Repair capacity and genome diversity in mammals

Informations projet

ReCAP

N° de convention de subvention: 724718

DOI

10.3030/724718

Projet clôturé

Date de signature de la CE 8 Juin 2017

Date de début 1 Juillet 2017

Date de fin 30 Juin 2023

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 997 592,92

Contribution de l’UE

€ 1 997 592,92

Coordonné par

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 4 - ReCAP (Repair capacity and genome diversity in mammals)

Période du rapport: 2022-01-01 au 2023-06-30

Résumé du contexte et des objectifs généraux du projet

We have long appreciated that children born carry unique genomes that are a mixture of their parents DNA. The diversity in our genomes is the result of the introduction of damage to DNA in the germ cells (sperm and eggs) and this creates a paradox. DNA damage is typically associated with genome instability: rearranged and mutated genomes associated with ageing, cancer and neurodegenerative disorders. However, in germ cells such as eggs and sperm the programmed introduction of DNA damage and its repair is essential to generate diversity in children.

In this programme (ReCAP), we have begun to study how the generation of diversity is balanced with genome stability, directly in human eggs and preimplantation embryos. This is because 20% of human eggs carry an extra or missing chromosome are thus highly unstable. Upon fertilization by sperm, this results in an unbalanced genome that is not able to sustain embryo and fetal development in the vast majority cases. This results in both preclinical and clinical pregnancy loss. In the rare live births, extra chromosomes can, but does not have to, result in congenital disorders.

Our overall objectives are to understand how genome diversification and DNA damage impact on reproductive health in women and the genetic health in children. We thereby aim to provide the underlying science on which health policies can be based and that may provide improved insight and social impact into pregnancy loss and infertility.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

ReCAP has enabled and facilitated research and capacity building in human fertility and genetics. The action has done so by creating synergy between private-public partnerships as well as basic, computational and clinical fields. Virtually all of the research outputs (publications) are private-public partnerships, which has enabled advanced and often proprietary knowledge to be used in public settings to allow research that is focussed on providing a step change in our understanding of human genetic inheritance and reproductive health. Specifically, our study on human aneuploidies (chromosomal errors) in human eggs has been groundbreaking in challenging the notion that eggs only get worse with female age: ReCAP shows that aneuploidies follow a U curve and that 50% of eggs contain a chromosome error in both 15 year olds as well as 38 years old. This has led to several retrospective and prospective studies on egg donation, where the lower age of female donors (typically 18 years) may have to be reconsidered and raised. The methodology and informatics developed in ReCAP have been instrumental in assessment of new genomic analyses of human embryos and in designing and executing a non-selection clinical trial that we particpated in. Using human genetics and mouse models, the action has also resulted in deciphering how DNA repair is also important for oocyte generation and atresia (death) to determine ovarian reserve and reproductive longevity (menopause) in women. These data have been used to initiate clinical studies and trials to determine whether polygenic assessments may improve genetic diagnosis of women with early onset menopause.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

ReCAP has progressed the field beyond the state of the art and catalyzed interactions across industry, academic and clinical practise. The research outputs together with establishing formalized and effective collaborations as new data or approaches emerged have created synergy and private-public partnerships that will outlast and provide a legacy for ReCAP. ReCAP has catalyzed private-public partnership activities and next-destinations for scientists directly employed in the action and those benefitting from it. This ensures that findings in research contexts are implemented in genomics providers privately and those in public settings as well. DNA damage can lead to specific outcomes, such as oocyte death and menopause or rearranged chromosomes and aneuploidies that result in infertility and pregnancy loss. ReCAP has provided synergy between the human genetics, fertility, and reproductive longevity (ageing) fieldss thereby providing opportunities for training and capacity building of using the molecular sciences to inform diagnostics and interventions for human fertility and pediatric disorders.

Repair capacity and reproductive senescence