Using signatures of mutation and selection in genome evolution to interpret contemporary genetic variation

Lead Research Organisation: University of Edinburgh

Abstract

Improving our understanding of genetic differences between species allows us to better interpret genetic risk in people. We are all at risk of developing a wide range of diseases, some very common, including heart disease, diabetes, dementia and cancer. But such risks differ hugely between individuals, and are to a large degree influenced by the sequence of DNA in our cells.

The big question is which of the many thousands of DNA differences between individuals are responsible for increasing or decreasing their risk of developing a given disease. The historic record of evolution can provide some answers. We can read it as the differences in DNA between species, for example human versus mouse. The pattern of differences between species can reveal functionally important regions of DNA. Contrasting the between species pattern with the differences between people can point to the critically important changes that influence disease risk.

More broadly, we compare how DNA has changed between species with the differences observed between people. This allows us to study why and where DNA changes (mutations) arise, and what the functional consequences of those changes are. We are applying these methods to understand the genetic basis of many rare and common diseases.

Technical Summary

We are endeavouring to understand the processes of selection and mutation that are acting to shape genomes. It is well known that selection shapes the pattern of genomic changes that accumulate as populations diverge from a common ancestor. This has proven to be a very useful signature for the identification of functionally important regions of the genome. But it is becoming increasingly clear that fluctuations in the pattern of new mutations can also generate superficially similar signals. Improved separation of these confounding evolutionary signatures is crucial if we are to understand how organisms evolve, and to relate contemporary genetic changes to human biology and disease.

The results of this research fall into three broad categories: (1) An improved understanding of mutational mechanisms - why and where particular types of mutation occur. This is of particular importance in understanding the progression of cancers and explaining why some genes appear to carry a higher detrimental mutational load in the population than others. (2) Better detection of both purifying and diversifying selection for the interpretation of function and relating functional genomic measures of the genome (e.g. chromatin, origins of replication, regulatory sequences) to evolution. (3) The development and application of methods to identify genes, pathways and biological systems enriched for deleterious mutations associated with human genetic diseases and cancer. These approaches build on established techniques from the field of evolutionary biology and can be applied to all genetic diseases.

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 Equipment funds
Amount £67,000 (GBP)
Funding ID C0440 
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 10/2013
 
Description MRC Capital Equipment
Amount £30,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2014 
End 02/2015
 
Description Scottish Genomes Partnership
Amount £6,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2016 
End 02/2018
 
Title EmRiboSeq 
Description A method to detect ribonucleotides embedded in DNA, a potential mutagenic lesion and also a means to track the enzymology of DNA replication. 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Multiple review articles covering technology, substantial twitter activity and rapidly and highly cited work (30 citations in first 12 months of publication). Popular scientific media reported on the work including Technobahn, Phys.org, Slash.dot, BioPortfolio, GenomeWeb, EurekAlert, NanoWerk and ScienceNewsline. 
 
Description Accurate measurement of nucleic acids 
Organisation Laboratory of the Government Chemist (LGC) Ltd
Country United Kingdom 
Sector Private 
PI Contribution Development of novel methods to explore the quantisation of DNA methylation.
Collaborator Contribution Preparation and generation of known reference data.
Impact PMID:22841564 PMID:25539843
Start Year 2012
 
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 FANTOM5 Consortium 
Organisation RIKEN
Department Omics Science Center
Country Japan 
Sector Public 
PI Contribution We are leading the evolutionary based analysis of this data. Comparing the patterns of transcriptional regulation between species to understand how the regulatory networks have evolved. We are also contributing to the primary filtering, quality control and interpretation of the data.
Collaborator Contribution Provision of exceptional primary data on which research is based.
Impact The FANTOM5 Consortium is a a multi-national, multi-disciplinary project to investigate transcriptional regulation across mammalian genomes. The project traverses the fields of genomics, immunology, neuroscience, computational and mathematical biology.
Start Year 2010
 
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 mir-941 
Organisation Chinese Academy of Sciences
Department CAS-MPG Partner Institute for Computational Biology (PICB)
Country China 
Sector Academic/University 
PI Contribution Data analysis, in-particular to show how the miR-941 locus evolved through the primate lineage from an evolutionarily volatile tandemly repetitive sequence. Writing and editing of the manuscript, preparation of figures.
Collaborator Contribution Generation of molecular biological data, genetic data analysis.
Impact Manuscript published PMID: 23093182. Agreement to seek joint funding to support further studies. Public engagement of science - this group took the lead in communicating the results and insights of this work to the general public: press release, radio interviews and articles in the poplar media (e.g. The Times, The Independent and news agencies across the world). See public engagement section.
Start Year 2012
 
Title LaggingStrand 
Description Software for the analysis of EmRibo-seq data to map embedded ribonucleotides in DNA and tracing the replication of the genome. 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact Major component of two manuscripts (Reijns et al, Nature 2015; Ding et al, Nature Protocols 2015) multiple review and news articles. Know to be in use by multiple other laboratories and work has been cited 30 times in the first 12 months since publication. Provides new insights into the enzymology of DNA replication. 
URL https://github.com/taylorLab/LaggingStrand
 
Title SuRFR 
Description Released under Artistic License 2.0 SuRFR prioritises variants in order of most likely to be functional to least on a combination of genomic annotations including conservation, chromatin states, minor allele frequency and DNase hypersensitivity. By combining data from multiple publicly available sources, this package can rank SNPs based on the likelihood of functionality. This method is particularly good at prioritising functional noncoding SNPs over a background set.We have designed this method as an aid to identifying disease causing and/or disease-associated SNPs for genomics projects such as next generation sequencing projects and genome wide association studies. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Use by multiple research groups to prioritise the investigation of candidate functional variants in positionally implicated regions of the genome. 
URL http://www.cgem.ed.ac.uk/resources/SuRFR/
 
Description A-IMBN of mice and men 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Assistance drafting a broad audience highlight of our recently published work. Wide audience in the Asia-Pacific biomedical research community.

Positive feedback from Australian and Japanese researchers.
Year(s) Of Engagement Activity 2012
 
Description Director Genetics Society studentship programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Coordination of summer projects for 34 undergraduate students in labs across UK (international participants). Running residential summer school for participants including media engagement.
Year(s) Of Engagement Activity 2015
URL http://www.genetics.org.uk/Funding/GeneticsSocietySummerStudentships.aspx
 
Description Edinburgh International Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact One on one interaction with over 100 children and their families. Demonstration, answering questions and provoking thought. Two doctoral candidate students participated in this activity.

Enthusiastic participation from children and parents. Answering more in-depth questions on genetics from the general public.
Year(s) Of Engagement Activity 2011,2012
 
Description Genetics Society board election 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Elected as voting member to the executive board of the Genetics Society. Presiding over grant applications, academic meetings.

Grants reviewed, awarded. Decisions made on support for meetings. Public engagement strategy discussions.
Year(s) Of Engagement Activity 2013
URL http://www.genetics.org.uk/
 
Description Interview for Guardian article explaining recently published research 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview for national newspaper to explain the findings and significance of a new study published by another group in the journal Nature. Theoretical print readership reach of 4.1m, online article was shared over 3000 times.
Year(s) Of Engagement Activity 2017
URL https://www.theguardian.com/science/2017/sep/20/fathers-pass-on-four-times-as-many-new-genetic-mutat...
 
Description Lab Times profile of group research 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research and approaches of the lab was profiled in extensive article published in Lab Times.
Year(s) Of Engagement Activity 2015
URL http://www.labtimes-archiv.de/epaper/LT_15_03/index.html#31
 
Description Press release and subsequent article in The Times 
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 Coordination of international press release regarding the FANTOM5 Nature publication. Interviewed by The Times and story picked up by many media outlets.

Asked about the relevant research at the school gate.
Year(s) Of Engagement Activity 2014
 
Description School visit (Edinburgh Nov 2012) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Presentations given to three groups of apx. 30 children (90 children in total). Each presentation lasted 40 minutes and included formal presentation, guided discussions and hands-on practical. Children were 8 to 9 years old.

Pupils very enthusiastic, parents commenting on positive reception. Invitation to return to school and make a regular annual contribution.
Year(s) Of Engagement Activity 2012
 
Description School visit and presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Presentation to 14-15 year olds, whole year group. Description of genomic medicine and discussion of whole genome sequencing.
Year(s) Of Engagement Activity 2017
 
Description Strategic planning for national development in high throughput sequencing 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Asked to provide technical and strategic insight into current and future high throughput sequencing technology. Influenced decision making on future investments and infrastructure planning.

Confidential.
Year(s) Of Engagement Activity 2014
 
Description miR-941 Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release describing the miR-941 story "New brain gene born".

Considerable press coverage with at least 33 resulting articles (as counted by Google News) both within the UK and internationally (US, Australia, China, Japan, Russia, Germany), invitations to interview on BBC radio.
Year(s) Of Engagement Activity 2012
 
Description miR-941 Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview for BBC radio describing the results of the miR-941 story.

Further interest from other media outlets.
Year(s) Of Engagement Activity 2012
 
Description miR-941 Times article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact A prominent almost full-page article in The Times describing our recent work on miR-941. Extensive interaction with the correspondent to ensure the correct message and technical accuracy of the article. http://www.thetimes.co.uk/tto/science/biology/article3600723.ece

Positive feedback from both colleagues and members of the public. Further questions from members of the public wanting to dig deeper into the story. Follow-up stories in many online and print publications across the world.
Year(s) Of Engagement Activity 2012