Mouse Models of Human Variation and Disease
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
Abstract
Laboratory mice are excellent models for the effects of human genetic mutations or variation. New methods now allow us to produce very precise changes in the DNA of mice, to mimic human genetic changes, and to see the effect on the biology of the mouse. This programme has two aspects. The first is to study the effects of genetic mutations on the eye, to understand why loss or change in a gene leads to faults in the retina and to effect on vision. The second aspect is to unravel the genetics of human hair colour. Although hair colour genetics is complicated (we have found more than 100 genes that are involved) it is much simpler than the genetics affecting many common diseases. Understanding hair colour genetics is a “halfway house” to a full understanding of these important disease genetics. In some cases we will introduce genetic changes into mice to see the effect on hair colour biology. In most cases we will use human cells grown in the laboratory and produce changes in them to measure the effect on the genes.
Technical Summary
1. Mouse Models of Eye Disease. We study a mouse mutant line which lacks the, Fam151b gene and as a consequence has very rapid photoreceptor degeneration. Fam151b encodes a protein of unknown function, with similarity to glycerophosphodiester phosphodiesterases. We aim to identify the function of the FAM151B protein and understand the basis of the photoreceptor degeneration. We are in addition making mouse models of retinal detachment, by editing changes in mice into genes identified in genome wide association studies (GWAS) of Scottish populations. Analysis of the impact of these genetic changes on retinal histopathology and function will validate the gene identification from the GWAS. These studies will furthermore aid the understanding of the biology of normal retinal function and may indicate therapeutic avenues.
2. Understanding the Genetic Basis of Hair Colour Variation, We have performed a GWAS of several hundred thousand individuals in the UK Biobank, and identified many loci affecting hair colour. We are editing genetic changes in the genomes of mice, melanocytes and keratinocytes in order to determine the effect of these variants on gene expression, cell biology and mouse phenotype. Hair colour variation is an excellent example of a phenotype under complex genetic control. The cells and cellular interactions involved are well understood, and the genotype to phenotype connections are potentially tractable. It serves as a model for more diseases where there may be environmental as well as genetic effects, and where the cell types involved may be not well known or be less accessible.
2. Understanding the Genetic Basis of Hair Colour Variation, We have performed a GWAS of several hundred thousand individuals in the UK Biobank, and identified many loci affecting hair colour. We are editing genetic changes in the genomes of mice, melanocytes and keratinocytes in order to determine the effect of these variants on gene expression, cell biology and mouse phenotype. Hair colour variation is an excellent example of a phenotype under complex genetic control. The cells and cellular interactions involved are well understood, and the genotype to phenotype connections are potentially tractable. It serves as a model for more diseases where there may be environmental as well as genetic effects, and where the cell types involved may be not well known or be less accessible.
People |
ORCID iD |
Ian Jackson (Principal Investigator) |
Publications
Pennamen P
(2021)
Dopachrome tautomerase variants in patients with oculocutaneous albinism.
in Genetics in medicine : official journal of the American College of Medical Genetics
Stanton CM
(2021)
A mouse model of brittle cornea syndrome caused by mutation in Zfp469.
in Disease models & mechanisms
Tingaud-Sequeira A
(2022)
The Dct -/- mouse model to unravel retinogenesis misregulation in patients with albinism
Tingaud-Sequeira A
(2022)
The Dct-/- Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism.
in Genes
Tolman NG
(2021)
Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice.
in Disease models & mechanisms
Wilkinson E
(2022)
Genetically engineered multicistronic allele of Pmel yielding highly specific CreERT2- mediated recombination in the melanocyte lineage
in Pigment Cell & Melanoma Research
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00007/1 | 31/03/2018 | 30/03/2023 | £662,000 | ||
MC_UU_00007/2 | Transfer | MC_UU_00007/1 | 31/03/2018 | 30/03/2023 | £3,730,000 |
MC_UU_00007/3 | Transfer | MC_UU_00007/2 | 31/03/2018 | 30/05/2022 | £3,053,000 |
MC_UU_00007/4 | Transfer | MC_UU_00007/3 | 31/03/2018 | 30/03/2023 | £1,772,000 |
MC_UU_00007/5 | Transfer | MC_UU_00007/4 | 31/03/2018 | 30/03/2023 | £4,524,000 |
MC_UU_00007/6 | Transfer | MC_UU_00007/5 | 31/03/2018 | 30/03/2023 | £2,878,000 |
MC_UU_00007/7 | Transfer | MC_UU_00007/6 | 31/03/2018 | 30/03/2023 | £2,829,000 |
MC_UU_00007/8 | Transfer | MC_UU_00007/7 | 31/03/2018 | 31/12/2022 | £4,072,000 |
MC_UU_00007/9 | Transfer | MC_UU_00007/8 | 31/03/2018 | 30/03/2023 | £3,137,000 |
MC_UU_00007/10 | Transfer | MC_UU_00007/9 | 31/03/2018 | 30/03/2023 | £6,948,000 |
MC_UU_00007/11 | Transfer | MC_UU_00007/10 | 31/03/2018 | 30/03/2023 | £2,421,000 |
MC_UU_00007/12 | Transfer | MC_UU_00007/11 | 31/03/2018 | 30/03/2023 | £1,205,000 |
MC_UU_00007/13 | Transfer | MC_UU_00007/12 | 31/03/2018 | 30/03/2023 | £1,174,000 |
MC_UU_00007/14 | Transfer | MC_UU_00007/13 | 31/03/2018 | 30/03/2023 | £1,838,000 |
MC_UU_00007/15 | Transfer | MC_UU_00007/14 | 31/03/2018 | 30/03/2023 | £2,551,000 |
MC_UU_00007/16 | Transfer | MC_UU_00007/15 | 31/03/2018 | 30/03/2023 | £1,496,000 |
MC_UU_00007/17 | Transfer | MC_UU_00007/16 | 31/03/2018 | 30/03/2023 | £1,886,000 |
Description | Infrafrontier 2019 |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | improved knowledge of genetic impacts on health. improved sharing of research materials |
Description | MRC Data Sharing |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | NC3Rs optimal strategy |
Geographic Reach | National |
Policy Influence Type | Contribution to new or Improved professional practice |
Impact | More effective use of mice on biomedical research, better welfare outcomes |
URL | https://www.nc3rs.org.uk/3rs-resources/breeding-and-colony-management/colony-management-best-practic... |
Title | Arl13-FUCCI |
Description | Transgenic mouse line that reports cell cycle stage by fluorescence, whilst simultaneously fluorescently labelling,cila |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Distribution to several labs, Publication PMID: 30458140 |
Title | Fam151b, the mouse homologue of C.elegans menorin gene, is essential for retinal function |
Description | mice mutant in Fam151 genes indicating role of Fam151b in retinal function |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | publication in scientific journal |
Title | Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse |
Description | 2 mouse models of human missense mutations in Tmem98 associated with nanophthalmos |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | publication in scientific journal |
Title | Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function |
Description | mouse model for retinal degeneration due to IDH3 deficiency |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | publication in scientific journal |
Description | Benoit |
Organisation | University of Bordeaux |
Country | France |
Sector | Academic/University |
PI Contribution | generated and analysis of mutant mice |
Collaborator Contribution | further ananlysis of mice |
Impact | publication |
Start Year | 2019 |
Description | Harwell |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We take the mice, map and identify the genes affected and analyse the phenotype |
Collaborator Contribution | screening of mice for chemically induced mutant eye phenotypesidentification of mutant mouse strains, and generation of mutant mouse models |
Impact | PMID: 20943750 PMID: 20056676 PMID: 18765564 PMID: 16825286 PMID: 24809698 PMID: 23902802 PMID: 23633653 PMID: 23902802 PMID: 24809698 PMID: 25179226 PMID: 25736793 PMID: 26542706 PMID: 27534441 PMID: 30478029 other papers pre 2006 other papers in preparation |
Description | Harwell |
Organisation | MRC Harwell |
Department | MRC Mammalian Genetics Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We take the mice, map and identify the genes affected and analyse the phenotype |
Collaborator Contribution | screening of mice for chemically induced mutant eye phenotypesidentification of mutant mouse strains, and generation of mutant mouse models |
Impact | PMID: 20943750 PMID: 20056676 PMID: 18765564 PMID: 16825286 PMID: 24809698 PMID: 23902802 PMID: 23633653 PMID: 23902802 PMID: 24809698 PMID: 25179226 PMID: 25736793 PMID: 26542706 PMID: 27534441 PMID: 30478029 other papers pre 2006 other papers in preparation |
Description | Headon |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | collaboration on idenfication of melanocyte stem cell in skin |
Collaborator Contribution | provision of transgenic mice analysis of data |
Impact | publication PMID:25847135 |
Start Year | 2014 |
Description | Jeff Schoenebeck |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | analysis of canine DNA samples |
Collaborator Contribution | access to research subjects, computational analysis |
Impact | ongoing analysis |
Start Year | 2018 |
Description | Sanger IMPC |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | analysis of mouse mutations |
Collaborator Contribution | provision of KO mice |
Impact | publications PMID:25736793 PMID:25356849 |
Start Year | 2010 |
Description | Tenesa hair colour |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | access to UK Biobank data, and knowledge of melanocyte biology |
Collaborator Contribution | analysis of Biobank data |
Impact | multidisciplinary collaboration: molecular develo0pmental biology and quantitative genetics |
Start Year | 2016 |
Description | zebra fish |
Organisation | Cancer Research UK |
Department | Edinburgh Cancer Research UK Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | expertise in mouse pigmentation genetics |
Collaborator Contribution | expertise in analysis of zebrafish pgmentation phenotypes |
Impact | papers published PMID:21771814 PMID:23831555 PMID:25670789 PMID: 28869972 |
Description | Doors Open Day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | A presentation of our work on hair colour for visitors to the Institute's Doors Open Day |
Year(s) Of Engagement Activity | 2018 |
Description | Inaugural Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Inaugural lecture to an audience of general public and including numerous studetns from local schools |
Year(s) Of Engagement Activity | 2018 |
Description | Irish Radio |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | live radio interview on Newstalk on National Radio of Ireland on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | Naked Scientist |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | An interview for the NAked Scientist radio programme and podcast about our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | Newspaper coverage |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | 115 newspaper articles in response to press release about our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018,2019 |
Description | RSE Festival Events |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | 4 small discussion events at the Royal Society of Edinburgh, focussing on DNA and genomics |
Year(s) Of Engagement Activity | 2019 |
Description | Radio NZ |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview with New Zealand Radio on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | Scotsman article |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | 500 word article for Scotsman newspaper about the genetics of red hair and prevalence in Scotland |
Year(s) Of Engagement Activity | 2021 |
Description | TV interview |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | TV news interview about our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018 |
Description | Talk Radio |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | live radio interview on TalkRadio on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2019 |
Description | Twitter hair colour |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | 526 twitter responses to newspaper reports on our publication on hair colour genetics |
Year(s) Of Engagement Activity | 2018,2019 |