Maintaining Genetic and Chromosomal Stability in the Mammalian Germline
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
Abstract
The egg and sperm cells that pass genetic information from parents to their children go through a specialised form of cell division called meiosis. Meiosis halves the number of chromosomes in the developing eggs and sperm, but mistakes during meiosis can result in embryos inheriting the wrong number of chromosomes. This can cause genetic disease and miscarriage, and is the basis of some common inherited conditions in humans such as Down Syndrome. Although we know some of the risk factors for these meiotic errors in humans, we don’t fully understand how risk factors like maternal age affects meiotic chromosomes, or how risk factors like the number of chromosomal exchanges in meiosis are normally regulated. We have previously identified new pathways operating in mice that prevent some of these meiotic mistakes from occurring in the developing eggs and sperm. The aim of this programme is to better understand how these pathways affect chromosome behaviour in meiosis in mice. We will use a combination of cultured cell lines and genetically modified mice to investigate which chromosome-associated molecules are regulated by these pathways, and to investigate if we can manipulate these pathways to reduce or prevent chromosomal abnormalities from arising in developing eggs and sperm. We hope that by understanding and manipulating these pathways in mice, we will learn more about how we might, in the future, be able to prevent chromosomal abnormalities from arising in humans.
Technical Summary
Genetic mutations and chromosomal aneuploidies that arise during germ cell development and meiosis can cause embryonic lethality, miscarriage and genetic disease in the next generation. Aneuploidies such as trisomy 21, which causes Down syndrome, are relatively common in human conceptions, and typically originate during the meiotic divisions of female oocytes. A number of risk factors, including meiotic recombination frequency, distribution of meiotic recombination sites, and maternal age have been identified for oocyte aneuploidy. Furthermore, data from mouse models suggests that age-dependent loss of chromosome cohesion is associated with age-dependent increases in meiotic segregation errors in post-natal oocytes. However, the fundamental mechanisms underlying these processes in mammalian meiosis are not completely understood. This research programme will investigate mechanisms regulating meiotic recombination in mammals, and mechanisms impacting on the maintenance of chromosome cohesion in post-natal mammalian oocytes.
We have previously identified components of the ubiquitin-proteasome system as regulators of meiotic recombination frequency in mice. Genetically modified mice carrying mutations in these components of the ubiquitin-proteasome system have reduced meiotic recombination frequencies and defects in pairing homologous chromosomes during meiosis that can cause chromosome segregation errors. However, we do not know how the ubiquitin-proteasome system regulates the early stages of recombination that are defective in these mutants. We will therefore use genetically modified mouse models to investigate how these enzymes influence the machinery that initiates meiotic recombination, and whether recombination in particular regions of the genome are more sensitive to these ubiquitin-proteasome system components. We will also investigate how meiotic chromosomes are organised in mouse spermatocytes and oocytes, and study how meiotic chromosome organisation impacts on the frequency and distribution of meiotic recombination in mice.
The second part of this research programme will investigate a novel pathway that we have identified operating in mouse oocytes which helps prevent loss of chromosome cohesion, meiotic chromosome mis-segregation and aneuploidy in post-natal mouse oocytes. This pathway also involves components of the ubiquitin-proteasome system, and regulates the abundance of cohesin proteins associated with meiotic chromosomes. As this pathway also appears to operate in embryonic stem cells, which are derived from early mouse embryos, we will use embryonic stem cell models to investigate how chromosome cohesion is regulated by the ubiquitin-proteasome system. We will use the mechanistic insights that we gain from embryonic stem cells to generate genetically modified mouse models to test whether manipulation of this pathway can slow the age-dependent loss of chromosome cohesion that occurs in post-natal mouse oocytes.
We have previously identified components of the ubiquitin-proteasome system as regulators of meiotic recombination frequency in mice. Genetically modified mice carrying mutations in these components of the ubiquitin-proteasome system have reduced meiotic recombination frequencies and defects in pairing homologous chromosomes during meiosis that can cause chromosome segregation errors. However, we do not know how the ubiquitin-proteasome system regulates the early stages of recombination that are defective in these mutants. We will therefore use genetically modified mouse models to investigate how these enzymes influence the machinery that initiates meiotic recombination, and whether recombination in particular regions of the genome are more sensitive to these ubiquitin-proteasome system components. We will also investigate how meiotic chromosomes are organised in mouse spermatocytes and oocytes, and study how meiotic chromosome organisation impacts on the frequency and distribution of meiotic recombination in mice.
The second part of this research programme will investigate a novel pathway that we have identified operating in mouse oocytes which helps prevent loss of chromosome cohesion, meiotic chromosome mis-segregation and aneuploidy in post-natal mouse oocytes. This pathway also involves components of the ubiquitin-proteasome system, and regulates the abundance of cohesin proteins associated with meiotic chromosomes. As this pathway also appears to operate in embryonic stem cells, which are derived from early mouse embryos, we will use embryonic stem cell models to investigate how chromosome cohesion is regulated by the ubiquitin-proteasome system. We will use the mechanistic insights that we gain from embryonic stem cells to generate genetically modified mouse models to test whether manipulation of this pathway can slow the age-dependent loss of chromosome cohesion that occurs in post-natal mouse oocytes.
Organisations
- University of Edinburgh (Lead Research Organisation)
- Columbia University (Collaboration)
- Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (Collaboration)
- Newcastle University (Collaboration)
- Erasmus MC (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
People |
ORCID iD |
Publications
Adams I
(2023)
Meiotic Chromosome Structure, the Synaptonemal Complex, and Infertility
in Annual Review of Genomics and Human Genetics
Crichton JH
(2018)
Defects in meiotic recombination delay progression through pachytene in Tex19.1-/- mouse spermatocytes.
in Chromosoma
Crichton JH
(2023)
Structural maturation of SYCP1-mediated meiotic chromosome synapsis by SYCE3.
in Nature structural & molecular biology
Ghosh T
(2022)
A retroviral origin of vertebrate myelin
Hall AE
(2022)
RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer.
in Nature communications
Haward F
(2021)
Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function
in eLife
Laureau R
(2021)
Meiotic Cells Counteract Programmed Retrotransposon Activation via RNA-Binding Translational Repressor Assemblies.
in Developmental cell
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00007/1 | 01/04/2018 | 31/03/2023 | £662,000 | ||
MC_UU_00007/2 | Transfer | MC_UU_00007/1 | 01/04/2018 | 31/03/2023 | £3,730,000 |
MC_UU_00007/3 | Transfer | MC_UU_00007/2 | 01/04/2018 | 31/05/2022 | £3,053,000 |
MC_UU_00007/4 | Transfer | MC_UU_00007/3 | 01/04/2018 | 31/03/2023 | £1,772,000 |
MC_UU_00007/5 | Transfer | MC_UU_00007/4 | 01/04/2018 | 31/03/2023 | £4,524,000 |
MC_UU_00007/6 | Transfer | MC_UU_00007/5 | 01/04/2018 | 31/03/2023 | £2,878,000 |
MC_UU_00007/7 | Transfer | MC_UU_00007/6 | 01/04/2018 | 31/03/2023 | £2,829,000 |
MC_UU_00007/8 | Transfer | MC_UU_00007/7 | 01/04/2018 | 31/12/2022 | £4,072,000 |
MC_UU_00007/9 | Transfer | MC_UU_00007/8 | 01/04/2018 | 31/03/2023 | £3,137,000 |
MC_UU_00007/10 | Transfer | MC_UU_00007/9 | 01/04/2018 | 31/03/2023 | £6,948,000 |
MC_UU_00007/11 | Transfer | MC_UU_00007/10 | 01/04/2018 | 31/03/2023 | £2,421,000 |
MC_UU_00007/12 | Transfer | MC_UU_00007/11 | 01/04/2018 | 31/03/2023 | £1,205,000 |
MC_UU_00007/13 | Transfer | MC_UU_00007/12 | 01/04/2018 | 31/03/2023 | £1,174,000 |
MC_UU_00007/14 | Transfer | MC_UU_00007/13 | 01/04/2018 | 31/03/2023 | £1,838,000 |
MC_UU_00007/15 | Transfer | MC_UU_00007/14 | 01/04/2018 | 31/03/2023 | £2,551,000 |
MC_UU_00007/16 | Transfer | MC_UU_00007/15 | 01/04/2018 | 31/03/2023 | £1,496,000 |
MC_UU_00007/17 | Transfer | MC_UU_00007/16 | 01/04/2018 | 31/03/2023 | £1,886,000 |
Description | University of Copenhagen - University of Edinburgh joint PhD |
Amount | 700,000 kr. (DKK) |
Organisation | University of Copenhagen |
Sector | Academic/University |
Country | Denmark |
Start | 10/2022 |
End | 10/2025 |
Description | David Elliott |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Analysis of meiosis defects in transgenic mice |
Collaborator Contribution | Generation and analysis of transgenic mice |
Impact | doi: 10.7554/eLife.39304 |
Start Year | 2016 |
Description | Jose Luis Garcia Perez |
Organisation | Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research |
Country | Spain |
Sector | Academic/University |
PI Contribution | Developed novel bioinformatic techniques to analyse repetitive elements expression in microarray data, analyse gene function |
Collaborator Contribution | Help in understanding repeat element biology, and interest in the field in the methodology, analyse gene function |
Impact | PMID: 22570599, PMID: 28806172, PMID: 27875251 |
Start Year | 2011 |
Description | Luke Berchowitz |
Organisation | Columbia University |
Country | United States |
Sector | Academic/University |
PI Contribution | Analysis of mammalian retrotransposons in meiosis. |
Collaborator Contribution | Analysis of retrotransposons in yeast meiosis. |
Impact | Research publication submitted |
Start Year | 2019 |
Description | Owen Davies |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Generation and analysis of structure-directed mutations in mouse meiosis |
Collaborator Contribution | Biochemical and structural analysis of mammalian meiosis proteins |
Impact | Research ongoing. Named collaborator in Wellcome Trust investigator award for Owen Davies |
Start Year | 2019 |
Description | Richard Anderson |
Organisation | University of Edinburgh |
Department | MRC Centre for Reproductive Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Culture methodology, analysis of meiosis, analysis of sequencing data, write manuscripts, joint supervision of PhD student |
Collaborator Contribution | Perform experiments, provide tissue, write manuscripts, joint supervision of PhD student |
Impact | PMID: 26989066, PMID: 27510889, PMID: 28364521 |
Start Year | 2015 |
Description | Willy Baarends |
Organisation | Erasmus MC |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Scientific research & analysis |
Collaborator Contribution | Reagents |
Impact | Crichton et al., biorxiv |
Start Year | 2021 |