Yeast genome sequencing: the power of comparative genomics

1. Yeast genome sequencing: the power of comparative genomics Molecular Microbiology (2004)53(2), 381–389 MEDG 505, 03/02/04, Han Hao

2. Outline • Introduction • Phylogenetic relationship • Speciation • Gene and regulatory motifs • Evolution • Conclusion • Discussion

3. Introduction • Over a dozen yeast genomes have been sequenced. • Coding potential and regulatory sequences • Genes specific for a certain species • Closely related yeasts genomes will provide information on: • Development of a methodological approach to study phylogenetic relationship • Mechanism involved in the generation of new species • Deduce yeast evolutionary history • Deduce important motifs (for example in gene expression) • Useful for industry application and fighting yeast pathogens • Newly sequenced yeasts will be new model organisms

4. Phylogenetic relationship • One of the most pervasive challenges in molecular phylogenetics is the incongruence between phylogenies obtained using different data sets, such as individual genes.

5. Phylogenetic relationship Trees generated from single-gene data sets frequently generate incongruences Rokas et al. 2003, Nature

6. Phylogenetic relationship • Combined analysis of multiple genes will have better solution plus congruences Phylogenetic tree derived from analysis of a dataset comprised of nucleotide sequences from 18S, 5.8S/alignable ITS, and 26S (three regions) rDNAs, EF-1 , mitochondrial small-subunit rDNA and COX II. Kurtzman and Robnett, 2003

7. Phylogenetic relationship

8. Phylogenetic relationship • Q: What is the minimal amount of gene that could be sufficient to recover a valid species tree? • A: For yeast, a minimum of 20 genes is required to recover 95% bootstrap values for each branch of the species tree (Rokas et al. 2003, Nature)

9. Phylogenetic relationship Phylogenetic tree based on18s rRNA Rokas et al. 2003, Nature

10. Phylogenetic relationship • Use of genome-wide data sets may provide unprecedented power not only in testing specific phylogenetic hypotheses but also in precise reconstruction of the historical associations of all the taxa analysed. • In other cases the amount of sequence information needed to resolve specific relationships will be dependent on the particular phylogenetic history under examination.

11. Speciation • Species: a group of organisms defined by their inability to mate successfully and produce viable offspring with other species. (species barrier) • What cause speciation? • Chromosome numbers and sizes changed • Chromosomal translocation • Gene order remodelled • Gene loss/gain • Horizon transfer

12. Speciation • The principal problem in studying the molecular mechanisms of speciation is the difficulty in separating the effects of karyotypic rearrangements from genome-wide genetic incompatibilities.

13. Speciation • Facts: • Rearrangements within the nuclear genome have been common during yeast evolution. • Saccharomyces sensu stricto yeasts can mate with each other but interspecific pairings result predominantly in sterile hybrids.

14. Speciation • Chromosomal translocations in yeast might contribute to the reproductive isolation among sensu stricto species, but are not the only cause of speciation. (Deineri et al. 2003, Nature) • A method for generating precisely located chromosomal translocations. • If the chromosome were rearranged, the species barrier almost disappeared. • New genome sequences will increase the opportunities for further experiments on chromosome stability and species barriers.

15. Gene and regulatory motifs • Large-scale comparisons of genomes address basic genomics questions • Number of functional genes • Identification of species-specific genes • Distribution of genes among functional families • Gene density, gene order et al

16. Gene and regulatory motifs • Multi-steps process of comparative sequence analysis Frazer et al. 2003, Genome Research

17. Gene and regulatory motifs • Based on comparative genomics: • The number of genes for S. cerevisiae predicted to be around 5800 ( Much less than previous prediction >6000) • Discovery of novel genes, novel introns et al. • Discovery of ncRNA genes. • Identification of regulatory sequences.

18. Gene and regulatory motifs Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

19. Gene and regulatory motifs Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

20. Gene and regulatory motifs Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

21. Gene and regulatory motifs Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

22. Gene and regulatory motifs • The genomes of higher eukaryotes consist a lot of non-functional sequences that are difficult to align and the regulatory motifs might locate far away from the genes they control.

23. Evolution • Facts: There are two kinds of yeasts, aerobic and anaerobi yeasts. • Facts: Sexually reproducing yeasts can undergo mating between either heterothallic lines or homothallic line. In S. cerevisiae, homothallism can be switched to heterothallism. (The present of HO gene is required for homothallism.) • Q: when and how did the progenitor of Saccharomyces yeasts develop these basic characters and what were the molecular mechanisms operating during this yeast’s evolutionary history?

24. Evolution • Two molecular mechanisms, whole-genome duplication and horizontal gene transfer, are proposed to play a major role in the evolutionary history of the Saccharomyces complex yeasts.

25. Evolution The whole-genome duplication and horizontal transfer of genetic material provided new genes, which became the background for the development of facultative anaerobic lifestyle, homothallism and efficient glucose repression circuit. Comparative genomics now helps to place these events at different branching points of the yeast phylogenetic tree and estimates the relative timing of these events The origin of several modern yeast traits.

26. Conclusion • Comparative genomics study of yeast genomes • Phylogenetic relationship • Speciation • Genes and regulatory motifs • Evolution

27. Discussion • How to organize the yeast genome sequences into a single database? (Ensembl/UCSC like Genome browser)?

28. Resources • Saccharomyces Genome Database: http://www.yeastgenome.org/ • SCPD: The Promoter Database of Saccharomyces cerevisiae: http://cgsigma.cshl.org/jian/ • MIPS Saccharomyces cerevisiae group: http://mips.gsf.de/genre/proj/yeast/ • Saccharomyces Genome Sequencing at the GSC: (Cliften et.al 2003, Science) http://www.genome.wustl.edu/projects/yeast

29. References • Cliften, P., et al. (2003) Finding functional features inSaccharomyces genomes by phylogenetic footprinting. Science 301: 71–76. • Delneri, D., et al. (2003) Engineering evolution to study speciation in yeasts. Nature 422: 68–72. • Frazer, K.A., et al. (2003) Cross-species sequence comparisons: a review of methods and available resources.Genome Res 13: 1–12. • Kellis, M., et al. (2003) Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423: 241–254. • Rokas, A., et al. (2003) Genome-scale approaches to resolving incongruence in molecular phylogenies. Nature 425: 798–804.

30. Thank you!