Eva Julià

Centre for Genomic Regulation

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i-10 index

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Co-Authors

Xavier Montalbán

Vall d'Hebron Institut de Recerca

Manuel Comabella

Universitat Autònoma de Barcelona

ÒF

Òscar Fornas

Pompeu Fabra University

Tomàs Marquès‐Bonet

Institut de Biologia Evolutiva

Esther Lizano

Institut de Biologia Evolutiva

David Juan

Pompeu Fabra University

Lukas F. K. Kuderna

Illumina (United States)

MÁ

Marina Álvarez-Estapé

Institut de Biologia Evolutiva

Jordi Río

Universitat Autònoma de Barcelona

Roland Martinꝉ

Karolinska Institutet

Cooperative Institutions

Pompeu Fabra University

Universitat Autònoma de Barcelona

Inserm

Centre for Genomic Regulation

Centre National de la Recherche Scientifique

Institut de Biologia Evolutiva

Vall d'Hebron Hospital Universitari

Universitat de Barcelona

Vall d'Hebron Institut de Recerca

Université Claude Bernard Lyon 1

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Papers

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Three-Dimensional Genomic Structure and Cohesin Occupancy Correlate with Transcriptional Activity during Spermatogenesis

Cell Reports (2019)

Covadonga Vara Andreu Paytuví-Gallart Yasmina Cuartero François Le Dily F. García

Mammalian gametogenesis involves dramatic and tightly regulated chromatin remodeling, whose regulatory pathways remain largely unexplored. Here, we generate a comprehensive high-resolution structural and functional atlas of mouse spermatogenesis by combining in situ chromosome conformation capture sequencing (Hi-C), RNA sequencing (RNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) of CCCTC-binding factor (CTCF) and meiotic cohesins, coupled with confocal and super-resolution microscopy. Spermatogonia presents well-defined compartment patterns and topological domains. However, chromosome occupancy and compartmentalization are highly re-arranged during prophase I, with cohesins bound to active promoters in DNA loops out of the chromosomal axes. Compartment patterns re-emerge in round spermatids, where cohesin occupancy correlates with transcriptional activity of key developmental genes. The compact sperm genome contains compartments with actively transcribed genes but no fine-scale topological domains, concomitant with the presence of protamines. Overall, we demonstrate how genome-wide cohesin occupancy and transcriptional activity is associated with three-dimensional (3D) remodeling during spermatogenesis, ultimately reprogramming the genome for the next generation.

Chromosome conformation capture

CTCF

Chromatin immunoprecipitation

SWI/SNF

10.1016/j.celrep.2019.06.037

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Citations (133)

Correction: Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis

The Journal of Immunology (2011)

Montse Camiña-Tato Carlos Morcillo-Suárez Marta F. Bustamante Israel Parra Ortega Arcadi Navarro

Controls MS Controls MS Controls rs885822 Allele A 480 (57.1) 643 (62.8) 1.3 (1.1-1.5)0.013 0.079 299 (57.5) 333 (60.3) 1.1 (0.9-1.4) 0.352 0.667 181 (56.6) 310 (65.7) 1.5 (1.1-2.0)0.011 0.071 G 360 (42.9) 381 (37.2) 221 (42.5) 219 (39.7) 139 (43.4) 162 (34.3)Genotype AA 143 (34.1) 204 (39.6) 0.8 (0.6-.02) 0.766 0.227 91 (35.0) 99 (35.9)0.9 (0.7-1.4) 0.857 0.999 52 (32.5) 105 (44.5) 0.6 (0.4-0.9) 0.021 0.107 AG 194 (46.2) 235 (45.9) 1.0 (0.8-1.3) 0.947 1.000 117 (45.0) 135 (48.9) 0.9 (0.6-1.2) 0.387 0.695 77 (48.1) 100 (42.4) 1.3 (0.8-1.9) 0.303 0.613 GG 83 (19.7) 73 (14.3) 1.5 (1.1-2.1)0.028 0.121 52 (20.0) 42 (15.2) 1.4 (0.9-2.2) 0.173 0.406 31 (19.4) 31 (13.1)1.6 (0.9-2.7) 0.121 0.317 rs10999426 Allele A 308 (36.7) 304 (29.7) 1.4 (1.1-1.7)0.002 0.020 183 (35.2) 184 (33.3) 1.1 (0.8-1.4) 0.562 0.821 125 (39.1) 120 (25.4) 1.9 (1.4-2.6)0.0001 0.003 G 532 (63.3) 720 (70.3) 337 (64.8) 368 (66.7) 195 (60.9) 352 (74.6)Genotype AA 55 (13.1) 47 (9.2) 1.5 (1.0-2.3)0.059 0.199 30 (11.5) 28 (10.1)1.2 (0.7-2.0) 0.677 0.880 25 (15.6)19 (8.1) 2.1 (1.1-4.0)0.022 0.107 AG 198 (47.1) 210 (41.0) 1.3 (1.0-1.7)0.063 0.211 123 (47.3) 128 (46.4) 1.0 (0.7-1.5) 0.863 0.998 75 (46.9)82 (34.7) 1.7 (1.1-2.5)0.016 0.091 GG 167 (39.8) 255 (49.8) 0.7 (0.5-0.9) 0.002 0.025 107 (41.2) 120 (43.5) 0.9 (0.7-1.3) 0.601 0.832 60 (37.5) 135 (57.2) 0.5 (0.3-0.7) 0.0001 0.003 rs3758562 Allele A 533 (63.5) 719 (70.2) 1.4 (1.1-1.7)0.002 0.025 334 (64.2) 369 (66.8) 1.1 (0.9-1.4) 0.369 0.681 199 (62.2) 350 (74.2) 1.7 (1.3-2.4)0.0004 0.007 G 307 (36.5) 305 (29.8) 186 (35.8) 183 (33.2) 121 (37.8) 122 (25.8)Genotype AA 169 (40.2) 256 (50.0) 0.7 (0.5-0.9) 0.003 0.028 105 (40.4) 122 (44.2) 0.9 (0.6-1.2) 0.383 0.697 64 (40.0) 134 (56.7) 0.5 (0.3-0.8) 0.002 0.020 AG 195 (46.4) 207 (40.4) 1.3 (1.0-1.7)0.727 0.226 124 (47.7) 125 (45.3) 1.1 (0.8-1.6) 0.604 0.832 71 (44.4) 82 (34.8) 1.5 (1.0-2.3)0.059 0.198 GG 56 (13.3) 49 (9.6) 1.5 (1.0-2.2) 0.077 0.226 31 (11.9) 29 (10.5)1.2 (0.7-2.0) 0.681 0.882 25 (15.6)20 (8.5) 2.0 (1.1-3.7)0.035 0.138 Boldface p values denote statistically significant associations.a The p values were obtained following multiple testing correction by Benjamini-Hochberg method.175 (41.9) 219 (39.7) 103 (44.8) 162 (34.3)Genotype AA 108 (33.3) 204 (39.8) 0.8 (0.6-1.0) 0.07 0.216 71 (34.0) 99 (35.9)0.9 (0.6-1.3) 0.701 0.890 37 (32.2) 105 (44.5) 0.6 (0.4-0.9) 0.028 0.123 AG 154 (47.5) 235 (45.9) 1.1 (0.8-1.4) 0.670 0.875 101 (48.3) 135 (48.9) 1.0 (0.7-1.4) 0.927 1.000 53 (46.1) 100 (42.4) 1.2 (0.7-1.8) 0.567 0.823 GG 62 (19.1) 73 (14.3) 1.4 (1.0-2.1)0.067 0.216 37 (17.7)42 (15.2) 1.2 (0.7-1.9) 0.535 0.802 25 (21.7) 31 (13.1)1.8 (1.0-3.3)0.044 0.158 rs10999426 Allele A 236 (36.4) 304 (29.7) 1.4 (1.1-1.7)0.004 0.036 145 (34.7) 184 (33.3) 1.1 (0.8-1.4) 0.681 0.878 91 (39.6) 120 (25.4) 1.9 (1.4-2.7)0.0002 0.005 G 412 (63.6) 720 (70.3) 273 (65.3) 368 (66.7) 139 (60.4) 352 (74.6)Genotype AA 41 (12.7) 47 (9.2) 1.4 (0.9-2.2) 0.132 0.341 22 (10.5)28 (10.1)1.0 (0.6-1.9) 0.882 0.995 19 (16.5) 19 (8.1) 2.3 (1.2-4.5)0.027 0.120 AG 154 (47.5) 210 (41.0) 1.3 (1.0-1.7)0.073 0.225 101 (48.3) 128 (46.4) 1.1 (0.8-1.6) 0.714 0.902 53 (37.4) 82 (34.7) 1.6 (1.0-2.5)0.047 0.167 GG 129 (39.8) 255 (49.8) 0.7 (0.5-0.9) 0.005 0.041 86 (41.1) 120 (43.5) 1.1 (0.8-1.6) 0.643 0.857 43 (37.4) 135 (57.2) 0.5 (0.3-0.7) 0.0006 0.01 rs3758562 Allele A 411 (63.4) 719 (70.2) 1.4 (1.1-1.7)0.005 0.036 270 (64.6) 369 (66.8) 1.11 (0.9-1.4) 0.491 0.794 141 (61.3) 350 (74.2) 1.8 (1.3-2.5)0.0006 0.01 G 237 (36.6) 305 (29.8) 148 (35.4) 183 (33.2) 89 (38.7) 122 (25.8)Genotype AA 128 (39.5) 256 (0.5) 0.7 (0.5-0.9) 0.004 0.031 83 (39.7) 122 (44.2) 0.8 (0.6-1.2) 0.354 0.666 45 (39.1) 134 (56.8) 0.5 (0.3-0.8) 0.002 0.025 AG 155 (47.8) 207 (40.4) 1.4 (1.0-1.8)0.038 0.146 104 (49.8) 125 (45.3) 1.2 (0.8-1.7) 0.359 0.666 51 (44.3) 82 (34.7) 1.5 (1.0-2.4)0.101 0.277 GG 41 (12.7) 49 (9.6) 1.4 (0.9-2.1) 0.170 0.408 22 (10.5)29 (10.5)1.0 (0.6-1.8) 1.000 1.000 a p value obtained following multiple testing correction by Benjamini-Hochberg method.RR/SP, patients with relapse-onset MS.

10.4049/jimmunol.1190036

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Y chromosome sequence and epigenomic reconstruction across human populations

Communications Biology (2023)

Paula Esteller-Cucala Marc Palmada‐Flores Lukas F. K. Kuderna Claudia Fontsere Aitor Serres‐Armero

Abstract Recent advances in long-read sequencing technologies have allowed the generation and curation of more complete genome assemblies, enabling the analysis of traditionally neglected chromosomes, such as the human Y chromosome (chrY). Native DNA was sequenced on a MinION Oxford Nanopore Technologies sequencing device to generate genome assemblies for seven major chrY human haplogroups. We analyzed and compared the chrY enrichment of sequencing data obtained using two different selective sequencing approaches: adaptive sampling and flow cytometry chromosome sorting. We show that adaptive sampling can produce data to create assemblies comparable to chromosome sorting while being a less expensive and time-consuming technique. We also assessed haplogroup-specific structural variants, which would be otherwise difficult to study using short-read sequencing data only. Finally, we took advantage of this technology to detect and profile epigenetic modifications among the considered haplogroups. Altogether, we provide a framework to study complex genomic regions with a simple, fast, and affordable methodology that could be applied to larger population genomics datasets.

Haplogroup

Minion

Epigenomics

International HapMap Project

10.1038/s42003-023-05004-9

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Citations (2)

Additional data for Kuderna, Lizano, et al. (2018)

Figshare (2018)

Lukas F. K. Kuderna Esther Lizano Eva Julià Jèssica Gómez‐Garrido Aitor Serres‐Armero

Whole genome assembly of NA24385; Repeatmasker annotations for GRCh38 chrY & HG02982 chrY;Methylation calls from Nanopore & Illumina WGBS

10.6084/m9.figshare.7358480

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Citations (0)

Genetic association of CASP8 polymorphisms with primary progressive multiple sclerosis

Journal of Neuroimmunology (2010)

M. Camiña-Tato M. Fernández Carlos Morcillo-Suárez Arcadi Navarro Eva Julià

SNP

Candidate gene

Genome-wide Association Study

Genetic Association

10.1016/j.jneuroim.2010.03.003

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Citations (12)

Transcriptome innovations in primates revealed by single-molecule long-read sequencing

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Luis Ferrández-Peral Xiaoyu Zhan Marina Álvarez-Estapé Cristina Chiva Paula Esteller-Cucala

Abstract Transcriptomic diversity greatly contributes to the fundamentals of disease, lineage-specific biology, and environmental adaptation. However, much of the actual isoform repertoire contributing to shaping primate evolution remains unknown. Here, we combined deep long- and short-read sequencing complemented with mass spectrometry proteomics in a panel of lymphoblastoid cell lines (LCLs) from human, three other great apes, and rhesus macaque, producing the largest full-length isoform catalog in primates to date. Our transcriptomes reveal thousands of novel transcripts, some of them under active translation, expanding and completing the repertoire of primate gene models. Our comparative analyses unveil hundreds of transcriptomic innovations and isoform usage changes related to immune function and immunological disorders. The confluence of these innovations with signals of positive selection and their limited impact in the proteome points to changes in alternative splicing in genes involved in immune response as an important target of recent regulatory divergence in primates.

Proteome

Rhesus macaque

10.1101/2021.11.10.468034

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Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis

Brain (2010)

Manuel Comabella Marta Fernández Roland Martinꝉ Stephanie Rivera-Vallvé Eva Borrás

In most patients with multiple sclerosis, the disease initiates with a first attack or clinically isolated syndrome. At this phase, magnetic resonance imaging is an important predictor of conversion to multiple sclerosis. With the exception of oligoclonal bands, the role of other biomarkers in patients with clinically isolated syndrome is controversial. In the present study, we aimed to identify proteins associated with conversion to multiple sclerosis in patients with clinically isolated syndrome. We applied a mass spectrometry-based proteomic approach (isobaric labelling) to previously collected pooled cerebrospinal fluid samples from patients with clinically isolated syndrome, who subsequently converted to clinically definite multiple sclerosis (n = 30) and patients who remained as having clinically isolated syndrome (n = 30). Next, three of the most represented differentially expressed proteins, i.e. ceruloplasmin, vitamin D-binding protein and chitinase 3-like 1 were selected for validation in individual cerebrospinal fluid samples by enzyme-linked immunosorbent assay. Only chitinase 3-like 1 was validated and cerebrospinal fluid levels were increased in patients who converted to clinically definite multiple sclerosis compared with patients who continued as clinically isolated syndrome (P = 0.00002) and controls (P = 0.012). High cerebrospinal fluid levels of chitinase 3-like 1 significantly correlated with the number of gadolinium enhancing lesions and the number of T2 lesions observed in brain magnetic resonance imaging scans performed at baseline, and were associated with disability progression during follow-up and shorter time to clinically definite multiple sclerosis (log-rank P-value = 0.003). Cerebrospinal fluid chitinase 3-like 1 levels were also measured in a second validation clinically isolated syndrome cohort and found to be increased in patients who converted to multiple sclerosis compared with patients who remained as having clinically isolated syndrome (P = 0.018). Our results indicate that patients who will convert to clinically definite multiple sclerosis could be distinguished from those patients who will remain as clinically isolated syndrome by proteomic analysis of cerebrospinal fluid samples. Although protein levels are also increased in other disorders characterized by chronic inflammation, chitinase 3-like 1 may serve as a prognostic biomarker for conversion to multiple sclerosis and development of disability which may help to improve the understanding of the aetiopathogenesis in the early stages of multiple sclerosis.

Clinically isolated syndrome

10.1093/brain/awq035

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Citations (269)

Transcriptome innovations in primates revealed by single-molecule long-read sequencing

Genome Research (2022)

Luis Ferrández-Peral Xiaoyu Zhan Marina Álvarez-Estapé Cristina Chiva Paula Esteller-Cucala

Transcriptomic diversity greatly contributes to the fundamentals of disease, lineage-specific biology, and environmental adaptation. However, much of the actual isoform repertoire contributing to shaping primate evolution remains unknown. Here, we combined deep long- and short-read sequencing complemented with mass spectrometry proteomics in a panel of lymphoblastoid cell lines (LCLs) from human, three other great apes, and rhesus macaque, producing the largest full-length isoform catalog in primates to date. Around half of the captured isoforms are not annotated in their reference genomes, significantly expanding the gene models in primates. Furthermore, our comparative analyses unveil hundreds of transcriptomic innovations and isoform usage changes related to immune function and immunological disorders. The confluence of these evolutionary innovations with signals of positive selection and their limited impact in the proteome points to changes in alternative splicing in genes involved in immune response as an important target of recent regulatory divergence in primates.

Proteome

Rhesus macaque

Lineage (genetic)

10.1101/gr.276395.121

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Citations (11)

A chromosome-assigned Mongolian gerbil genome with sequenced centromeres provides evidence of a new chromosome

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Thomas D. Brekke Alexander S. T. Papadopulos Eva Julià Òscar Fornas Beiyuan Fu

Abstract Chromosome-scale genome assemblies based on ultra-long read sequencing technologies are able to illuminate previously intractable aspects of genome biology such as fine-scale centromere structure and large-scale variation in genome features such as heterochromatin, GC content, recombination rate, and gene content. We present here a new chromosome-scale genome of the Mongolian gerbil ( Meriones unguiculatus ) which includes the complete sequence of all centromeres. Gerbil centromeres are composed of four different repeats of length 6pb, 37bp, 127bp, or 1747bp which occur in simple alternating arrays and span 1-6Mb. Gerbil genomes have both an extensive set of GC-rich genes and chromosomes strikingly enriched for constitutive heterochromatin. We sought to determine if there was a link between these two phenomena and found that the two heterochromatic chromosomes of the Mongolian gerbil have distinct underpinnings: Chromosome 5 has a large block of intra-arm heterochromatin as the result of a massive expansion of centromeric repeats, while chromosome 13 is comprised of extremely large (>150kb) repeated sequences. In addition to characterizing centromeres, our results demonstrate the importance of including karyotypic features such as chromosome number and the locations of centromeres in the interpretation of genome sequence data, and highlight novel patterns involved in the evolution of chromosomes.

Constitutive heterochromatin

Repeated sequence

10.1101/2022.09.21.508825

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Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis

The Journal of Immunology (2010)

Montse Camiña-Tato Carlos Morcillo-Suárez Marta F. Bustamante Israel Ortega Arcadi Navarro

The granule-dependent exocytosis pathway is an important mechanism to induce apoptosis by CD8(+) T cells and NK cells and involves lytic molecules such as perforin. In the current study, we investigated the perforin 1 gene (PRF1) as a candidate for multiple sclerosis (MS) susceptibility in the Spanish population. We genotyped three PRF1 single nucleotide polymorphisms (rs885822, rs10999426, and rs3758562) in 420 patients with MS and 512 controls. Associations of PRF1 polymorphisms with the disease were restricted to male patients with MS, and the finding was consistently observed at the allele, genotype, and haplotype levels. Gender-associated differences were validated in an additional replication cohort comprised of 292 MS cases and 300 controls. In addition, we identified minor risk haplotypes strongly associated with male patients having primary progressive MS (PPMS). Further characterization of male patients with PPMS carrying the risk haplotypes by means of gene expression microarrays revealed overrepresentation of the cell killing gene ontology category among downregulated genes in these patients compared with male patients with PPMS carrying protective haplotypes. Moreover, PRF1 mRNA expression levels were significantly lower in patients with risk haplotypes, and changes in perforin protein expression by CD8(+) T cells mirrored those observed in gene expression. These findings suggest a gender dimorphism in the PRF1 association with MS and point to the presence of a generalized defect in the expression of genes that code for proteins involved in cell killing in a subgroup of male patients with PPMS.

10.4049/jimmunol.1000102

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Citations (28)