Insights from the rescue and breeding management of Cuvier’s gazelle (Gazella cuvieri) through whole-genome sequencing

Captive breeding programmes represent the most intensive type of ex situ population management for threatened species. One example is the Cuvier’s gazelle programme that started in 1975 with only four founding individuals, and after more than four decades of management in captivity, a reintroduction effort was undertaken in Tunisia in 2016, to establish a population in an area historically included within its range. Here, we aim to determine the genetic consequences of this reintroduction event by assessing the genetic diversity of the founder stock as well as of their descendants. We present the first whole-genome sequencing dataset of 30 Cuvier’s gazelles including captive-bred animals, animals born in Tunisia after a reintroduction and individuals from a genetically unrelated Moroccan population. Our analyses revealed no difference between the founder and the offspring cohorts in genome-wide heterozygosity and inbreeding levels, and in the amount and length of runs of homozygosity. The captive but unmanaged Moroccan gazelles have the lowest genetic diversity of all genomes analysed. Our findings demonstrate that the Cuvier’s gazelle captive breeding programme can serve as source populations for future reintroductions of this species. We believe that this study can serve as a starting point for global applications of genomics to the conservation plan of this species.K-P. Koepfli and B. Pukazhenthi acknowledge the Sichel Endowment Fund for research support on dama gazelle genomics. M.A.E. is supported by an FPI (Formación de Personal Investigador) PRE2018-083966 from Ministerio de Ciencia, Universidades e Investigación. P.D. was supported as a postdoctoral fellow by the Smithsonian Institution Fellowship Program. K.-P.K. was supported by funding from the Smithsonian Institution's George E. Burch Fellowship in Theoretical Medicine and Affiliated Theoretical Science. T.M.-B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 864203), BFU2017-86471-P (MINECO/FEDER, UE), ‘Unidad de Excelencia María de Maeztu’, funded by the AEI (CEX2018-000792-M), Howard Hughes International Early Career and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). E.M. received financial support from the project PGC2018-097426-B-C22 (Spanish Ministry of Universities. Spanish State Research Agency. FEDER Program, European Union). E.L. is supported by CGL2017-82654-P (MINECO/FEDER, UE).Peer reviewe

A comparative genomics multitool for scientific discovery and conservation

A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.Peer reviewe

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Understanding dog breed copy number differences in the framework of gray wolf copy number variation

Universitat Pompeu Fabra. Departamento de Ciencias Experimentales y de la Salud.The study of structural variation complements and synergizes with the study of sequence variation to unravel the intricacies of phenotypic variation. Dogs are the most phenotypically variable domesticated species existing today despite their remarkably low nucleotide diversity. As such, the systematized study of copy number variation in an extensive panel of over 100 dog breeds has the potential to unravel a fraction of the bases of phenotypic diversity which remain unexplored. This study finds an excess of structural variants in dogs compared to the expectation given their genetic history, which can potentially account for some of their morphometric, anatomical and pathological variance. Indeed, trait mapping finds over 90 copy number variants associated with more than 10 phenotypes, some of which were previously unknown or uncharacterized. Moreover, there is a correlation between low effect, associated copy number variants and other relevant genomic features such as the expression patterns of long non-coding RNA or the presence of long-range chromatin contacts. Our characterization of copy number variation in dogs has generated a wealth of hypotheses for further functional testing and validation

Understanding dog breed copy number differences in the framework of gray wolf copy number variation

L’estudi de la variació estructural complementa l’estudi de la variació de seqüència per revelar les complexitats de la variació fenotípica. Els gossos són l’espècie domesticada amb més variació fenotípica que existeix avui en dia, malgrat la seva baixa diversitat nucleotídica. Com a tal, estudiar sistemàticament la variació del nombre de còpies en un panell compost de més de 100 races de gossos, permet descobrir algunes de les bases d’aquesta diversitat fenotípica. En la recerca presentada en aquesta tesi, hem descrit un excés de variants estructurals en gossos si ho comparem amb el que s’esperaria segons la seva història genètica. Aquest fet podria explicar part de la seva variació morfomètrica, anatòmica i patològica. Per altra banda, l’estudi d’associació fenotípica que hem realitzat troba més de 90 variants de nombre de còpia associades a més de 10 fenotips, alguns dels quals desconeguts fins al moment. A més a més, hem trobat una correlació entre variants de nombre de còpia de baix efecte estadístic i altres variants genòmiques rellevants, com ara els patrons d’expressió d’ARN llargs no codificants o la presència de contactes de cromatina. El nostre estudi ha generat una gran quantitat d’hipòtesis que poden donar lloc a validacions funcionals posteriors.The study of structural variation complements and synergizes with the study of sequence variation to unravel the intricacies of phenotypic variation. Dogs are the most phenotypically variable domesticated species existing today despite their remarkably low nucleotide diversity. As such, the systematized study of copy number variation in an extensive panel of over 100 dog breeds has the potential to unravel a fraction of the bases of phenotypic diversity which remain unexplored. This study finds an excess of structural variants in dogs compared to the expectation given their genetic history, which can potentially account for some of their morphometric, anatomical and pathological variance. Indeed, trait mapping finds over 90 copy number variants associated with more than 10 phenotypes, some of which were previously unknown or uncharacterized. Moreover, there is a correlation between low effect, associated copy number variants and other relevant genomic features such as the expression patterns of long non-coding RNA or the presence of long-range chromatin contacts. Our characterization of copy number variation in dogs has generated a wealth of hypotheses for further functional testing and validation

Copy number variation underlies complex phenotypes in domestic dog breeds and other canids

Extreme phenotypic diversity, a history of artificial selection, and socioeconomic value make domestic dog breeds a compelling subject for genomic research. Copy number variation (CNV) is known to account for a significant part of inter-individual genomic diversity in other systems. However, a comprehensive genome-wide study of structural variation as it relates to breed-specific phenotypes is lacking. We have generated whole genome CNV maps for more than 300 canids. Our data set extends the canine structural variation landscape to more than 100 dog breeds, including novel variants that cannot be assessed using microarray technologies. We have taken advantage of this data set to perform the first CNV-based genome-wide association study (GWAS) in canids. We identify 96 loci that display copy number differences across breeds, which are statistically associated with a previously compiled set of breed-specific morphometrics and disease susceptibilities. Among these, we highlight the discovery of a long-range interaction involving a CNV near MED13L and TBX3, which could influence breed standard height. Integration of the CNVs with chromatin interactions, long noncoding RNA expression, and single nucleotide variation highlights a subset of specific loci and genes with potential functional relevance and the prospect to explain trait variation between dog breeds.J.P. and E.A.O. were funded by the Intramural Program of the National Human Genome Research Institute of the National Institutes of Health. T.M.-B. was funded by European Research Council ERC-CON-2019-864203, BFU2017-86471-P (MINECO/FEDER, UE), “Unidad de Excelencia María de Maeztu,” funded by the Agencia Estatal de Investigación (CEX2018-000792-M), Howard Hughes International Early Career, Obra Social “La Caixa” and Secretaria d'Universitats i Recerca and CERCA Programme del Departament d'Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880)

The contribution of historical processes to contemporary extinction risk in placental mammals

Altres ajuts: CERCA Programme/Generalitat de Catalunya ; Secretaria d'Universitats i RecercaSpecies persistence can be influenced by the amount, type, and distribution of diversity across the genome, suggesting a potential relationship between historical demography and resilience. Here, we surveyed genetic variation across single genomes of 240 mammals comprising the Zoonomia alignment to evaluate how historical effective population size (N ) impacts heterozygosity and deleterious genetic load and how these factors may contribute to extinction risk. We find that species with smaller historical N carry a proportionally larger burden of deleterious alleles due to long-term accumulation and fixation of genetic load, and have higher risk of extinction. This suggests that historical demography can inform contemporary resilience. Models that included genomic data were predictive of species' conservation status, suggesting that, in the absence of adequate census or ecological data, genomic information may provide an initial risk assessment. Genomic data from 240 species show that information encoded within a single genome can provide a conservation risk assessment

Interspecific gene flow shaped the evolution of the genus canis

The evolutionary history of the wolf-like canids of the genus Canis has been heavily debated, especially regarding the number of distinct species and their relationships at the population and species level [1-6]. We assembled a dataset of 48 resequenced genomes spanning all members of the genus Canis except the black-backed and side-striped jackals, encompassing the global diversity of seven extant canid lineages. This includes eight new genomes, including the first resequenced Ethiopian wolf (Canis simensis), one dhole (Cuon alpinus), two East African hunting dogs (Lycaon pictus), two Eurasian golden jackals (Canis aureus), and two Middle Eastern gray wolves (Canis lupus). The relationships between the Ethiopian wolf, African golden wolf, and golden jackal were resolved. We highlight the role of interspecific hybridization in the evolution of this charismatic group. Specifically, we find gene flow between the ancestors of the dhole and African hunting dog and admixture between the gray wolf, coyote (Canis latrans), golden jackal, and African golden wolf. Additionally, we report gene flow from gray and Ethiopian wolves to the African golden wolf, suggesting that the African golden wolf originated through hybridization between these species. Finally, we hypothesize that coyotes and gray wolves carry genetic material derived from a "ghost" basal canid lineage.We also acknowledge the following for funding our research: the Qimmeq project funded by The Velux Foundations and Aage og Johanne Louis-Hansens Fond; Carlsbergfondet grant CF14–0995 and Marie Skłodowska-Curie Actions grant 655732-WhereWolf to S.G.; grant 676154-ArchSci2020 to J.N.; NSFC grant 91531303 to G.-D.W.; Danish National Research Foundation grant DNRF94, Lundbeckfonden grant R52–5062, and ERC Consolidator grant 681396-Extinction Genomics to M.T.P.G.; and the Universities of Oslo and Copenhagen for a PhD stipend awarded to M.-H.S.S. T.M.-B. is supported by MINECO/FEDER, UE, grant BFU2017-86471-P, NIMH grant U01 MH106874, a Howard Hughes Medical Institute International Early Career grant, Obra Social “La Caixa,” and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya

Insights from the rescue and breeding management of Cuvier’s gazelle (Gazella cuvieri) through whole-genome sequencing

Data de publicació electrònica: 17-12-2021Captive breeding programmes represent the most intensive type of ex situ population management for threatened species. One example is the Cuvier’s gazelle programme that started in 1975 with only four founding individuals, and after more than four decades of management in captivity, a reintroduction effort was undertaken in Tunisia in 2016, to establish a population in an area historically included within its range. Here, we aim to determine the genetic consequences of this reintroduction event by assessing the genetic diversity of the founder stock as well as of their descendants. We present the first whole-genome sequencing dataset of 30 Cuvier’s gazelles including captive-bred animals, animals born in Tunisia after a reintroduction and individuals from a genetically unrelated Moroccan population. Our analyses revealed no difference between the founder and the offspring cohorts in genome-wide heterozygosity and inbreeding levels, and in the amount and length of runs of homozygosity. The captive but unmanaged Moroccan gazelles have the lowest genetic diversity of all genomes analysed. Our findings demonstrate that the Cuvier’s gazelle captive breeding programme can serve as source populations for future reintroductions of this species. We believe that this study can serve as a starting point for global applications of genomics to the conservation plan of this species.T.M.-B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 864203), BFU2017-86471-P (MINECO/FEDER, UE), ‘Unidad de Excelencia María de Maeztu’, funded by the AEI (CEX2018-000792-M), Howard Hughes International Early Career and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). E.M. received financial support from the project PGC2018-097426-B-C22 (Spanish Ministry of Universities. Spanish State Research Agency. FEDER Program, European Union). E.L. is supported by CGL2017-82654-P (MINECO/FEDER, UE)

A 3-way hybrid approach to generate a new high-quality chimpanzee reference genome (Pan_tro_3.0)

The chimpanzee is arguably the most important species for the study of human origins. A key resource for these studies is a high-quality reference genome assembly; however, as with most mammalian genomes, the current iteration of the chimpanzee reference genome assembly is highly fragmented. In the current iteration of the chimpanzee reference genome assembly (Pan_tro_2.1.4), the sequence is scattered across more then 183 000 contigs, incorporating more than 159 000 gaps, with a genome-wide contig N50 of 51 Kbp. In this work, we produce an extensive and diverse array of sequencing datasets to rapidly assemble a new chimpanzee reference that surpasses previous iterations in bases represented and organized in large scaffolds. To this end, we show substantial improvements over the current release of the chimpanzee genome (Pan_tro_2.1.4) by several metrics, such as increased contiguity by >750% and 300% on contigs and scaffolds, respectively, and closure of 77% of gaps in the Pan_tro_2.1.4 assembly gaps spanning >850 Kbp of the novel coding sequence based on RNASeq data. We further report more than 2700 genes that had putatively erroneous frame-shift predictions to human in Pan_tro_2.1.4 and show a substantial increase in the annotation of repetitive elements. We apply a simple 3-way hybrid approach to considerably improve the reference genome assembly for the chimpanzee, providing a valuable resource for the study of human origins. Furthermore, we produce extensive sequencing datasets that are all derived from the same cell line, generating a broad non-human benchmark dataset.J.G.G. is funded by the RED-BIO project of the Spanish National Bioinformatics Institute (INB) under grant number PT13/0001/0044. The INB is funded by the Spanish National Health Institute Carlos III (ISCIII) and the Spanish Ministry of Economy and Competitiveness (MINECO). L.F.K.K. is supported by an FPI fellowship associated with BFU2014-55090-P (FEDER); L.F. is supported by the Swedish Foundation for Strategic Research F06-0045 and the Swedish Research Council; E.E.E. is an investigator of the Howard Hughes Medical Institute. A.J.S. is supported by US National Institutes of Health (NIH) grants DA033660, HG006696, HD073731, and MH097018, and research grant 6-FY13-92 from the March of Dimes. This work was supported, in part, by grants from the NIH (grants R01HG002385 and U24HG009081 to E.E.E., HG007990 and HG007234 to B.P.). T.M.B. is supported by MINECO BFU2014-55090-P (FEDER), BFU2015-7116-ERC, and BFU2015-6215-ERC, Fundacio Zoo Barcelona and Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya