Basic Research Team 8 « Population genomics and complex traits »
Dr Gianni LITI, CR1 CNRS, Team Leader
From left to right :
Gianni Liti, Lucie Malard, Agnès Llored, Anders Bergström, Alexandre Leroy, Jordie Tronchoni, Francisco Salinas, Benjamin Barre
Most human traits, including cancer susceptibility and ageing, are regulated by multiple interacting quantitative trait loci (QTLs). Dissecting the genetic mechanisms underlying this phenotypic variation is a major challenge. In order to advance our understanding of complex traits there is a need for a suitable genetic system that can be used in high-throughput studies. In our lab, we use the budding yeast, S. cerevisiae, to dissect the genetic architecture of multiple traits. The objectives are relevant for human health in two ways: the first consists of modelling complex traits in a simple genetic system; the second aims to dissect traits directly relevant to the complex biology of cancer and ageing. In all aspects of our research, we exploit natural variation in the budding yeast as a tool for understanding how a phenotype is genetically regulated. Given that many pathways (e.g. longevity) are conserved from yeast to humans, there is an opportunity to test previously uncharacterised genes in other model systems. Once the architecture of complex traits is fully dissected, the next step is to extrapolate this knowledge to make predictions (based on population genomics data) of the standing variation in natural populations. Finally, the long-term challenge is to understand what evolutionary forces maintain the variability in natural populations.
Our past and present areas of research are :
1. Telomeres and genomic instability: telomere maintenance in the absence of telomerase in S. cerevisiae. Telomerase negative yeast has been an excellent model for understanding the underlying genetic mechanisms leading to ALT (alternative lengthening of telomeres) tumours and associated genomic instability. We have found dramatic differences in genome stability rates between haploid and diploid cells, in the absence of telomerase. We have also shown a paradoxical role for a gene, NEJ1, which promotes DNA repair in wild type cells while protecting the telomere from end fusions in telomerase negative cells.
2. Exploiting natural variation to map quantitative trait loci (QTLs) of various telomere properties including length, silencing, ageing, and senescence. We have found dramatic differences in telomere length and telomeric transcriptional silencing in natural population. We are characterising this variation with the aim to identify novel genes that affect telomeric properties. One of the QTL that contribute to telomere length variation is the RNA template of telomerase (hortolog of hTERT) and allelic variants of this gene are associated with telomere length variation in human populations.
3. Evolution of the RAS signalling pathway. This pathway is highly conserved in all eukaryotes and is a key regulator of cell growth and malignant transformation. We found that widespread sequence variation in this pathway regulate internal levels of cAMP and contribute to quantitative differences in ageing (chronological life span), virulence (ability to grow at high temperature) and mitochondrial genome stability. Part of the variation in the RAS signalling pathway is due to sequence polymorphisms in the IRA1 and IRA2. The IRA genes are of specific interest as they are highly conserved orthologs of the human disease gene NF1, which causes neurofibromatosis type 1, and as mutations in patients with neurofibromatosis also have similar detrimental effects on the yeast Ira1p activity.
4. Genome evolution. Our studies on genome evolution lay the foundation for understanding the population structure of Saccharomyces yeasts and highlighted how classical phylogeny is inadequate to present the true relationship between strains and species. We are also interested in the relationship between sequence divergence and meiotic sterility.
5. Population genomics. I have been part of a joint effort, the Saccharomyces Genome Resequencing Project (SGRP), involving Richard Durbin’s group at The Sanger Institute and Edward Louis’ group at Universtiy of Nottingham to sequence and release genome sequence data of 72 strains of S. cerevisiae and its closest known species S. paradoxus. This study led to a landmark paper published in March 2009 that initiate the field of population genomics and revealed the impact of human activity on the population structure of the baker’s yeast.
LITI Gianni, CR1 CNRS, Team Leader
BARRE Benjamin, Research Assistant
LLORED Agnès, Univ. Technician
SALINAS Francisco, Post-Doc
Bergström A, Simpson JT, Salinas F, Barré B, Parts L, Zia A, Nguyen Ba AN, Moses AM, Louis EJ, Mustonen V, Warringer W, Durbin R and Liti G*. 2014. A high-definition view of functional genetic variation from natural yeast genomes. Molecular Biology and Evolution. In press.
Brown WR, Thomas G, Lee NC, Blythe M, Liti G, Warringer J, Loose MW. 2014. Kinetochore assembly and heterochromatin formation occur autonomously in Schizosaccharomyces pombe. PNAS. In press.
Cubillos FA, Pièces L, Salinas F, Bergström A, Scovacricchi E, Zia A, Chef Illingworth, Mustonen V, Ibstedt S, Warringer J, Louis EJ, Durbin R, Liti G., High resolution mapping of complex traits with a four-parent advanced intercross yeast population. Genetics, September 20, 2013,113,155515.
Illingworth CJ, Parts L, Bergström A, Liti G and Mustonen V. 2013. Inferring genome-wide recombination landscapes from advanced intercross lines: application to yeast crosses. PLoS One. In press.
Zörgö E, Chwialkowska K, Gjuvsland A, Garre E, Sunnerhagen P, Liti G, Blomberg A, Omholt SW and Warringer J. 2013. Ancient evolutionary trade-offs between yeast ploidy states. PLoS Genetics. In press.
Dunn B, Paulish T, Stanbery A, Piotrowski J, Koniges G, Kroll E, Louis EJ, Liti G, Sherlock G and Rosenzweig F. 2013. Recurrent rearrangement during adaptive evolution in an interspecific yeast hybrid suggests a model for rapid introgression. PLoS Genetics. In press.
Liti G, Nguyen Ba AN, Blythe M, Müller CA, Bergström A, Cubillos FA, Dafhnis-Calas F, Khoshraftar S, Malla S, Mehta N, Siow CC, Warringer J, Moses AM, Louis EJ and Nieduszynski CA. 2013. High quality de novo sequencing and assembly of the Saccharomyces arboricolus genome. BMC Genomics. 14(1), 69.
Salinas F, Cubillos FA, Soto D, Garcia V, Bergström A, Warringer J, Ganga MA, Louis EJ, Liti G and Martinez C. 2012. The genetic basis of natural variation in oenological traits in Saccharomyces cerevisiae. PLoS One. 7(11), e49640.
Armstrong J, Davis D, Liti G, Oliver S. 2012. 'New' yeasts for a new Yeast. Yeast. 29(10), 407.
Liti G and Louis EJ. 2012. Advances in quantitative trait analysis in yeast. PLoS Genetics. 8(8), e1002912.
Wang Q-M, Liu W-Q, Liti G, Wang SA and Bai F-Y. 2012. Surprisingly diverged populations of Saccharomyces cerevisiae in natural environments remote from human activity. Molecular Ecology. 21(22), 5404-17.
McLaughlan MJ, Liti G, Sharp S, Maslowska A and Louis EJ. 2012. Apparent ploidy effects on silencing are post-transcriptional at HML and telomeres in Saccharomyces cerevisiae. PLoS One. 7(7), e39044.
Zörgö E, Gjuvsland A, Cubillos FA, Louis EJ, Liti G, Blomberg A, Omholt SW and Warringer J. 2012. Life history shapes trait heredity by promoting accumulation of loss-of-function alleles in yeast. Molecular Biology and Evolution. 29(7), 1781-9.
Illingworth CJ, Parts L, Schiffels S, Liti G and Mustonen V. 2012. Quantifying selection acting on a complex trait using allele frequency time-series data. Molecular Biology and Evolution. 29(4), 1187-97.
Brown WRA, Liti G, Rosa C, James S, Roberts I, Robert V, Jolly N, Tang W, Baumann P, Green C, Schlegel K, Young J, Hirchaud F, Leek S, Thomas G, Blomberg A and Warringer J. 2011. A Geographically diverse collection of Schizosaccharomyces pombe isolates shows limited phenotypic variation but extensive karyotypic diversity. G3: Genes, Genomes, Genetics. 1(7), 615-26.
Liti G and Schacherer J. 2011. The rise of yeast population genomics. Comptes Rendus Biologies. 334 (8-9), 612-619.
Warringer J, Zörgö E, Cubillos FA, Zia A, Gjuvsland A, Simpson JT, Forsmark A, Durbin R, Omholt SW, Louis EJ, Liti G, Moses AM and Blomberg A. 2011. Trait variation in yeast is defined by population history. PLoS Genetics. 7(6), e1002111.
Parts L, Cubillos FA, Warringer J, Jain K, Salinas F, Bumpstead SJ, Molin M, Zia A, Simpson JT, Quail MA, Moses AM, Louis EJ, Durbin R and Liti G. 2011. Revealing the genetic structure of a trait by sequencing a population under selection. Genome Research. 21(7), 1131-8.
Nieduszynski CA and Liti G. 2011. From sequence to function: insights from natural variation in budding yeasts. Biochemical Biophysical Acta. 1810 (10), 959-66.
Cubillos FA, Billi E, Zörgö E, Parts L, Fargier P, Omholt S, Blomberg A, Warringer J, Louis EJ and Liti G. 2011. Assessing the Complex Architecture of polygenic traits in yeast. Molecular Ecology. 20(7), 1401-13.
Cubillos FA, Louis EJ, Liti G. 2009. Generation of a large set of genetically tractable haploid and diploid Saccharomyces strains. FEMS Yeast Research. 9, 1217-1225.
Liti G, Haricharan S, Cubillos FA, Tierney AL, Sharp S, Bertuch AA, Parts L, Bailes E, Louis EJ. 2009. Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast. PLoS Genetics. 5 (9); e1000659.
Liti G, Carter DM, Moses AM, Warringer J, Parts L, James SA, Davey RP, Roberts IN, Burt A, Koufopanou V, Tsai IJ, Bergman CM, Bensasson D, O’Kelly MJT, van Oudenaarden A, Barton DBH, Bailes E, Nguyen Ba AN, Jones M, Quail MA, Goodhead I, Sims S, Smith F, Blomberg A, Durbin R and Louis EJ. 2009. Population genomics of domestic and wild yeasts. Nature. 19; 458(7236), 337-41.
1) “Yeast complex trait genetics : beyond classical crosses” grant coordinator, co-applicants : Alain Nicolas (Institut Curie, Paris) and Sylvie Dequin (INRA, Montpellier) funded by ANR Programme Blanc, 3.5-years.
2) “The 1002 yeast genomes project : a framework for genome-wide association studies” co-applicant with Prof. Schacherer, funded by the France Génomique within the call Grands Projets de Séquençage.
Marie Curie Career Integration Grant “Modelling the complexity of ageing in a simple genetic system”, 4-years.
1) “Modelling the complexity of cancer in a simple genetic system”, funded by Association pour la Recherche sur le Cancer (ARC), 2-years.
2) “Understanding the genetic mechanisms underlying quantitative traits” ATIP-AVENIR program funded by CNRS and INSERM, 3-years, 2 years extension possible.