The evolution of protein synthesis rates in mammals

• Applicant: Professor Henrik Kaessmann, Ph.D.
• Subject Area: Evolution, Anthropology ; Bioinformatics and Theoretical Biology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325413057

A primary goal in biology is to understand the molecular basis of phenotypic evolution, most notably that of humans and other mammals. Most phenotypic differences between species are likely due to regulatory mutations that affect gene expression. Recent evolutionary transcriptome studies, based on high-throughput RNA sequencing data, have provided initial insights into mammalian gene expression evolution. Our own previous work, which was based on the first cross-mammalian transcriptome dataset, revealed general principles underlying gene expression evolution and its phenotypic implications. However, the expression output of protein-coding genes may be substantially affected by regulatory events that occur after transcription. Thus, our understanding of gene expression evolution has remained limited.In the framework of this proposal, we will therefore investigate the evolution of protein synthesis rates in major organs (brain, liver, testis) across all major mammalian lineages (placental mammals, marsupials, egg-laying monotremes) based on a recently developed high-throughput approach (ribosome profiling) that measures translation at high resolution. Our integrated analyses of these data and matched transcriptome data will address long-standing hypotheses of mammalian gene expression evolution.First, we will define the full set of protein-coding regions in transcriptomes from the different organs and species and assess their functional conservation. We will thus be able to address key questions regarding the translation capacities of mammalian genomes and their evolutionary dynamics. Specifically, we will explore the hypothesis of widespread translational repression in testis (spermatogenic cells), the functionality of newly emerged genes, and the functional evolution of upstream open reading frames (uORFs).Second, based on quantitative analyses, we will investigate global patterns of gene expression evolution and underlying selective forces at the levels of both transcription and translation. We will then assess selectively driven gene expression shifts and compensatory evolution at the two gene expression layers, in particular the potential translational upregulation of the X chromosome following sex chromosome origination and Y chromosome decay. Finally, we will begin to unravel the regulatory basis of evolutionary translation change, focusing on the role of uORFs.Altogether, the proposed work will substantially advance our understanding of evolutionary changes at the two principal layers of gene expression regulation and their contribution to the specific organ biology of different mammals. Our study will thus also provide novel perspectives on the molecular evolution that led to the unique biology of our own species.

• DFG Programme: Research Grants