Bio

Honors & Awards


  • Postdoctoral fellowship, Stanford Center for Computational, Evolutionary and Human Genomics (2015-2016)
  • PhD Fellowship, La Ligue contre le cancer (2014)
  • PhD fellowship, Erasmus Mundus (2010-2013)

Education & Certifications


  • PhD, Institute Curie, University Pierre et Marie Curie, Evolutionary Genomics (2013)
  • MS, University of Pune, Bioinformatics (2008)

Publications

All Publications


  • Vertebrate diapause preserves organisms long term through Polycomb complex members. Science (New York, N.Y.) Hu, C., Wang, W., Brind'Amour, J., Singh, P. P., Reeves, G. A., Lorincz, M. C., Alvarado, A. S., Brunet, A. 2020; 367 (6480): 870?74

    Abstract

    Diapause is a state of suspended development that helps organisms survive extreme environments. How diapause protects living organisms is largely unknown. Using the African turquoise killifish (Nothobranchius furzeri), we show that diapause preserves complex organisms for extremely long periods of time without trade-offs for subsequent adult growth, fertility, and life span. Transcriptome analyses indicate that diapause is an active state, with dynamic regulation of metabolism and organ development genes. The most up-regulated genes in diapause include Polycomb complex members. The chromatin mark regulated by Polycomb, H3K27me3, is maintained at key developmental genes in diapause, and the Polycomb member CBX7 mediates repression of metabolism and muscle genes in diapause. CBX7 is functionally required for muscle preservation and diapause maintenance. Thus, vertebrate diapause is a state of suspended life that is actively maintained by specific chromatin regulators, and this has implications for long-term organism preservation.

    View details for DOI 10.1126/science.aaw2601

    View details for PubMedID 32079766

  • OHNOLOGS v2: a comprehensive resource for the genes retained from whole genome duplication in vertebrates NUCLEIC ACIDS RESEARCH Singh, P., Isambert, H. 2020; 48 (D1): D724?D730

    Abstract

    All vertebrates including human have evolved from an ancestor that underwent two rounds of whole genome duplication (2R-WGD). In addition, teleost fish underwent an additional third round of genome duplication (3R-WGD). The genes retained from these genome duplications, so-called ohnologs, have been instrumental in the evolution of vertebrate complexity, development and susceptibility to genetic diseases. However, the identification of vertebrate ohnologs has been challenging, due to lineage specific genome rearrangements since 2R- and 3R-WGD. We previously identified vertebrate ohnologs using a novel synteny comparison across multiple genomes. Here, we refine and apply this approach on 27 vertebrate genomes to identify ohnologs from both 2R- and 3R-WGD, while taking into account the phylogenetically biased sampling of available species. We assemble vertebrate ohnolog pairs and families in an expanded OHNOLOGS v2 database. We find that teleost fish have retained more 2R-WGD ohnologs than mammals and sauropsids, and that these 2R-ohnologs have retained significantly more ohnologs from the subsequent 3R-WGD than genes without 2R-ohnologs. Interestingly, species with fewer extant genes, such as sauropsids, have retained similar or higher proportions of ohnologs. OHNOLOGS v2 should allow deeper evolutionary genomic analysis of the impact of WGD on vertebrates and can be freely accessed at http://ohnologs.curie.fr.

    View details for DOI 10.1093/nar/gkz909

    View details for Web of Science ID 000525956700097

    View details for PubMedID 31612943

    View details for PubMedCentralID PMC7145513

  • Mutations in calmodulin-binding domains of TRPV4/6 channels confer invasive properties to colon adenocarcinoma cells CHANNELS Arbabian, A., Iftinca, M., Altier, C., Singh, P., Isambert, H., Coscoy, S. 2020; 14 (1): 101?9

    Abstract

    Transient receptor potential (TRP) channels form a family of polymodal cation channels gated by thermal, mechanical, or chemical stimuli, with many of them involved in the control of proliferation, apoptosis, or cell cycle. From an evolutionary point of view, TRP family is characterized by high conservation of duplicated genes originating from whole-genome duplication at the onset of vertebrates. The conservation of such "ohnolog" genes is theoretically linked to an increased probability of generating phenotypes deleterious for the organism upon gene mutation. We aimed to test experimentally the hypothesis that TRP mutations, in particular gain-of-function, could be involved in the generation of deleterious phenotypes involved in cancer, such as gain of invasiveness. Indeed, a number of TRP channels have been linked to cancer progression, and exhibit changes in expression levels in various types of cancers. However, TRP mutations in cancer have been poorly documented. We focused on 2 TRPV family members, TRPV4 and TRPV6, and studied the effect of putative gain-of-function mutations on invasiveness properties. TRPV channels have a C-terminal calmodulin-binding domain (CaMBD) that has important functions for regulating protein function, through different mechanisms depending on the channel (channel inactivation/potentiation, cytoskeleton regulation). We studied the effect of mutations mimicking constitutive phosphorylation in TRPV4 and TRPV6 CaMBDs: TRPV4 S823D, S824D and T813D, TRPV6 S691D, S692D and T702. We found that most of these mutants induced a strong gain of invasiveness of colon adenocarcinoma SW480 cells, both for TRPV4 and TRPV6. While increased invasion with TRPV6 S692D and T702D mutants was correlated to increased mutant channel activity, it was not the case for TRPV4 mutants, suggesting different mechanisms with the same global effect of gain in deleterious phenotype. This highlights the potential importance to search for TRP mutations involved in cancer.

    View details for DOI 10.1080/19336950.2020.1740506

    View details for Web of Science ID 000519986200001

    View details for PubMedID 32186440

  • The Genetics of Aging: A Vertebrate Perspective. Cell Singh, P. P., Demmitt, B. A., Nath, R. D., Brunet, A. 2019; 177 (1): 200?220

    Abstract

    Aging negatively impacts vitality and health. Many genetic pathways that regulate aging were discovered in invertebrates. However, the genetics of aging is more complex in vertebrates because of their specialized systems. This Review discusses advances in the genetic regulation of aging in vertebrates from work in mice, humans, and organisms with exceptional lifespans. We highlight challenges for the future, including sex-dependent differences in lifespan and the interplay between genes and environment. We also discuss how the identification of reliable biomarkers of age and development of new vertebrate models can be leveraged for personalized interventions to counter aging and age-related diseases.

    View details for PubMedID 30901541

  • Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses. Genome research Benayoun, B. A., Pollina, E. A., Singh, P. P., Mahmoudi, S., Harel, I., Casey, K. M., Dulken, B. W., Kundaje, A., Brunet, A. 2019

    Abstract

    Aging is accompanied by the functional decline of tissues. However, a systematic study of epigenomic and transcriptomic changes across tissues during aging is missing. Here, we generated chromatin maps and transcriptomes from four tissues and one cell type from young, middle-aged, and old mice-yielding 143 high-quality data sets. We focused on chromatin marks linked to gene expression regulation and cell identity: histone H3 trimethylation at lysine 4 (H3K4me3), a mark enriched at promoters, and histone H3 acetylation at lysine 27 (H3K27ac), a mark enriched at active enhancers. Epigenomic and transcriptomic landscapes could easily distinguish between ages, and machine-learning analysis showed that specific epigenomic states could predict transcriptional changes during aging. Analysis of data sets from all tissues identified recurrent age-related chromatin and transcriptional changes in key processes, including the up-regulation of immune system response pathways such as the interferon response. The up-regulation of the interferon response pathway with age was accompanied by increased transcription and chromatin remodeling at specific endogenous retroviral sequences. Pathways misregulated during mouse aging across tissues, notably innate immune pathways, were also misregulated with aging in other vertebrate species-African turquoise killifish, rat, and humans-indicating common signatures of age across species. To date, our data set represents the largest multitissue epigenomic and transcriptomic data set for vertebrate aging. This resource identifies chromatin and transcriptional states that are characteristic of young tissues, which could be leveraged to restore aspects of youthful functionality to old tissues.

    View details for PubMedID 30858345

  • The genome of Austrofundulus limnaeus offers insights into extreme vertebrate stress tolerance and embryonic development BMC GENOMICS Wagner, J. T., Singh, P., Romney, A. L., Riggs, C. L., Minx, P., Woll, S. C., Roush, J., Warren, W. C., Brunet, A., Podrabsky, J. E. 2018; 19: 155

    Abstract

    The annual killifish Austrofundulus limnaeus inhabits ephemeral ponds in northern Venezuela, South America, and is an emerging extremophile model for vertebrate diapause, stress tolerance, and evolution. Embryos of A. limnaeus regularly experience extended periods of desiccation and anoxia as a part of their natural history and have unique metabolic and developmental adaptations. Currently, there are limited genomic resources available for gene expression and evolutionary studies that can take advantage of A. limnaeus as a unique model system.We describe the first draft genome sequence of A. limnaeus. The genome was assembled de novo using a merged assembly strategy and was annotated using the NCBI Eukaryotic Annotation Pipeline. We show that the assembled genome has a high degree of completeness in genic regions that is on par with several other teleost genomes. Using RNA-seq and phylogenetic-based approaches, we identify several candidate genes that may be important for embryonic stress tolerance and post-diapause development in A. limnaeus. Several of these genes include heat shock proteins that have unique expression patterns in A. limnaeus embryos and at least one of these may be under positive selection.The A. limnaeus genome is the first South American annual killifish genome made publicly available. This genome will be a valuable resource for comparative genomics to determine the genetic and evolutionary mechanisms that support the unique biology of annual killifishes. In a broader context, this genome will be a valuable tool for exploring genome-environment interactions and their impacts on vertebrate physiology and evolution.

    View details for PubMedID 29463212

  • Progranulin, lysosomal regulation and neurodegenerative disease NATURE REVIEWS NEUROSCIENCE Kao, A. W., McKay, A., Singh, P. P., Brunet, A., Huang, E. J. 2017; 18 (6): 325-333

    Abstract

    The discovery that heterozygous and homozygous mutations in the gene encoding progranulin are causally linked to frontotemporal dementia and lysosomal storage disease, respectively, reveals previously unrecognized roles of the progranulin protein in regulating lysosome biogenesis and function. Given the importance of lysosomes in cellular homeostasis, it is not surprising that progranulin deficiency has pleiotropic effects on neural circuit development and maintenance, stress response, innate immunity and ageing. This Progress article reviews recent advances in progranulin biology emphasizing its roles in lysosomal function and brain innate immunity, and outlines future avenues of investigation that may lead to new therapeutic approaches for neurodegeneration.

    View details for DOI 10.1038/nrn.2017.36

    View details for Web of Science ID 000401517300006

    View details for PubMedID 28435163

  • Learning causal networks with latent variables from multivariate information in genomic data. PLoS computational biology Verny, L., Sella, N., Affeldt, S., Singh, P. P., Isambert, H. 2017; 13 (10): e1005662

    Abstract

    Learning causal networks from large-scale genomic data remains challenging in absence of time series or controlled perturbation experiments. We report an information- theoretic method which learns a large class of causal or non-causal graphical models from purely observational data, while including the effects of unobserved latent variables, commonly found in many genomic datasets. Starting from a complete graph, the method iteratively removes dispensable edges, by uncovering significant information contributions from indirect paths, and assesses edge-specific confidences from randomization of available data. The remaining edges are then oriented based on the signature of causality in observational data. The approach and associated algorithm, miic, outperform earlier methods on a broad range of benchmark networks. Causal network reconstructions are presented at different biological size and time scales, from gene regulation in single cells to whole genome duplication in tumor development as well as long term evolution of vertebrates. Miic is publicly available at https://github.com/miicTeam/MIIC.

    View details for DOI 10.1371/journal.pcbi.1005662

    View details for PubMedID 28968390

  • The African Turquoise Killifish Genome Provides Insights into Evolution and Genetic Architecture of Lifespan CELL Valenzano, D. R., Benayoun, B. A., Singh, P. P., Zhang, E., Etter, P. D., Hu, C., Clement-Ziza, M., Willemsen, D., Cui, R., Harel, I., Machado, B. E., Yee, M., Sharp, S. C., Bustamante, C. D., Beyer, A., Johnson, E. A., Brunet, A. 2015; 163 (6): 1539-1554

    Abstract

    Lifespan is a remarkably diverse trait ranging from a few days to several hundred years in nature, but the mechanisms underlying the evolution of lifespan differences remain elusive. Here we de novo assemble a reference genome for the naturally short-lived African turquoise killifish, providing a unique resource for comparative and experimental genomics. The identification of genes under positive selection in this fish reveals potential candidates to explain its compressed lifespan. Several aging genes are under positive selection in this short-lived fish and long-lived species, raising the intriguing possibility that the same gene could underlie evolution of both compressed and extended lifespans. Comparative genomics and linkage analysis identify candidate genes associated with lifespan differences between various turquoise killifish strains. Remarkably, these genes are clustered on the sex chromosome, suggesting that short lifespan might have co-evolved with sex determination. Our study provides insights into the evolutionary forces that shape lifespan in nature.

    View details for DOI 10.1016/j.cell.2015.11.008

    View details for Web of Science ID 000366044800024

    View details for PubMedID 26638078

    View details for PubMedCentralID PMC4684691

  • Identification of Ohnolog Genes Originating from Whole Genome Duplication in Early Vertebrates, Based on Synteny Comparison across Multiple Genomes PLOS COMPUTATIONAL BIOLOGY Singh, P. P., Arora, J., Isambert, H. 2015; 11 (7)

    Abstract

    Whole genome duplications (WGD) have now been firmly established in all major eukaryotic kingdoms. In particular, all vertebrates descend from two rounds of WGDs, that occurred in their jawless ancestor some 500 MY ago. Paralogs retained from WGD, also coined 'ohnologs' after Susumu Ohno, have been shown to be typically associated with development, signaling and gene regulation. Ohnologs, which amount to about 20 to 35% of genes in the human genome, have also been shown to be prone to dominant deleterious mutations and frequently implicated in cancer and genetic diseases. Hence, identifying ohnologs is central to better understand the evolution of vertebrates and their susceptibility to genetic diseases. Early computational analyses to identify vertebrate ohnologs relied on content-based synteny comparisons between the human genome and a single invertebrate outgroup genome or within the human genome itself. These approaches are thus limited by lineage specific rearrangements in individual genomes. We report, in this study, the identification of vertebrate ohnologs based on the quantitative assessment and integration of synteny conservation between six amniote vertebrates and six invertebrate outgroups. Such a synteny comparison across multiple genomes is shown to enhance the statistical power of ohnolog identification in vertebrates compared to earlier approaches, by overcoming lineage specific genome rearrangements. Ohnolog gene families can be browsed and downloaded for three statistical confidence levels or recompiled for specific, user-defined, significance criteria at http://ohnologs.curie.fr/. In the light of the importance of WGD on the genetic makeup of vertebrates, our analysis provides a useful resource for researchers interested in gaining further insights on vertebrate evolution and genetic diseases.

    View details for DOI 10.1371/journal.pcbi.1004394

    View details for Web of Science ID 000360620100035

    View details for PubMedID 26181593

  • A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell Harel, I., Benayoun, B. A., Machado, B., Singh, P. P., Hu, C., Pech, M. F., Valenzano, D. R., Zhang, E., Sharp, S. C., Artandi, S. E., Brunet, A. 2015; 160 (5): 1013-1026

    Abstract

    Aging is a complex process that affects multiple organs. Modeling aging and age-related diseases in the lab is challenging because classical vertebrate models have relatively long lifespans. Here, we develop the first platform for rapid exploration of age-dependent traits and diseases in vertebrates, using the naturally short-lived African turquoise killifish. We provide an integrative genomic and genome-editing toolkit in this organism using our de-novo-assembled genome and the CRISPR/Cas9 technology. We mutate many genes encompassing the hallmarks of aging, and for a subset, we produce stable lines within 2-3 months. As a proof of principle, we show that fish deficient for the protein subunit of telomerase exhibit the fastest onset of telomere-related pathologies among vertebrates. We further demonstrate the feasibility of creating specific genetic variants. This genome-to-phenotype platform represents a unique resource for studying vertebrate aging and disease in a high-throughput manner and for investigating candidates arising from human genome-wide studies.

    View details for DOI 10.1016/j.cell.2015.01.038

    View details for PubMedID 25684364

    View details for PubMedCentralID PMC4344913

  • Human Dominant Disease Genes Are Enriched in Paralogs Originating from Whole Genome Duplication PLOS COMPUTATIONAL BIOLOGY Singh, P. P., Affeldt, S., Malaguti, G., Isambert, H. 2014; 10 (7)

    View details for DOI 10.1371/journal.pcbi.1003754

    View details for Web of Science ID 000339890900056

    View details for PubMedID 25080083

  • On the retention of gene duplicates prone to dominant deleterious mutations THEORETICAL POPULATION BIOLOGY Malaguti, G., Singh, P. P., Isambert, H. 2014; 93: 38-51

    Abstract

    Recent studies have shown that gene families from different functional categories have been preferentially expanded either by small scale duplication (SSD) or by whole-genome duplication (WGD). In particular, gene families prone to dominant deleterious mutations and implicated in cancers and other genetic diseases in human have been greatly expanded through two rounds of WGD dating back from early vertebrates. Here, we strengthen this intriguing observation, showing that human oncogenes involved in different primary tumors have retained many WGD duplicates compared to other human genes. In order to rationalize this evolutionary outcome, we propose a consistent population genetics model to analyze the retention of SSD and WGD duplicates taking into account their propensity to acquire dominant deleterious mutations. We solve a deterministic haploid model including initial duplicated loci, their retention through sub-functionalization or their neutral loss-of-function or deleterious gain-of-function at one locus. Extensions to diploid genotypes are presented and population size effects are analyzed using stochastic simulations. The only difference between the SSD and WGD scenarios is the initial number of individuals with duplicated loci. While SSD duplicates need to spread through the entire population from a single individual to reach fixation, WGD duplicates are de facto fixed in the small initial post-WGD population arising through the ploidy incompatibility between post-WGD individuals and the rest of the pre-WGD population. WGD duplicates prone to dominant deleterious mutations are then shown to be indirectly selected through purifying selection in post-WGD species, whereas SSD duplicates typically require positive selection. These results highlight the long-term evolution mechanisms behind the surprising accumulation of WGD duplicates prone to dominant deleterious mutations and are shown to be consistent with cancer genome data on the prevalence of human oncogenes with WGD duplicates.

    View details for DOI 10.1016/j.tpb.2014.01.004

    View details for Web of Science ID 000333727800004

    View details for PubMedID 24530892

  • Evolution and cancer: expansion of dangerous gene repertoire by whole genome duplications M S-MEDECINE SCIENCES Affeldt, S., Singh, P. P., Cascone, I., Selimoglu, R., Camonis, J., Isambert, H. 2013; 29 (4): 358-361

    View details for DOI 10.1051/medsci/2013294008

    View details for Web of Science ID 000318668300008

    View details for PubMedID 23621930

  • On the Expansion of "Dangerous'' Gene Repertoires by Whole-Genome Duplications in Early Vertebrates CELL REPORTS Singh, P. P., Affeldt, S., Cascone, I., Selimoglu, R., Camonis, J., Isambert, H. 2012; 2 (5): 1387-1398

    Abstract

    The emergence and evolutionary expansion of gene families implicated in cancers and other severe genetic diseases is an evolutionary oddity from a natural selection perspective. Here, we show that gene families prone to deleterious mutations in the human genome have been preferentially expanded by the retention of "ohnolog" genes from two rounds of whole-genome duplication (WGD) dating back from the onset of jawed vertebrates. We further demonstrate that the retention of many ohnologs suspected to be dosage balanced is in fact indirectly mediated by their susceptibility to deleterious mutations. This enhanced retention of "dangerous" ohnologs, defined as prone to autosomal-dominant deleterious mutations, is shown to be a consequence of WGD-induced speciation and the ensuing purifying selection in post-WGD species. These findings highlight the importance of WGD-induced nonadaptive selection for the emergence of vertebrate complexity, while rationalizing, from an evolutionary perspective, the expansion of gene families frequently implicated in genetic disorders and cancers.

    View details for DOI 10.1016/j.celrep.2012.09.034

    View details for Web of Science ID 000314457700032

    View details for PubMedID 23168259

  • Case for an RNA-prion world: a hypothesis based on conformational diversity JOURNAL OF BIOLOGICAL PHYSICS Singh, P. P., Banerji, A. 2011; 37 (2): 185-188

    Abstract

    Prions and other misfolded proteins can impart their structure and functions to normal molecules. Based upon a thorough structural assessment of RNA, prions and misfolded proteins, especially from the perspective of conformational diversity, we propose a case for co-existence of these in the pre-biotic world. Analyzing the evolution of physical aspects of biochemical structures, we put forward a case for an RNA-prion pre-biotic world, instead of, merely, the "RNA World".

    View details for DOI 10.1007/s10867-011-9219-7

    View details for Web of Science ID 000287929000002

    View details for PubMedID 22379228

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