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Comparative Study
. 2013 Dec;19(12):1693-702.
doi: 10.1261/rna.039206.113. Epub 2013 Oct 23.

Evolutionary and ontogenetic changes in RNA editing in human, chimpanzee, and macaque brains

Zhongshan Li, Hindrike Bammann, Mingshuang Li, Hongyu Liang, Zheng Yan, Yi-Ping Phoebe Chen, Min Zhao, Philipp Khaitovich
Comparative Study

Evolutionary and ontogenetic changes in RNA editing in human, chimpanzee, and macaque brains

Zhongshan Li et al. RNA. 2013 Dec.

Abstract

Adenosine-to-inosine (A-to-I) substitutions are the most common type of RNA editing in mammals. A-to-I RNA editing is particularly widespread in the brain and is known to play important roles in neuronal functions. In this study we investigated RNA-editing changes during human brain development and maturation, as well as evolutionary conservation of RNA-editing patterns across primates. We used high-throughput transcriptome sequencing (RNA-seq) to quantify the RNA-editing levels and assess ontogenetic dynamics of RNA editing at more than 8000 previously annotated exonic A-to-I RNA-editing sites in two brain regions--prefrontal cortex and cerebellum--of humans, chimpanzees, and rhesus macaques. We observed substantial conservation of RNA-editing levels between the brain regions, as well as among the three primate species. Evolutionary changes in RNA editing were nonetheless evident, with 40% of the annotated editing sites studied showing divergent editing levels among the three species and 16.5% of sites displaying statistically significant human-specific editing patterns. Across lifespan, we observed an increase of the RNA-editing level with advanced age in both brain regions of all three primate species.

Keywords: RNA editing; aging; brain; chimpanzee; evolution; human.

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Figures

FIGURE 1.
FIGURE 1.
Characteristics of A-to-I RNA editing at DARNED sites in the PFC and CBC of humans, chimpanzees, and rhesus macaques. (A) Comparison of the A-to-G and non-A-to-G (A-to-C and A-to-T) substitution frequencies between DARNED sites and neighboring non-DARNED sites located within 1000 bp on the same genome strand. Shown are nucleotide substitution ratios between DARNED and neighboring non-DARNED sites for A-to-G substitutions (empty boxes) and non-A-to-G substitutions hatched boxes). The colors represent species, and shades of colors represent brain regions. The variance of nucleotide substitution ratio estimates was obtained by bootstrapping over genomic sites 1000 times. (B) Editing level correlation between samples. Shown are Pearson correlation coefficients (Pearson C.C) of RNA-editing level between samples representing biological replicates sharing the same species, age, and brain region (Dup), samples representing different age groups for the same brain region of the same species (Age), samples representing different brain regions for the same age group of the same species (Region), and human-chimpanzee (Hu-Ch), human-rhesus macaque (Hu-Ma), and chimpanzee-rhesus macaque (Ch-Ma) comparisons conducted within the same brain region and the same age group. This analysis is based on 162 DARNED sites with sufficient sequence read coverage (greater or equal to five reads) in all samples and showing detectable A-to-I RNA editing in at least one sample. (C) Proportion of DARNED sites with detectable A-to-I RNA editing. The bar represents the mean proportion of A-to-I edited sites among all DARNED sites with sufficient sequence read coverage. The error bars show 95% confidence intervals obtained by bootstrapping over genomic sites 1000 times. The colors represent species, and shades of colors represent brain regions. (D) Overlap of DARNED sites with detectable A-to-I RNA editing between humans and chimpanzees in CBC and PFC. The height of colored bars represents numbers of edited sites identified in each sample. The colors represent species, and shades of colors the brain regions. Comparisons were conducted between all human and chimpanzee individuals within the same brain region and age group (NB, newborns; AD, adults). Comparisons involving younger and older human samples within the same age group are distinguished by numbers (NB1 or AD1, younger human samples; NB2 or AD2, older human samples). Extended white parts of chimpanzee bars represent edited sites specific to chimpanzees that might have been lost in the analysis, assuming that chimpanzees and humans have equal numbers of species-specific edited sites. The dashed lines show the overlap of detected edited sites between a human and a chimpanzee sample. The numbers show overlap proportions. The proportions calculated, including assumed chimpanzee-specific editing (white part of the bar), are shown in parentheses. The black part shows the overlap expected by chance, calculated in 1000 permutations of editing status labels (edited or non-edited) among detected DARNED sites, and assuming that chimpanzees have as many edited sites as humans (colored and white part of the bar combined). The red stars above bars indicate overlap significance; (***) permutation P< 0.001. (E) Overlap of DARNED sites with detectable A-to-I RNA editing between CBC and PFC samples from the same human individual. Colors and bars are as in D.
FIGURE 2.
FIGURE 2.
Editing level variation among species and brain regions. (A) PCA and (B) the UPGMA tree based on A-to-I RNA-editing levels across all samples (refer to Materials and Methods for detail). Each diamond represents a sample. The diamond size is proportional to the median age of individuals within the sample. The colors represent species: brown, humans; blue, chimpanzees; and green, rhesus macaques. The shades of color represent brain regions: dark, CBC; light, PFC. This analysis is based on 162 DARNED sites with sufficient sequence read coverage in all samples and showing detectable A-to-I RNA editing in at least one sample. (C) Examples of DARNED sites showing significant human-specific A-to-I RNA editing-level changes. Each diamond represents a sample. The color scheme is the same as in panels A and B. Different species samples are located separately on the x-axis (H, human; C, chimpanzee; and M, rhesus macaque). The eight sites shown correspond to the following genomic locations based on the hg19 human genome assembly: chr2:201842479, chr2:128950497, chr1:204521712, chr1:6282587, chr5:115165632, chr9:136229572, chr5:156904785, and chr7:44917278 (sites 1 to 8, respectively). (D,E) Validation A-to-I RNA-editing level differences among species at two DARNED sites using conventional sequencing. Shown are A-to-I RNA-editing levels estimated using RNA-seq (left panels) and conventional sequencing (cDNA, central panels), as well as genomic DNA sequences determined using conventional sequencing (gDNA, right panels). RNA-seq data represented in the same way as in panel C. Conventional sequencing results are represented by the chromatogram traces from three individuals of each species—humans (Hu), chimpanzees (Ch), and rhesus macaques (Ma)—at two DARNED sites: chr12:5021742 (KCNA1 gene) showing editing level difference in the CBC and chr19:58372069 (ZNF587 gene) showing editing level difference in the PFC.
FIGURE 3.
FIGURE 3.
Age-related A-to-I RNA-editing level changes. (A) Linear regression trajectories based on A-to-I RNA-editing levels in human brain samples at 29 DARNED sites showing significant editing level changes with age with amplitude >10% (GLM, P< 0.05). Editing level increases with age are shown in red and decreases in blue. (B) Correlation between DNA sequence conservation and significance of the age-related A-to-I RNA-editing change calculated across 388 DARNED sites with sufficient sequence read coverage across human samples. The significance estimates were binned into 30 intervals based on their ANOVA F-statistics values. Higher age effect rank corresponds to higher F-statistics values. Higher phastCons scores represent higher DNA sequence conservation (refer to Materials and Methods for detail). (C) Numbers of DARNED sites showing significant age-related editing level changes with amplitude >10% in each species (GLM, P< 0.05). Editing level increases with age are shown in red and decreases in blue.
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