RNA sequencing yields new insights into the regulation and evolution of gene expression

A large-scale study conducted by molecular biologists from Heidelberg University has yielded groundbreaking new insights into the evolution and regulation of gene expression in mammalian organs. The scientists investigated RNA synthesis and subsequent protein synthesis in the organs of humans and other representative mammals, and with the aid of sequencing technologies, they analysed more than 100 billion gene expression fragments from various organs. They were able to demonstrate that the finely tuned interplay of the two synthesis processes during evolution was crucial for shaping organ functions.

A complex interplay of activity between a large number of genes – known as gene expression – underlies organ functions.

“Until now, our understanding of these essential genetic programmes in mammals was limited to the first layer of gene expression – the production of messenger RNAs,” explains Prof. Dr Henrik Kaessmann, group leader of the “Functional evolution of mammalian genomes” research team at the Center for Molecular Biology of Heidelberg University (ZMBH). “The next layer – the actual synthesis of proteins at the ribosome through the translation of the messenger RNAs – remained largely unknown.”

It is this second synthesis process that the Heidelberg researchers have now studied more closely. Using so-called next-generation sequencing technologies, they analysed the gene expression of various organs on both layers. They studied the brain, liver and testes from humans and other selected mammals, including rhesus monkeys, mice, opossum and platypus.

“On the basis of these data, we could jointly investigate both gene expression layers and compare them across mammalian organs using state-of-the-art bioinformatics approaches,” explains Dr Evgeny Leushkin of the ZMBH.

In their large-scale study, the ZMBH researchers showed that the finely tuned interplay of the two synthesis processes during evolution was critical for shaping organ functions. For the first time, they were able to show that – in addition to regulation of messenger RNA production – other regulatory mechanisms at the layer of translation are crucial for optimising the amount of protein produced in all organs. This is especially true in the testes, where translational regulation is key for sperm development. Another important finding concerns mutational changes in gene expression regulation that arose during evolution. These changes were often balanced between the two layers. Changes that offset one another were primarily maintained to ensure the production of consistent amounts of protein.

Evolution of gene expression across expression layers

Fig. 2

ac, Gene-expression phylogenies of 5,060 robustly expressed (FPKM > 1 across all libraries) 1:1 orthologues at the transcriptome (light and thick branches) and translatome (dark and thin branches) layers for brain (a), liver (b) and testis (c). Branch lengths represent the fractions of expression variation, which correspond to evolutionary changes in expression levels. Owing to the lack of a biological replicate, the branch leading to human was omitted in the liver phylogeny for the transcriptome layer. Proportions of bootstrapped trees that support branching patterns are indicated next to the respective nodes. df, Differences in evolution between transcriptome and translatome layers for individual genes in brain (d), liver (e) and testis (f). The gene-expression (log2(FPKM + 1)) values are based on RNA-seq. The density distribution, median Δ, IQR of Δ and number of cases with Δ significantly higher (potentially driven by directional selection) or lower (stabilizing selection) than zero are shown to the right. All genes in graphs df can be interactively explored in our Ex2plorer database (https://ex2plorer.kaessmannlab.org/). g, Similarity of gene-expression (rank) changes between human and mouse brains at the proteome layer compared to the changes at the underlying translatome and transcriptome expression layers, respectively, as assessed by Spearman’s correlation coefficients (ρ). Proteomics data were retrieved from previous studies. Organ and species icons are from a previous study.

Source – Heidelberg University

Wang ZY, Leushkin E, Liechti A, Ovchinnikova S, Mößinger K, Brüning T, Rummel C, Grützner F, Cardoso-Moreira M, Janich P, Gatfield D, Diagouraga B, de Massy B, Gill ME, Peters AHFM, Anders S, Kaessmann H. (2020) Transcriptome and translatome co-evolution in mammals. Nature [Epub ahead of print]. [abstract]

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