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Abstract

A primary goal in evolutionary biology is to understand the molecular basis responsible for phenotypic differences between species, most notably between humans and other species. Regulatory mutations affecting gene expression likely underlie most phenotypic changes. Re-cent evolutionary studies of mammalian transcriptomes have provided initial insights into mammalian gene expression evolution. However, mRNA levels are, in general, limited proxies for protein levels due to a sequence of regulations that succeed transcription. The fact that the evolution of mammalian translatomes or proteomes is essentially unexplored has severely lim-ited our understanding of gene expression evolution and its phenotypic implications.

To fill this gap and explore the co-evolution of regulatory processes across the transcriptome and translatome layers of gene expression, we generated, in the framework of my thesis pro-ject, ribosome profiling (high-throughput sequencing of ribosome-protected fragments) and matched RNA sequencing data for three major mammalian organs (brain, liver, testis) from representatives of all major mammalian lineages (human, macaque, mouse, opossum, platy-pus) and a bird (chicken), which serves as an evolutionary outgroup.

My analyses identified strong and highly differential patterns of translational buffering among organs, gene classes and chromosomes. Specifically, to assess the extent to which transcrip-tional changes of individual genes are reflected at the level of protein synthesis, we devised a "translational tuning index" (TTI), and found that translational forces frequently counteracted but rarely boosted transcriptional changes. Expression changes of functionally cooperating genes tend to be balanced by concerted (modular) translational changes to preserve ancestral cellular stoichiometries. Contrary to individual gene compensation, this concerted buffering is more pronounced in brain and liver than in testis. By contrasting the evolutionary dynamics of transcriptomes and translatomes, my analyses furthermore revealed that the widespread translational buffering more strongly preserved dosage-sensitive and, especially, housekeeping genes. I also found that translational upregulation acts to globally counterbalance the global dosage reduction that arose in the wake of mammalian sex chromosome differentiation; trans-lational buffering thus represents a novel mechanism for X chromosome dosage compensation.

In summary, my PhD thesis work revealed that fine-tuned translational buffering substantially stabilized gene expression levels during mammalian evolution.