OC 08.3 - Insights of retrotransposon insertions in antithrombin deficiency lead to a complete study of the landscape of mobile elements throughout the whole genome with nanopore sequencing

Saturday, June 22, 2024

13:30 – 13:45 ICT

Room: 211 A-D

Presenting Author(s)

Belén de la Morena-Barrio, PhD

Post-doc
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Co-Author(s)

JC

Javier Cuenca-Guardiola

PhD student
Departamento de Informática y Sistemas, Universidad de Murcia, CEIR Campus Mare Nostrum, IMIB-Arrixaca, Facultad de Informática, Campus de Espinardo
Murcia, Murcia, Spain
Pedro Garrido-Rodríguez

PhD student
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
EN

Esther Navarro

Post-doc
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
ML

María Llamas-López, PhD-Student

Bioinformatician
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
JP

José Padilla

Tech
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
María Eugenia de la Morena-Barrio, PhD

PhD
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
AM

Antonia Miñano

Tech
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
EW

Ewa Wypasek

MD
The John Paul II Hospital
Krakov, Malopolskie, Poland
AR

Agustín Rodríguez-Alen

Hematologist
Servicio de Hematología, Hospital Universitario de Toledo, Toledo, Spain
Toledo, Castilla-La Mancha, Spain
ML

María F. López-Fernández

PhD MD
Servicio de Hematología, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
La Coruña, Galicia, Spain
JF

Jesualdo T. Fernández-Breis

Prof
Departamento de Informática y Sistemas, Universidad de Murcia, CEIR Campus Mare Nostrum, IMIB-Arrixaca, Facultad de Informática, Campus de Espinardo
Murcia, Murcia, Spain
VV

Vicente Vicente

Senior Researcher
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
ML

María Luisa Lozano

Hematologist
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
Javier Corral

Professor
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Background: The molecular base of antithrombin deficiency (ATD), the strongest thrombophilia caused by variants in SERPINC1, is not identified in 15% of cases. Complex genetic mechanisms such as retrotransposons insertions can be skipped by short-read sequencing methods.

Aims: To detect retrotransposon insertions in ATD, exploring the landscape of mobile elements in the human genome by long-read sequencing.

Methods: Whole genome sequencing was done using PromethION. We developed a specific pipeline for the identification, characterization and annotation of retrotransposons throughout the genome.

Results: Whole genome analysis of retrotransposons in 25 unrelated ATD cases identified 7,344 insertions and 3,056 deletions of retrotransposons, 2,926 not described in available databases (Figure-1). A median of 230 retrotransposons/patient directly affected genes, 12 of them in coding regions. Representative new insertions were validated by other methods.
4/15 ATD cases without molecular diagnosis had one retrotransposon inserted in SERPINC1 (Figure-2). Family studies confirmed segregation of these insertions with ATD. P1-P3 shared a new SVA (close to SVA-E) inserted in intron 6 with founder effect. P4 had a human-specific SVA-F1 inserted in intron 3, which has its own mechanism of insertion involving MAST2. P4 had 5 additional specific new insertions of this SVA-F1 in the genome.

Conclusion(s): The high number of retrotransposons (45% of the human genome), their high homology and mobility makes very difficult to detect them by short-read sequencing. We demonstrate the utility of long-reads sequencing for the detection of retrotransposons through the genome, showing that these elements are underestimated. Moreover, our study support that retrotransposon insertion has a high impact in genetic variability and disease. Indeed 1% of cases with ATD (27% of cases with unknown molecular base) are explained by retrotransposon insertions in SERPINC1. Our data encourage the development of a complete retrotransposon map in the genome.

Funding: PI21/00174&PMP21/00052 (ISCIII&NextGeneration UE); 21886/PI/22 (Fundación Séneca)