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Phylogenetic analysis of mRNA polyadenylation sites reveals a role of transposable elements in evolution of the 3'-end of genes.

Lee JY, Ji Z, Tian B - Nucleic Acids Res. (2008)

Bottom Line: We found that the 3'-most poly(A) sites tend to be more conserved than upstream ones, whereas poly(A) sites located upstream of the 3'-most exon, also termed intronic poly(A) sites, tend to be much less conserved.We also found that nonconserved poly(A) sites are associated with transposable elements (TEs) to a much greater extent than conserved ones, albeit less frequently utilized.Our results establish a conservation pattern for alternative poly(A) sites in several vertebrate species, and indicate that the 3'-end of genes can be dynamically modified by TEs through evolution.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Biomedical Sciences and Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.

ABSTRACT
mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs, and is tightly coupled with termination of transcription in defining the 3'-end of genes. Large numbers of human and mouse genes harbor alternative polyadenylation sites [poly(A) sites] that lead to mRNA variants containing different 3'-untranslated regions (UTRs) and/or encoding distinct protein sequences. Here, we examined the conservation and divergence of different types of alternative poly(A) sites across human, mouse, rat and chicken. We found that the 3'-most poly(A) sites tend to be more conserved than upstream ones, whereas poly(A) sites located upstream of the 3'-most exon, also termed intronic poly(A) sites, tend to be much less conserved. Genes with longer evolutionary history are more likely to have alternative polyadenylation, suggesting gain of poly(A) sites through evolution. We also found that nonconserved poly(A) sites are associated with transposable elements (TEs) to a much greater extent than conserved ones, albeit less frequently utilized. Different classes of TEs have different characteristics in their association with poly(A) sites via exaptation of TE sequences into polyadenylation elements. Our results establish a conservation pattern for alternative poly(A) sites in several vertebrate species, and indicate that the 3'-end of genes can be dynamically modified by TEs through evolution.

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Conservation of human poly(A) sites in mouse, rat and chicken. (A) Percent of human poly(A) sites of different types that are conserved in mouse and rat. P-values (Chi-squared test) for difference in conservation between F and L types are 3.52 × 10−67 for human versus mouse, and 3.72 × 10−56 for human versus rat. Error bars are standard deviation. (B) Conservation of poly(A) site type between human and mouse orthologous poly(A) sites (P < 2.2 × 10−16, Chi-squared test). (C) Percent of human and mouse poly(A) sites conserved in chicken. P-values (Chi-squared test) for difference in conservation between F and L types are 1.34 × 10−16 for human versus chicken and 4.39 × 10−7 for mouse versus chicken. (D) Percent of genes with alternative poly(A) sites for genes with orthologs in chicken (named ‘old’, 8140 in total) and genes without orthologs in chicken (named ‘new’, 4284 in total). P-value (Chi-squared test) for the difference is 8.39 × 10−145.
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Figure 2: Conservation of human poly(A) sites in mouse, rat and chicken. (A) Percent of human poly(A) sites of different types that are conserved in mouse and rat. P-values (Chi-squared test) for difference in conservation between F and L types are 3.52 × 10−67 for human versus mouse, and 3.72 × 10−56 for human versus rat. Error bars are standard deviation. (B) Conservation of poly(A) site type between human and mouse orthologous poly(A) sites (P < 2.2 × 10−16, Chi-squared test). (C) Percent of human and mouse poly(A) sites conserved in chicken. P-values (Chi-squared test) for difference in conservation between F and L types are 1.34 × 10−16 for human versus chicken and 4.39 × 10−7 for mouse versus chicken. (D) Percent of genes with alternative poly(A) sites for genes with orthologs in chicken (named ‘old’, 8140 in total) and genes without orthologs in chicken (named ‘new’, 4284 in total). P-value (Chi-squared test) for the difference is 8.39 × 10−145.

Mentions: To understand how poly(A) sites have evolved, we mapped orthologous poly(A) sites using human, mouse, rat and chicken poly(A) sites and pair-wise genome alignments between these organisms (see Materials and Methods and Supplementary Figure 1 for detail). We focused on these aminotes because there are a large number of poly(A/T)-tailed cDNA/ESTs available for mapping poly(A) sites in their genomes and previous bioinformatic studies have indicated that the cis-element structure of poly(A) site is essentially the same across aminotes (17, Lee,J.Y. and Tian,B., unpublished data). Of 37 591 human sites, 11 255 (30%) were found to be conserved in mouse, 10 526 (28%) in rat and 922 (2%) in chicken. As shown in Figure 2A, human versus mouse and human versus rat conservation patterns are largely identical. The S type sites are the most conserved among all types, the L type sites are significantly more conserved than F or M type sites and intronic sites are the least conserved ones (Figure 2A). Of the intronic sites, H type sites are more conserved than C type sites. For conserved sites in 3′-most exons, conservation of poly(A) site type is statistically significant (P = 2.2 × 10−16, Chi-squared test, Figure 2B), despite that some human sites are mapped to a different type than their mouse orthologs and vice versa. The same conclusions can be drawn from analyses of mouse versus human and mouse versus rat sites (Supplementary Figure 2).Figure 2.


Phylogenetic analysis of mRNA polyadenylation sites reveals a role of transposable elements in evolution of the 3'-end of genes.

Lee JY, Ji Z, Tian B - Nucleic Acids Res. (2008)

Conservation of human poly(A) sites in mouse, rat and chicken. (A) Percent of human poly(A) sites of different types that are conserved in mouse and rat. P-values (Chi-squared test) for difference in conservation between F and L types are 3.52 × 10−67 for human versus mouse, and 3.72 × 10−56 for human versus rat. Error bars are standard deviation. (B) Conservation of poly(A) site type between human and mouse orthologous poly(A) sites (P < 2.2 × 10−16, Chi-squared test). (C) Percent of human and mouse poly(A) sites conserved in chicken. P-values (Chi-squared test) for difference in conservation between F and L types are 1.34 × 10−16 for human versus chicken and 4.39 × 10−7 for mouse versus chicken. (D) Percent of genes with alternative poly(A) sites for genes with orthologs in chicken (named ‘old’, 8140 in total) and genes without orthologs in chicken (named ‘new’, 4284 in total). P-value (Chi-squared test) for the difference is 8.39 × 10−145.
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Figure 2: Conservation of human poly(A) sites in mouse, rat and chicken. (A) Percent of human poly(A) sites of different types that are conserved in mouse and rat. P-values (Chi-squared test) for difference in conservation between F and L types are 3.52 × 10−67 for human versus mouse, and 3.72 × 10−56 for human versus rat. Error bars are standard deviation. (B) Conservation of poly(A) site type between human and mouse orthologous poly(A) sites (P < 2.2 × 10−16, Chi-squared test). (C) Percent of human and mouse poly(A) sites conserved in chicken. P-values (Chi-squared test) for difference in conservation between F and L types are 1.34 × 10−16 for human versus chicken and 4.39 × 10−7 for mouse versus chicken. (D) Percent of genes with alternative poly(A) sites for genes with orthologs in chicken (named ‘old’, 8140 in total) and genes without orthologs in chicken (named ‘new’, 4284 in total). P-value (Chi-squared test) for the difference is 8.39 × 10−145.
Mentions: To understand how poly(A) sites have evolved, we mapped orthologous poly(A) sites using human, mouse, rat and chicken poly(A) sites and pair-wise genome alignments between these organisms (see Materials and Methods and Supplementary Figure 1 for detail). We focused on these aminotes because there are a large number of poly(A/T)-tailed cDNA/ESTs available for mapping poly(A) sites in their genomes and previous bioinformatic studies have indicated that the cis-element structure of poly(A) site is essentially the same across aminotes (17, Lee,J.Y. and Tian,B., unpublished data). Of 37 591 human sites, 11 255 (30%) were found to be conserved in mouse, 10 526 (28%) in rat and 922 (2%) in chicken. As shown in Figure 2A, human versus mouse and human versus rat conservation patterns are largely identical. The S type sites are the most conserved among all types, the L type sites are significantly more conserved than F or M type sites and intronic sites are the least conserved ones (Figure 2A). Of the intronic sites, H type sites are more conserved than C type sites. For conserved sites in 3′-most exons, conservation of poly(A) site type is statistically significant (P = 2.2 × 10−16, Chi-squared test, Figure 2B), despite that some human sites are mapped to a different type than their mouse orthologs and vice versa. The same conclusions can be drawn from analyses of mouse versus human and mouse versus rat sites (Supplementary Figure 2).Figure 2.

Bottom Line: We found that the 3'-most poly(A) sites tend to be more conserved than upstream ones, whereas poly(A) sites located upstream of the 3'-most exon, also termed intronic poly(A) sites, tend to be much less conserved.We also found that nonconserved poly(A) sites are associated with transposable elements (TEs) to a much greater extent than conserved ones, albeit less frequently utilized.Our results establish a conservation pattern for alternative poly(A) sites in several vertebrate species, and indicate that the 3'-end of genes can be dynamically modified by TEs through evolution.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Biomedical Sciences and Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.

ABSTRACT
mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs, and is tightly coupled with termination of transcription in defining the 3'-end of genes. Large numbers of human and mouse genes harbor alternative polyadenylation sites [poly(A) sites] that lead to mRNA variants containing different 3'-untranslated regions (UTRs) and/or encoding distinct protein sequences. Here, we examined the conservation and divergence of different types of alternative poly(A) sites across human, mouse, rat and chicken. We found that the 3'-most poly(A) sites tend to be more conserved than upstream ones, whereas poly(A) sites located upstream of the 3'-most exon, also termed intronic poly(A) sites, tend to be much less conserved. Genes with longer evolutionary history are more likely to have alternative polyadenylation, suggesting gain of poly(A) sites through evolution. We also found that nonconserved poly(A) sites are associated with transposable elements (TEs) to a much greater extent than conserved ones, albeit less frequently utilized. Different classes of TEs have different characteristics in their association with poly(A) sites via exaptation of TE sequences into polyadenylation elements. Our results establish a conservation pattern for alternative poly(A) sites in several vertebrate species, and indicate that the 3'-end of genes can be dynamically modified by TEs through evolution.

Show MeSH