Qualifying the relationship between sequence conservation and molecular function

Cooper, Gregory M.; Brown, Christopher D.

doi:10.1101/gr.7205808

Cited by 99 publications

(72 citation statements)

References 53 publications

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“…Together, these data demonstrate that CREs with conserved nucleotide sequence are significantly more likely to have conserved regulatory activity and are associated with conserved gene expression, as previously suggested (Brown et al 2007;Cooper and Brown …”

Section: −16supporting

confidence: 78%

Transposable elements are the primary source of novelty in primate gene regulation

et al. 2017

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Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNAseq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome.

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Section: −16supporting

confidence: 78%

Transposable elements are the primary source of novelty in primate gene regulation

et al. 2017

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“…As mentioned previously, some neutral sites may appear to be constrained simply by chance (Cooper et al 2005;Eddy 2005), while other sites may have been functionally constrained during mammalian evolution but have more recently lost function in the human or ape lineages. Conversely, there are some functional sites in the genome that cannot be detected through comparative means, either because of limited alignment depth at these sites or because the function they perform is limited to a subset of the mammalian tree containing human (Cooper and Brown 2008). Nevertheless, by focusing on constrained sites one can obtain a set of SNVs that is highly enriched for functional variants.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary constraint facilitates interpretation of genetic variation in resequenced human genomes

Goode

Cooper²,

Schmutz³

et al. 2010

Genome Res.

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Here, we demonstrate how comparative sequence analysis facilitates genome-wide base-pair-level interpretation of individual genetic variation and address two questions of importance for human personal genomics: first, whether an individual's functional variation comes mostly from noncoding or coding polymorphisms; and, second, whether populationspecific or globally-present polymorphisms contribute more to functional variation in any given individual. Neither has been definitively answered by analyses of existing variation data because of a focus on coding polymorphisms, ascertainment biases in favor of common variation, and a lack of base-pair-level resolution for identifying functional variants. We resequenced 575 amplicons within 432 individuals at genomic sites enriched for evolutionary constraint and also analyzed variation within three published human genomes. We find that single-site measures of evolutionary constraint derived from mammalian multiple sequence alignments are strongly predictive of reductions in modern-day genetic diversity across a range of annotation categories and across the allele frequency spectrum from rare (<1%) to high frequency (>10% minor allele frequency). Furthermore, we show that putatively functional variation in an individual genome is dominated by polymorphisms that do not change protein sequence and that originate from our shared ancestral population and commonly segregate in human populations. These observations show that common, noncoding alleles contribute substantially to human phenotypes and that constraint-based analyses will be of value to identify phenotypically relevant variants in individual genomes.[Supplemental material is available online at http://www.genome.org. All sequences can be retrieved from the NCBI Trace Archive (http://www.ncbi.nlm.nih.gov/Traces/trace.cgi) using the search string CENTER_NAME = ''SHGC'' and SPE-CIES_CODE = ''HOMO SAPIENS' '.] As the sequencing of human genomes becomes routine, a growing challenge is how to assess the functional consequences of the genetic variation carried by a given individual. Of the >3 million variants present in any given human genome (Levy et al. 2007;Bentley et al. 2008;Wang et al. 2008;Kim et al. 2009;Mardis et al. 2009;McKernan et al. 2009), only a small fraction are expected to be phenotypically relevant (Kimura 1983;Ng et al. 2008;Mardis et al. 2009); among those that are, there is a great range in the degree to which they contribute to phenotype . Therefore, to fully leverage the benefits of genome-wide variation data, methods for detecting and evaluating functional variants across the entire genome are required, as is an improved understanding of the nature of functional human genetic variation.One strategy for identifying potentially important genetic variants is to focus on polymorphisms that fall into regions that have well-defined molecular functions, such as protein-coding exons. Several methods exist to estimate the impact of nonsynonymous changes on protein function, using data on the physicochem...

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“…At the same time, clusters of low-fidelity rare codons, which act as translation attenuation patterns, caused by ribosome pauses, are preserved across species, suggesting a concerted selective pressure on codon matching and species-specific tRNA abundance in these regions (7,8). In other words, to maintain protein function, from an evolutionary perspective it may be more critical to preserve translation attenuation patterns than to preserve amino acid sequences, a clear illustration of a noncoding functional sequence conservation (9). Several examples in prokaryotic and eukaryotic genomes suggest a critical role of rare codons in protein folding and function (2,7).…”

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confidence: 99%

Hepatitis A Virus Adaptation to Cellular Shutoff Is Driven by Dynamic Adjustments of Codon Usage and Results in the Selection of Populations with Altered Capsids

Costafreda

Pérez-Rodríguez

D’Andrea

et al. 2014

J Virol

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Hepatitis A virus (HAV) has a highly biased and deoptimized codon usage compared to the host cell and fails to inhibit host protein synthesis. It has been proposed that an optimal combination of abundant and rare codons controls the translation speed required for the correct capsid folding. The artificial shutoff host protein synthesis results in the selection of variants containing mutations in the HAV capsid coding region critical for folding, stability, and function. Here, we show that these capsid mutations resulted in changes in their antigenicity; in a reduced stability to high temperature, low pH, and biliary salts; and in an increased efficacy of cell entry. In conclusion, the adaptation to cellular shutoff resulted in the selection of large-plaque-producing virus populations. IMPORTANCEHAV has a naturally deoptimized codon usage with respect to that of its cell host and is unable to shut down the cellular translation. This fact contributes to the low replication rate of the virus, in addition to other factors such as the highly inefficient internal ribosome entry site (IRES), and explains the outstanding physical stability of this pathogen in the environment mediated by a folding-dependent highly cohesive capsid. Adaptation to artificially induced cellular transcription shutoff resulted in a redeoptimization of its capsid codon usage, instead of an optimization. These genomic changes are related to an overall change of capsid folding, which in turn induces changes in the cell entry process. Remarkably, the adaptation to cellular shutoff allowed the virus to significantly increase its RNA uncoating efficiency, resulting in the selection of large-plaque-producing populations. However, these populations produced much-debilitated virions.

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Qualifying the relationship between sequence conservation and molecular function

Cited by 99 publications

References 53 publications

Transposable elements are the primary source of novelty in primate gene regulation

Transposable elements are the primary source of novelty in primate gene regulation

Evolutionary constraint facilitates interpretation of genetic variation in resequenced human genomes

Hepatitis A Virus Adaptation to Cellular Shutoff Is Driven by Dynamic Adjustments of Codon Usage and Results in the Selection of Populations with Altered Capsids

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