Computational Biology and Evolutionary Genomics: Discovering phenotype-genotype associations
Previous and Current Research
Evolution has led to an incredible diversity of phenotypes in all major species clades, exemplified by mammals like bats that fly or dolphins that live entirely in the water. This phenotypic diversity is often the result of changes or loss of ancestral phenotypes or gain of novel phenotypes during evolution. Phenotypic differences between species are due to differences in their genomes. For example, loss of a regulatory element led to the adaptive loss of spines in sticklebacks (PMID 20007865) and the loss of a forebrain enhancer in humans may partially contribute to the gain of human brain complexity (PMID 21390129). The availability of many sequenced genomes together with the availability hundreds of additional genomes in the near future allows us now to study how molecular and morphological phenotypic diversity is encoded in the genome.
The lab’s goal is to develop computational approaches to study phenotype - genotype associations using the power of comparative and evolutionary genomics, followed by experimental verifications. In particular, we are interested in
- What in the genome makes species different at the molecular and morphological level?
- How does nature’s incredible phenotypic diversity arise?
- How does a biological system change and adapt to loss of some of its components?
- How does a genome change in evolution as the result of species phenotype changes?
To address these questions, we are developing and improving comparative genomics approaches such as Forward Genomics to associate phenotypic changes between species to changes in genomic elements. To obtain predictions of high accuracy, we have to solve problems associated with the incompleteness and inaccuracy of genome assemblies. Since our analyses are often based on multiple genome alignments, we are also interested in improving whole genome alignment methods. Furthermore, we are sequencing and assembling genomes of species selected for having interesting phenotypes in order to find genomic loci involved in these phenotypes. Subsequent validation experiments in model organisms will test if and how the elements pinpointed by the computational approaches are involved in changing molecular and morphological phenotypes.
Future Projects and Goals
We are interested in genome-wide computational analysis and comparative genomics focusing on species biology and natural history.
Our projects include:
- Development of computational approaches to predict associations between phenotype and genotype (Forward and Reverse Genomics)
- Application of these tools to interesting molecular and morphological phenotypic differences in vertebrates, insects and nematodes
- Development of novel methods to improve multiple genome alignments
Methodological and Technical Expertise
- computational biology
Hiller M, Schaar BT, Indjeian VB, Kingsley DM, Hagey LR, and Bejerano G.
A “forward genomics” approach links genotype to phenotype using independent phenotypic losses among related species.
Cell Reports, 2(4), 817–823 (2012)
Hiller M, Schaar BT, and Bejerano G
Hundreds of conserved non-coding genomic regions are independently lost in mammals.
Nucleic Acids Res, doi:10.1093/nar/gks905 (2012)
McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G.
GREAT improves functional interpretation of cis-regulatory regions.
Nature Biotechnol., 28(5), 495–501 (2010)
Hiller M, Findeiss S, Lein S, Marz M, Nickel C, Rose D, Schulz C, Backofen R, Prohaska SJ, Reuter G and Stadler PF.
Conserved Introns Reveal Novel Transcripts in Drosophila melanogaster.
Genome Res. 19(7), 1289–1300 (2009)
Hiller M, Zhang Z, Backofen R, and Stamm S.
Pre-mRNA secondary structures influence exon recognition.
PLoS Genet. 3(11), e204 (2007)
Hiller M*, Huse K*, Szafranski K, Jahn N, Hampe J, Schreiber S, Backofen R, and Platzer M.
Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity.
Nature Genet. 36(12), 1255–7 (2004)