Exploiting natural genetic variation to map QTLs of telomere properties in Yeast: Length silencing ageing and senescence

Lead Research Organisation: University of Nottingham
Department Name: School of Life Sciences

Abstract

Most properties of an organism are under the control of many genes rather than single major genes. Genetics in the past 100 years has been split into two modes of analysis. The first is breeding genetics which generally dealt with complex traits that were inherited, such as egg production, milk yield and crop yields, but were not inherited in a simple fashion. Very complex statistical analyses have been generated over the decades to deal with the inheritance of these traits. The second mode of analysis deals with the simple single gene effects where a variant or mutant has a visible phenotypic effect. Modern molecular genetics has generally dealt with this single gene approach where a knockout or mutation of a gene has been assessed for the effect on particular phenotypes. This has grown to large scale genome wide approaches where the effect on a particular phenotype of every gene knockout is assessed. There are now concerted efforts to assess many if not all double gene knockouts to look at gene interactions. There hasn't yet been an effective marriage of the complex quantitative traits with the modern molecular approach though there have been some efforts with limited success. The advent of genome wide mapping of SNPs and other variation has improved the mapping of genes involved in complex traits but it is still a slow and arduous task. Nature has provided us with the necessary experimental material to undertake a modern molecular approach to complex traits in the form of populations that have diverged in sequence and phenotypic characteristics. In yeast populations we have found up to 4.5% sequence divergence as well as divergence in a number of phenotypes such as the length of telomeres. We can show that this difference in phenotypes is due to a number of genes rather than a few major genes. A global screen of all single gene knockouts has already been done on a laboratory strain of yeast which has identified a large number of genes that may be involved in telomere length. We will use the natural genetic variation to map all the genes involved in telomere length control, which will include essential genes not detectable in the previous studies, as well as their interactions. By comparing our approach to the previous approach we will identify new genetic factors but more importantly how these factors interact. We will assess the relative efficiency of our approach to the previous gene knockout approach and will also assess the relative workload required to determine the genetic factors of telomere length as well as related phenotypes of aging and nearby gene repression. The approach will definitely reveal further genetic factors involved in these traits but if it proves to be as feasible we will apply it to complex phenotypes in general and make the materials available to the community.

Technical Summary

We will combine classical quantitative trait analysis with modern molecular genetics in the yeast system in order to determine the genes involved in telomere length regulation, telomere repression of nearby genes and genes involved in aging, both replicative and chronological which may or may not be related to telomeres. The ability to isolate all four meiotic products as F1 progeny along with having the genome sequence of several strains will allow us to map precisely the QTLs involved in these telomere properties and assess their complex multilocus interactions. The ability to manipulate the genomes of these yeasts in any way will allow us to test hypothesis of the role of specific genetic variants in specific genome contexts for their role in the quantitative traits. We will then expand this approach to phenotypes in general, particularly those easily tested by high throughput screening. We can compare this approach to the more classical gene knockout approach that has already been done for telomere length regulation in yeast. By using natural genetic variation that has passed the test of evolutionary constraints we will be able to identify new genetic factors that cannot be revealed via the gene knockout approach, such as essential genes and many genes with synthetic interactions. A resource of sequences, oligos, genotyped F1 progeny, and phenotypes will be provided to the community.
 
Description We have shown that yeast is an excellent model for dissecting complex traits and have developed new methods based on the findings that increase resolution and sensitivity of finding underlying causal genetic variation. We have applied this to several traits.
Exploitation Route The findings have already been used to further quantitative genetic studies in yeast by other groups. They have been exploited to identify genes involved in industrially relevant traits and will be used in our new project on hybrids for brewing and other fermentation processes.
Sectors Agriculture, Food and Drink,Chemicals,Creative Economy,Manufacturing, including Industrial Biotechology

URL http://www2.le.ac.uk/colleges/medbiopsych/research/gact/projects
 
Description So far no direct demonstrable impact however the advanced QTL analysis generated has had a profound impact on the academic science derived and will soon have real impact in terms of developing yeast strains for the biofuel industry as well as IBB production of high value chemicals.
First Year Of Impact 2009
 
Description 3rd International VIBes PhD-Student Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Over 300 PhD students from across Belgium attended with lots of discussion and interactions via seminars and workshops.

Many students attending had important career decisions ahead of them and the Symposium helped inform those decisions.
Year(s) Of Engagement Activity 2012
URL http://www.vibes2012.org
 
Description Australasian Yeast Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Annual meeting of academic and industrial yeast users from Australia and New Zealand.
Year(s) Of Engagement Activity 2013
 
Description Biannual Novozyme Research Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Worldwide Novozyme researchers gather outside Copenhagen to hear the latest techniques from academic scientists which may be relevant to their R and D programmes. Several discussions with relevant sections have occurred that may lead to collaboration or uptake of techniques developed.
Year(s) Of Engagement Activity 2013
 
Description FEMS 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion in yeast for biotechnology session with a mixed audience resulting in longer term interactions on developing yeast and hybrids for industrial uses.
Year(s) Of Engagement Activity 2015
 
Description Fundacion Ramon Areces - Yeast in Bioeconomics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Of the 250 participants one Industry representative has agreed to act as a scientific advisor, one student came to the lab to learn new techniques and published their work before going on to a postdoc, numerous discussions have resulted that may lead to new collaborations.

A student published work based on a short visit to learn new techniques from us relevant to their project. Several additional invitations and interactions have resulted.
Year(s) Of Engagement Activity 2013
 
Description Keynote at Benelux annual yeast meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Several Universities and Industries attended and interest in future collaborations was expressed.
Year(s) Of Engagement Activity 2018
URL https://www.yeasterday.nl
 
Description iGenolevure 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 100 people attended the European yeast genome network for a day in Utrecht where the latest advances in comparative genomics and yeast biodiversity were discussed.
Year(s) Of Engagement Activity 2016