Yeast genome sequencing: the power of comparative genomics

MEDG 505, 03/02/04, Han Hao

Molecular Microbiology (2004)53(2), 381–389

Outline

Introduction Phylogenetic relationship Speciation Gene and regulatory motifs Evolution Conclusion Discussion

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

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.

Phylogenetic relationshipTrees generated from single-gene data sets frequently generate incongruences

Rokas et al. 2003, Nature

Phylogenetic relationship

Kurtzman and Robnett, 2003

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.

Combined analysis of multiple genes will have better solution plus congruences

Phylogenetic relationship

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)

Phylogenetic relationship

Phylogenetic tree based on18s rRNA

Rokas et al. 2003, Nature

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.

Speciation Species: a group of organisms defined by th

eir 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

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.

Speciation

Facts: Rearrangements within the nuclear geno

me have been common during yeast evolution.

Saccharomyces sensu stricto yeasts can mate with each other but interspecific pairings result predominantly in sterile hybrids.

Speciation Chromosomal translocations in yeast might contri

bute 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.

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

Gene and regulatory motifs

Multi-steps process of comparative sequence analysis

Frazer et al. 2003, Genome Research

Gene and regulatory motifs

Based on comparative genomics: The number of genes for S. cerevisiae pre

dicted 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.

Gene and regulatory motifs

Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

Gene and regulatory motifs

Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

Gene and regulatory motifs

Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

Gene and regulatory motifs

Cliften et. al. 2003, Science, Finding Functional Features in Saccharomyces Genomes by Phylogenetic Footprinting

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.

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?

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.

EvolutionThe 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 eventsThe origin of several modern yeast traits.

Conclusion

Comparative genomics study of yeast genomes Phylogenetic relationship Speciation Genes and regulatory motifs Evolution

Discussion How to organize the yeast genome sequences into a single

database? (Ensembl/UCSC like Genome browser)?

Resources Saccharomyces Genome Database:

http://www.yeastgenome.org/ SCPD: The Promoter Database of Saccharo

myces 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

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.

Thank you!