The evolution of gene expression levels in mammalian organs

Journal name:
Nature
Volume:
478,
Pages:
343–348
Date published:
DOI:
doi:10.1038/nature10532
Received
Accepted
Published online

Abstract

Changes in gene expression are thought to underlie many of the phenotypic differences between species. However, large-scale analyses of gene expression evolution were until recently prevented by technological limitations. Here we report the sequencing of polyadenylated RNA from six organs across ten species that represent all major mammalian lineages (placentals, marsupials and monotremes) and birds (the evolutionary outgroup), with the goal of understanding the dynamics of mammalian transcriptome evolution. We show that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation. Although gene expression evolution in mammals was strongly shaped by purifying selection, we identify numerous potentially selectively driven expression switches, which occurred at different rates across lineages and tissues and which probably contributed to the specific organ biology of various mammals.

At a glance

Figures

  1. Global patterns of gene expression differences among mammals.
    Figure 1: Global patterns of gene expression differences among mammals.

    a, Factorial map of the principal-component analysis of messenger RNA expression levels. The proportion of the variance explained by the principal components is indicated in parentheses. b, Mammalian gene expression phylogenies. Neighbour-joining trees based on pairwise distance matrices (1ρ, Spearman’s correlation coefficient) for cerebellum and testis (see Supplementary Fig. 2 for all six organs). Bootstrap values (5,636 1:1 orthologous amniote genes were randomly sampled with replacement 1,000 times) are indicated by circles: white, >0.9; yellow, ≤0.9. Species colour codes: platypus, light blue; opossum, dark blue; eutherians (mice and primates), black.

  2. Expression divergence rates across tissues and chromosomes.
    Figure 2: Expression divergence rates across tissues and chromosomes.

    a, Comparisons of total branch lengths of expression trees among the six tissues (br, brain; cb, cerebellum; ht, heart; kd, kidney; lv, liver; ts, testis), for the all-amniote and primate data sets. Errors, 95% confidence intervals based on bootstrapping analysis (1,000 replicates, with one individual per species sampled in each replicate). b, Spearman’s correlations between humans and the other species. Coloured envelopes show ranges of values obtained in 100 bootstrap replicates. c, Expression evolution rates on therian X chromosome versus autosomes. Rectangles reflect median branch lengths (1,000 bootstrap replicates) in X-chromosome expression trees (102 1:1 orthologues located in the X-chromosome conserved region34; red) relative to those in autosome trees (5,494 autosomal orthologues; white). P values are based on bootstrap replicates: an asterisk indicates two-tailed P<0.05 (that is, branch longer in X-chromosome tree in more than 97.5% of replicates) and a plus sign indicates P<0.1.

  3. Lineage-specific expression shifts of transcription modules and individual genes.
    Figure 3: Lineage-specific expression shifts of transcription modules and individual genes.

    a, Modules with specific expression states in human brain (prefrontal cortex; 259 genes) and primate cerebellum (189 genes) are shown. Bars represent the weighted average expression of all genes in a module, for each sample (horizontal grey line indicates average bar height). The horizontal red line represents the cut-off of the biclustering algorithm; samples above the red line are considered to have a distinct expression state. See Supplementary Note and our searchable database (http://www.unil.ch/cbg/ISA/species) for details. b, Examples of genes that evolved new optimal expression levels in human prefrontal cortex (LIX1; ENSG00000145721), primate cortex (COL25A1; ENSG00000188517) and platypus cerebellum (TRMT1L; ENSG00000121486). Expression levels are indicated as log2-transformed RPKM (reads per kilobase of exon model per million mapped reads) (see Supplementary Tables 11–26 for details). Errors, range of expression values for the different individuals for a given species or tissue.

Accession codes

Primary accessions

Gene Expression Omnibus

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Author information

  1. These authors contributed equally to this work.

    • David Brawand,
    • Magali Soumillon &
    • Anamaria Necsulea

Affiliations

  1. Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland

    • David Brawand,
    • Magali Soumillon,
    • Anamaria Necsulea,
    • Philippe Julien,
    • Manuela Weier,
    • Angélica Liechti &
    • Henrik Kaessmann
  2. Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland

    • David Brawand,
    • Magali Soumillon,
    • Anamaria Necsulea,
    • Philippe Julien,
    • Gábor Csárdi,
    • Sven Bergmann &
    • Henrik Kaessmann
  3. Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland

    • Gábor Csárdi &
    • Sven Bergmann
  4. Department of Integrative Biology, University of California, Berkeley, California 94720, USA

    • Patrick Harrigan &
    • Rasmus Nielsen
  5. Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany

    • Ayinuer Aximu-Petri,
    • Martin Kircher,
    • Frank W. Albert &
    • Svante Pääbo
  6. Chair of Systematic Zoology, Humboldt-University, 10099 Berlin, Germany

    • Ulrich Zeller
  7. CAS-MPG Partner Institute for Computational Biology, 200031 Shanghai, China

    • Philipp Khaitovich
  8. The Robinson Institute, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia

    • Frank Grützner
  9. The Bioinformatics Center, University of Copenhagen, 2200 Copenhagen, Denmark

    • Rasmus Nielsen
  10. Present address: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA.

    • Frank W. Albert

Contributions

D.B., G.C., H.K., A.N. and P.H. performed biological data analyses. M.S. organized the RNA-seq data production. D.B. and A.N. processed and mapped the reads. A.N. refined genome annotations and established definitions and alignments of constitutive exons. M.S., A.L., F.W.A. and A.A.-P. prepared samples and generated RNA-seq libraries. M.W. prepared samples. P.J. contributed ideas regarding data analyses. F.W.A. coordinated ape RNA-seq data production. M.K. processed ape RNA-seq data. U.Z. extracted and organized Monodelphis domestica samples and advised on this species’ biology. P.K. organized Macaca mulatta samples and provided general advice on gene expression evolution. F.G. organized and extracted platypus RNA samples and advised on this species’ biology. P.H. developed the gene expression selection method and performed all corresponding analyses under the guidance of R.N. G.C. performed analyses using the iterative signature algorithm under the guidance of S.B. S.P. guided ape RNA-seq data production and processing. The project was supervised and originally designed by H.K. The paper was written by H.K. with input from all authors.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Sequencing data have been deposited in the Gene Expression Omnibus under accession code GSE30352.

Author details

Supplementary information

PDF files

  1. Supplementary Figures (614K)

    This file contains Supplementary Figures 1-9 with legends.

  2. Supplementary Information (1.6M)

    This file contains Supplementary Notes, which include Supplementary Methods, Supplementary Results and a Supplementary Discussion; Supplementary Tables 1-12, Supplementary Figures 1-27 with legends and additional references.

Zip files

  1. Supplementary Tables (2.8M)

    This zipped file contains 5 Supplementary Tables files as follows: Supplementary Tables 1-2 provide detailed information about all samples used in the study; Supplementary Table 3 provides examples of genes with sex-biased expression in various amniote species; Supplementary Tables 4-10 provide detailed data and overviews regarding transcription modules in the all-amniote and primate-specific datasets; Supplementary Tables 11-26 describe all statistically significant expression shifts of individual genes that occurred in the different amniote/primate lineages and Supplementary Tables 27-42 show the most overrepresented GO biological processes among lineage-specific expression changes of individual genes.

  2. Supplementary Data 1 (15.7M)

    This file provides all normalized expression values for all-amniote and primate-specific sets of orthologs.

  3. Supplementary Data 2 (23.7M)

    This file provides all normalized expression values for all-amniote and primate-specific sets of orthologs.

Additional data