Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression | Flicek Lab | Institute for Systems Genomics

C Berthelot, D Villar, JE Horvath, DT Odom, P Flicek. Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression. Nat Ecol Evol 2018;2(1):152–163. doi:10.1038/s41559-017-0377-2
[BibTeX] [Abstract]

To gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from 15 species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilize gene expression. In contrast, recently evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and are robust to potential confounders, such as the gene expression level. Using liver as a representative somatic tissue, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.

@Article{29180706,
author = {Berthelot C and Villar D and Horvath JE and Odom DT and Flicek P},
title = {Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression},
journal = {Nat Ecol Evol},
volume = {2},
number = {1},
pages = {152--163},
year = {2018},
doi = {10.1038/s41559-017-0377-2},
howpublished = {Advanced online publication: 27 November 2017},
note = {First posted as a preprint: 7 April 2017},
abstract = {To gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from 15 species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilize gene expression. In contrast, recently evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and are robust to potential confounders, such as the gene expression level. Using liver as a representative somatic tissue, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.},}

Description

To gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from fifteen species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilise gene expression. In contrast, recently-evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and robust to potential confounders, such as gene expression level. Using liver as a representative somatic tissue, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.

Full details are available in our paper published in Nature Ecology and Evolution with full text freely available at EuropePMC .

Raw Data

The raw RNA-seq data from livers of 25 mammalian species can be found in ArrayExpress with the accession number E-MTAB-4550 , with the exception of three human and four mouse datasets, previously reported in E-MTAB-4052 .

The processed RNA-seq datasets are also available from ArrayExpress with E-MTAB-4550 (after read alignment with TopHat2 and transcript quantifications with Cufflinks – please refer to Methods in the bioRxiv preprint ).

Average gene expression levels per species

The gene expression summaries for all replicates in each species are accessible here . Expression levels are provided both as FPKM (as output by Cufflinks) and after TPM transform for each replicate.

Promoter and enhancer datasets

Please refer to the companion webpage for Villar et al. 2015 for the raw datasets, consensus ChIP-seq peaks and evolutionary conservation analyses.

Putative target genes of the active promoters and enhancers in each species are accessible here (please refer to the Methods in the bioRxiv preprint for details on the putative target assignation).

Gene expression levels across species

The set of orthologous genes used in this study is accessible here .

The table comparing normalized average expression levels across species is accessible here .
This table additionally includes the following information:

orthtype	Whether the gene is a strict 1-to-1 ortholog across all study species (0=no, 1=yes)
meanexp	Mean expression across species
stdexp	Standard deviation of expression across species
cvexp	Coefficient of variation across species
core	Whether the gene is a core liver gene (0=no, 1=yes)
hk	Whether the gene is a housekeeping gene (0=no, 1=yes)
cvstab	Whether the gene was classified as stable, variable, not expressed or unmatched (see Methods).

Meta-genes and their regulatory landscapes

The integrated summary of the regulatory landscape over 20 species (meta-promoters and meta-enhancers) is accessible here .
Important: This file is an overview of cross-alignable regulatory regions based on whole-genome alignments, and their putative target genes. It was designed to investigate global trends (rather than individual loci) and may be locally affected by alignment anomalies. Please pay careful attention to the ‘flag’ column (see below) if interested in specific loci.

This table includes the following information:

id	The species identifiers of the active regulatory elements that form the meta-element
activeAll	Number of species where the meta-element is active (out of all twenty)
activeRefs	Number of reference species where the meta-element is active (out of ten reference species)
sequenceFound	Number of reference species with an identifiable orthologous sequence (out of ten reference species)
averageLength	Average length of the meta-element across the species where it is active
gene	Putative target gene (Ensembl human Gene ID)
flag	“Warning” indicates instances of regulatory elements that are included in the meta-element by sequence alignment, but are not in the vicinity of the putative target gene. Most of the time this is due to assembly fragmentation – but in some instances this may result from erroneous alignment of paralogous sequences. For these cases, the species identifiers of affected regulatory elements are given (e.g. Warning: sarHarH3K4me33870).
type	Whether the meta-element is annotated as a promoter or an enhancer, based on its histone marking across species