Mutagenesis and its Biomedical Impact

Lead Research Organisation: University of Edinburgh

Abstract

Of the many thousands of DNA differences between individuals, only a minority have important contributions to disease risk or other traits that differ between them.
Finding those rare consequential differences is the basis for genetic diagnosis and predicting traits like height and drug response. It is also often the first step in understanding the basis of a disease at a molecular level.
As a community we can only efficiently find the consequential differences if they directly alter an encoded protein, the vast majority don’t. We are developing ways to understand the consequences of the majority of DNA changes regardless of whether they alter a protein.
Our approaches are often based on studying how large numbers of DNA sequence differences are inherited through generations of the human population. It allows us to tease apart two patterns, the pattern of new mutations and the pattern shaped by the health of people that carried those mutations.
The pattern of new mutations tells us about the underlying biology of the DNA, how it is replicated and repaired as well as showing how likely a piece of DNA is likely to be disrupted by a new mutation. The second pattern is what tells us if a type of DNA change is likely to have a consequence for human health. Although described here in the context of inherited DNA differences, we apply similar approaches to interpret the new mutations that arise in and drive the development of cancer.

Technical Summary

Discriminating mutations of medical and functional importance from the many more that are of negligible biological consequence is a major unmet challenge for genomic medicine. This problem is particularly acute for sequence changes in the non-protein-coding majority of the genome. Solving this is a key component of realizing the MRC’s objective “to use genetics, imaging and biological indicators to understand predispositions to disease”. We will help address this problem by disentangling the mutually confounding patterns of mutation and selection, both of which if separately resolved can give insight into the biology of the genome and the phenotypic consequences of a DNA sequence change. Our three main aims are to: 1. Reveal the fine-scale mutation landscape of the genome and identify the processes that shape it. 2. Understand the molecular consequences of mutation at regulatory sites in the non-protein-coding genome. 3. Relate molecular phenotypes to organism biology through improved measures of selection that are applicable to the non-protein-coding genome.

Our approach is predominately computational, applying statistical analyses to somatic (cancer), population and between species variation obtained from genome sequencing studies. These data are intersected with transcription and chromatin state measurements and key missing data generated by collaborators such as the international FANTOM consortium, or ourselves in which case may involve obtaining and processing primary human tissue samples. Specific hypotheses generated from our initial analyses, such as mutagenic processes are explored experimentally using yeast or in vitro systems where tractable.

Publications

10 25 50
 
Description ECAT Fellowship for Thomas Williams
Amount £233,584 (GBP)
Funding ID 204802/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2016 
End 07/2019
 
Description Detection of DNA embedded ribonucleotides in the mitochondrial genome 
Organisation Biodonostia Health Research Institute
Country Spain 
Sector Hospitals 
PI Contribution Developed computational tools, co-developed original emRibo-seq methodology and performed analysis on generated data.
Collaborator Contribution Generation of genetic model mouse, preparation of tissues and high purity mitochondrial DNA from cells and tissues. Experimental perturbation of cultured cells.
Impact Publication: Moss et al, Nucleic Acids Research 2017 doi:10.1093/nar/gkx1009
Start Year 2015
 
Description Detection of DNA embedded ribonucleotides in the mitochondrial genome 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed computational tools, co-developed original emRibo-seq methodology and performed analysis on generated data.
Collaborator Contribution Generation of genetic model mouse, preparation of tissues and high purity mitochondrial DNA from cells and tissues. Experimental perturbation of cultured cells.
Impact Publication: Moss et al, Nucleic Acids Research 2017 doi:10.1093/nar/gkx1009
Start Year 2015
 
Description Detection of DNA embedded ribonucleotides in the mitochondrial genome 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed computational tools, co-developed original emRibo-seq methodology and performed analysis on generated data.
Collaborator Contribution Generation of genetic model mouse, preparation of tissues and high purity mitochondrial DNA from cells and tissues. Experimental perturbation of cultured cells.
Impact Publication: Moss et al, Nucleic Acids Research 2017 doi:10.1093/nar/gkx1009
Start Year 2015
 
Description FANTOM6 Consortium 
Organisation RIKEN
Department Institute of Physical and Chemical Research (RIKEN)
Country Japan 
Sector Public 
PI Contribution Planning of large scale systematic study on lncRNA and their effect on gene regulation. Planning and initiating analysis of the resulting data.
Collaborator Contribution Planning, coordination and primary data generation.
Impact Project is ongoing - no impact yet.
Start Year 2015
 
Description Liver Cancer Evolution Consortium 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Computational analysis of tumor whole genome and transcriptome sequence data to profile mutation patterns.
Collaborator Contribution Generation, histological profiling and whole genome and transcriptome sequencing of carcinogen induced tumors in rodents.
Impact No published outcomes yet, less that 1 year into project and data generation still under way.
Start Year 2017
 
Description Liver Cancer Evolution Consortium 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Computational analysis of tumor whole genome and transcriptome sequence data to profile mutation patterns.
Collaborator Contribution Generation, histological profiling and whole genome and transcriptome sequencing of carcinogen induced tumors in rodents.
Impact No published outcomes yet, less that 1 year into project and data generation still under way.
Start Year 2017
 
Description Liver Cancer Evolution Consortium 
Organisation Institute for Research in Biomedicine (IRB)
Country Spain 
Sector Academic/University 
PI Contribution Computational analysis of tumor whole genome and transcriptome sequence data to profile mutation patterns.
Collaborator Contribution Generation, histological profiling and whole genome and transcriptome sequencing of carcinogen induced tumors in rodents.
Impact No published outcomes yet, less that 1 year into project and data generation still under way.
Start Year 2017
 
Description Chelsea Flower Show 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Manned information stand & display on genetics including live demonstrations of genome sequencing. Stand staffed by 2-4 people continuously through the week long event. Engaged with >500 members of the public varying from a few seconds to 20min interaction with individuals and small groups. Many people highly engaged, both in the implications of genetic variation, the "rules" of inheritance and the wider implications of genetics. Though initially plant-genetics focused, discussions often ventured into implications for human biology and health.
Year(s) Of Engagement Activity 2019
URL https://genetics.org.uk/news/centenary-garden-exhibit-at-chelsea-flower-show-2019/
 
Description Genetics Society Centenary 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Organising the Genetics Society Centenary gathering for society members and relevant policy makers and influences in the field of genetics, both academia and industry.
Year(s) Of Engagement Activity 2019
URL https://genetics.org.uk/centenary/birthday-celebration/
 
Description Negotiated and commissioned "Genetics Unzipped" podcast series 
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 Over 4,500 unique subscribers to podcast channel to date on RSS, additional listeners and subscribers on Spotify and iTunes. Fortnightly podcasts showing steady growth episode on episode.
Year(s) Of Engagement Activity 2018,2019
URL https://geneticsunzipped.com/
 
Description Public engagement event at Edinburgh Botanic Gardens 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Students from the lab Thomas Williams and Kathryn Jones presented a genetics workshop event open on a drop-in basis to the general public. This included supervised activities such as preparation of DNA from strawberries and live demonstration of DNA sequencing using ONT MinIon technology. This was a pilot event for a larger scale engagement activity at the Chelsea Flower Show and subsequent roadshow through Q2 2019.
Year(s) Of Engagement Activity 2018
URL http://www.genetics.org.uk/centenary/centenary-garden-exhibit-at-chelsea-flower-show-2019/
 
Description Royal Institution Christmas Lectures 2018 
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 Through my role as Honorary Treasurer of The Genetics Society I had a substantial roll in organising the theme "Who am I?" and logistics of the 2018 Christmas Lectures broadcast by the BBC and available online. The activity includes information packs sent out to schools and a series of internationally touring lectures.
Year(s) Of Engagement Activity 2018,2019
URL https://www.rigb.org/christmas-lectures/2018-who-am-i