmed that genetic subclones mapped to distinct clades, as inferred solely on the basis of epimutation information. Finally, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells that were preferentially expelled from the lymph node after treatment, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts the lineage history of CLL and its evolution with therapy.
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http://dx.doi.org/10.1038/s41586-019-1198-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533116PMC
May 2019

Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.

Nat Commun 2019 04 23;10(1):1874. Epub 2019 Apr 23.

New York Genome Center, New York, 10013, NY, USA.

Cancer evolution is fueled by epigenetic as well as genetic diversity. In chronic lymphocytic leukemia (CLL), intra-tumoral DNA methylation (DNAme) heterogeneity empowers evolution. Here, to comprehensively study the epigenetic dimension of cancer evolution, we integrate DNAme analysis with histone modification mapping and single cell analyses of RNA expression and DNAme in 22 primary CLL and 13 healthy donor B lymphocyte samples. Our data reveal corrupted coherence across different layers of the CLL epigenome. This manifests in decreased mutual information across epigenetic modifications and gene expression attributed to cell-to-cell heterogeneity. Disrupted epigenetic-transcriptional coordination in CLL is also reflected in the dysregulation of the transcriptional output as a function of the combinatorial chromatin states, including incomplete Polycomb-mediated gene silencing. Notably, we observe unexpected co-mapping of typically mutually exclusive activating and repressing histone modifications, suggestive of intra-tumoral epigenetic diversity. Thus, CLL epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging cellular identities.
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http://dx.doi.org/10.1038/s41467-019-09645-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478836PMC
April 2019

De Novo Plant Transcriptome Assembly and Annotation Using Illumina RNA-Seq Reads.

Methods Mol Biol 2019 ;1933:265-275

School of Biological Sciences, The University of Queensland, St Lucia, QLD, Australia.

The ability to identify and quantify transcribed sequences from a multitude of organisms using high-throughput RNA sequencing has revolutionized our understanding of genetics and plant biology. However, a number of computational tools used in these analyses still require a reference genome sequence, something that is seldom available for non-model organisms. Computational tools employing de Bruijn graphs to reconstruct full-length transcripts from short sequence reads allow for de novo transcriptome assembly. Here we provide detailed methods for generating and annotating de novo transcriptome assembly from plant RNA-seq data.
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http://dx.doi.org/10.1007/978-1-4939-9045-0_16DOI Listing
August 2019

Early metazoan cell type diversity and the evolution of multicellular gene regulation.

Nat Ecol Evol 2018 07 25;2(7):1176-1188. Epub 2018 Jun 25.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

A hallmark of metazoan evolution is the emergence of genomic mechanisms that implement cell-type-specific functions. However, the evolution of metazoan cell types and their underlying gene regulatory programmes remains largely uncharacterized. Here, we use whole-organism single-cell RNA sequencing to map cell-type-specific transcription in Porifera (sponges), Ctenophora (comb jellies) and Placozoa species. We describe the repertoires of cell types in these non-bilaterian animals, uncovering diverse instances of previously unknown molecular signatures, such as multiple types of peptidergic cells in Placozoa. Analysis of the regulatory programmes of these cell types reveals variable levels of complexity. In placozoans and poriferans, sequence motifs in the promoters are predictive of cell-type-specific programmes. By contrast, the generation of a higher diversity of cell types in ctenophores is associated with lower specificity of promoter sequences and the existence of distal regulatory elements. Our findings demonstrate that metazoan cell types can be defined by networks of transcription factors and proximal promoters, and indicate that further genome regulatory complexity may be required for more diverse cell type repertoires.
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http://dx.doi.org/10.1038/s41559-018-0575-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040636PMC
July 2018

Sex Determination in Is Accompanied by Transcriptome Changes That Drive Epigenetic Reprogramming of the Young Gametophyte.

G3 (Bethesda) 2018 07 2;8(7):2205-2214. Epub 2018 Jul 2.

Department of Botany and Plant Pathology, Purdue University, West Lafayette, IN 47907

The fern is an important model for studies of sex determination and gamete differentiation in homosporous plants. Here we use RNA-seq to assemble a transcriptome and identify genes differentially expressed in young gametophytes as their sex is determined by the presence or absence of the male-inducing pheromone called antheridiogen. Of the 1,163 consensus differentially expressed genes identified, the vast majority (1,030) are up-regulated in gametophytes treated with antheridiogen. GO term enrichment analyses of these DEGs reveals that a large number of genes involved in epigenetic reprogramming of the gametophyte genome are up-regulated by the pheromone. Additional hormone response and development genes are also up-regulated by the pheromone. This gametophyte transcriptome and gene expression dataset will prove useful for studies focusing on sex determination and differentiation in plants.
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http://dx.doi.org/10.1534/g3.118.200292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027899PMC
July 2018

Sponge Long Non-Coding RNAs Are Expressed in Specific Cell Types and Conserved Networks.

Noncoding RNA 2018 Mar 7;4(1). Epub 2018 Mar 7.

School of Biological Sciences, University of Queensland, Brisbane, QLD 4072, Australia.

Although developmental regulation by long non-coding RNAs (lncRNAs) appears to be a widespread feature amongst animals, the origin and level of evolutionary conservation of this mode of regulation remain unclear. We have previously demonstrated that the sponge -a morphologically-simple animal-developmentally expresses an array of lncRNAs in manner akin to more complex bilaterians (insects + vertebrates). Here, we first show that lncRNAs are expressed in specific cell types in larvae, juveniles and adults. Thus, as in bilaterians, sponge developmental regulation involves the dynamic, cell type- and context-specific regulation of specific lncRNAs. Second, by comparing gene co-expression networks between and -a distantly-related calcisponge-we identify several putative co-expression modules that appear to be shared in sponges; these network-embedded sponge lncRNAs have no discernable sequence similarity. Together, these results suggest sponge lncRNAs are developmentally regulated and operate in conserved gene regulatory networks, as appears to be the case in more complex bilaterians.
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http://dx.doi.org/10.3390/ncrna4010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890393PMC
March 2018

Long non-coding regulatory RNAs in sponges and insights into the origin of animal multicellularity.

RNA Biol 2018 25;15(6):696-702. Epub 2018 May 25.

a School of Biological Sciences, University of Queensland , Brisbane , Australia.

How animals evolved from a single-celled ancestor over 700 million years ago is poorly understood. Recent transcriptomic and chromatin analyses in the sponge Amphimedon queenslandica, a morphologically-simple representative of one of the oldest animal phyletic lineages, have shed light on what innovations in the genome and its regulation underlie the emergence of animal multicellularity. Comparisons of the regulatory genome of this sponge with those of more complex bilaterian model species and even simpler unicellular relatives have revealed that fundamental changes in genome regulatory complexity accompanied the evolution of animal multicellularity. Here, we review and discuss the results of these recent investigations by specifically focusing on the contribution of long non-coding RNAs to the evolution of the animal regulatory genome.
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http://dx.doi.org/10.1080/15476286.2018.1460166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152434PMC
November 2018

Landscape of histone modifications in a sponge reveals the origin of animal -regulatory complexity.

Elife 2017 04 11;6. Epub 2017 Apr 11.

School of Biological Sciences, University of Queensland, Brisbane, Australia.

Combinatorial patterns of histone modifications regulate developmental and cell type-specific gene expression and underpin animal complexity, but it is unclear this regulatory system evolved. By analysing histone modifications in a morphologically-simple, early branching animal, the sponge , we show that the regulatory landscape used by complex bilaterians was already in place at the dawn of animal multicellularity. This includes distal enhancers, repressive chromatin and transcriptional units marked by H3K4me3 that vary with levels of developmental regulation. Strikingly, enhancers are enriched in metazoan-specific microsyntenic units, suggesting that their genomic location is extremely ancient and likely to place constraints on the evolution of surrounding genes. These results suggest that the regulatory foundation for spatiotemporal gene expression evolved prior to the divergence of sponges and eumetazoans, and was necessary for the evolution of animal multicellularity.
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http://dx.doi.org/10.7554/eLife.22194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429095PMC
April 2017

De novo transcriptome assembly reveals high transcriptional complexity in Pisum sativum axillary buds and shows rapid changes in expression of diurnally regulated genes.

BMC Genomics 2017 03 2;18(1):221. Epub 2017 Mar 2.

The University of Queensland, School of Biological Sciences, St Lucia, QLD, 4072, Australia.

Background: The decision for a bud to grow into a branch is a key regulatory process affecting plant architecture. In order to study molecular processes regulating axillary bud outgrowth in the model plant garden pea (Pisum sativum), we sequenced the axillary bud transcriptome and performed de novo transcriptome assembly.

Results: We assembled a pea axillary bud transcriptome into 81,774 transcripts comprised of 194,067 isoforms. This new pea transcriptome resource is both comprehensive and representative, as shown by comparison to other available pea sequence resources. Over half of the transcriptome could be annotated based on sequence homology to Arabidopsis thaliana proteins, while almost one quarter of the isoforms were identified as putative long non-coding RNAs (lncRNAs). This transcriptome will be useful in studies of pea buds because it includes genes expressed specifically in buds which are not represented in other transcriptome studies. We also investigated the impact of a short time collection series on gene expression. Differential gene expression analysis identified 142 transcripts changing within the short 170 min time frame that the buds were harvested within. Thirty-three of these transcripts are implicated in diurnal fluctuations in other flowering plants, while the remaining transcripts include 31 putative lncRNA. Further investigation of the differentially expressed transcripts found an enrichment of genes involved in post-transcriptional regulation, including RNA processing and modification, as well as genes involved in fatty acid biosynthesis and oxidative phosphorylation.

Conclusions: We have sequenced and assembled a high quality pea bud transcriptome containing both coding and non-coding RNA transcripts that will be useful for further studies into axillary bud outgrowth. Over the short sample collection time frame of just 170 min, we identified differentially expressed coding and non-coding RNA, some of which are implicated in diurnal regulation, highlighting the utility of our transcriptome resource in identifying gene expression changes and informing future experimental designs.
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http://dx.doi.org/10.1186/s12864-017-3577-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335751PMC
March 2017

Origin and evolution of the metazoan non-coding regulatory genome.

Dev Biol 2017 07 20;427(2):193-202. Epub 2016 Nov 20.

School of Biological Sciences, University of Queensland, Brisbane, Australia. Electronic address:

Animals rely on genomic regulatory systems to direct the dynamic spatiotemporal and cell-type specific gene expression that is essential for the development and maintenance of a multicellular lifestyle. Although it is widely appreciated that these systems ultimately evolved from genomic regulatory mechanisms present in single-celled stem metazoans, it remains unclear how this occurred. Here, we focus on the contribution of the non-coding portion of the genome to the evolution of animal gene regulation, specifically on recent insights from non-bilaterian metazoan lineages, and unicellular and colonial holozoan sister taxa. High-throughput next-generation sequencing, largely in bilaterian model species, has led to the discovery of tens of thousands of non-coding RNA genes (ncRNAs), including short, long and circular forms, and uncovered the central roles they play in development. Based on the analysis of non-bilaterian metazoan, unicellular holozoan and fungal genomes, the evolution of some ncRNAs, such as Piwi-interacting RNAs, correlates with the emergence of metazoan multicellularity, while others, including microRNAs, long non-coding RNAs and circular RNAs, appear to be more ancient. Analysis of non-coding regulatory DNA and histone post-translational modifications have revealed that some cis-regulatory mechanisms, such as those associated with proximal promoters, are present in non-animal holozoans, while others appear to be metazoan innovations, most notably distal enhancers. In contrast, the cohesin-CTCF system for regulating higher-order chromatin structure and enhancer-promoter long-range interactions appears to be restricted to bilaterians. Taken together, most bilaterian non-coding regulatory mechanisms appear to have originated before the divergence of crown metazoans. However, differential expansion of non-coding RNA and cis-regulatory DNA repertoires in bilaterians may account for their increased regulatory and morphological complexity relative to non-bilaterians.
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http://dx.doi.org/10.1016/j.ydbio.2016.11.013DOI Listing
July 2017

Dynamic and Widespread lncRNA Expression in a Sponge and the Origin of Animal Complexity.

Mol Biol Evol 2015 Sep 14;32(9):2367-82. Epub 2015 May 14.

School of Biological Sciences, University of Queensland, Brisbane, QLD, Australia

Long noncoding RNAs (lncRNAs) are important developmental regulators in bilaterian animals. A correlation has been claimed between the lncRNA repertoire expansion and morphological complexity in vertebrate evolution. However, this claim has not been tested by examining morphologically simple animals. Here, we undertake a systematic investigation of lncRNAs in the demosponge Amphimedon queenslandica, a morphologically simple, early-branching metazoan. We combine RNA-Seq data across multiple developmental stages of Amphimedon with a filtering pipeline to conservatively predict 2,935 lncRNAs. These include intronic overlapping lncRNAs, exonic antisense overlapping lncRNAs, long intergenic nonprotein coding RNAs, and precursors for small RNAs. Sponge lncRNAs are remarkably similar to their bilaterian counterparts in being relatively short with few exons and having low primary sequence conservation relative to protein-coding genes. As in bilaterians, a majority of sponge lncRNAs exhibit typical hallmarks of regulatory molecules, including high temporal specificity and dynamic developmental expression. Specific lncRNA expression profiles correlate tightly with conserved protein-coding genes likely involved in a range of developmental and physiological processes, such as the Wnt signaling pathway. Although the majority of Amphimedon lncRNAs appears to be taxonomically restricted with no identifiable orthologs, we find a few cases of conservation between demosponges in lncRNAs that are antisense to coding sequences. Based on the high similarity in the structure, organization, and dynamic expression of sponge lncRNAs to their bilaterian counterparts, we propose that these noncoding RNAs are an ancient feature of the metazoan genome. These results are consistent with lncRNAs regulating the development of animals, regardless of their level of morphological complexity.
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http://dx.doi.org/10.1093/molbev/msv117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540969PMC
September 2015