Mouse Models of Human Variation and Disease

Lead Research Organisation: University of Edinburgh

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.

Publications

10 25 50
 
Description Infrafrontier 2018
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Infrafrontier advisory
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description MRC Data Sharing
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description NC3Rs Board
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact National Centre for 3Rs influences academia, government and industry in their use of animals in research
 
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 
 
Description Harwell 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Public 
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 Public 
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 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 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 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