Comprehensive analysis of the pseudogenes of glycolytic enzymes in vertebrates: the anomalously high number of GAPDH pseudogenes highlights a recent burst of retrotrans-positional activity
© Liu et al; licensee BioMed Central Ltd. 2009
Received: 25 March 2009
Accepted: 16 October 2009
Published: 16 October 2009
Pseudogenes provide a record of the molecular evolution of genes. As glycolysis is such a highly conserved and fundamental metabolic pathway, the pseudogenes of glycolytic enzymes comprise a standardized genomic measuring stick and an ideal platform for studying molecular evolution. One of the glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has already been noted to have one of the largest numbers of associated pseudogenes, among all proteins.
We assembled the first comprehensive catalog of the processed and duplicated pseudogenes of glycolytic enzymes in many vertebrate model-organism genomes, including human, chimpanzee, mouse, rat, chicken, zebrafish, pufferfish, fruitfly, and worm (available at http://pseudogene.org/glycolysis/). We found that glycolytic pseudogenes are predominantly processed, i.e. retrotransposed from the mRNA of their parent genes. Although each glycolytic enzyme plays a unique role, GAPDH has by far the most pseudogenes, perhaps reflecting its large number of non-glycolytic functions or its possession of a particularly retrotranspositionally active sub-sequence. Furthermore, the number of GAPDH pseudogenes varies significantly among the genomes we studied: none in zebrafish, pufferfish, fruitfly, and worm, 1 in chicken, 50 in chimpanzee, 62 in human, 331 in mouse, and 364 in rat. Next, we developed a simple method of identifying conserved syntenic blocks (consistently applicable to the wide range of organisms in the study) by using orthologous genes as anchors delimiting a conserved block between a pair of genomes. This approach showed that few glycolytic pseudogenes are shared between primate and rodent lineages. Finally, by estimating pseudogene ages using Kimura's two-parameter model of nucleotide substitution, we found evidence for bursts of retrotranspositional activity approximately 42, 36, and 26 million years ago in the human, mouse, and rat lineages, respectively.
Overall, we performed a consistent analysis of one group of pseudogenes across multiple genomes, finding evidence that most of them were created within the last 50 million years, subsequent to the divergence of rodent and primate lineages.
Pseudogenes are inheritable genomic sequences sharing large amounts of sequence similarity to genes but exhibit limited or altered functionality because of disablements. They occur in many prokaryotic and eukaryotic genomes [1–11], but the abundance of pseudogenes is specific to each species. Pseudogenes comprise a significant portion of mammalian genomes and can be found primarily in non-coding regions such as intergenic regions and introns. Because of the high level of sequence similarity shared with the parent genes, the genes from which they were mostly likely generated, it has been a difficult task to biochemically and computationally distinguish pseudogenes from genes. Resolving the functional differences between genes and pseudogenes in spite of their sequence similarity would increase our understanding of regulatory mechanisms that determine gene expression [12, 13].
Pseudogenes can be classified into two main types, processed and duplicated . Processed pseudogenes are generated via retrotransposition of the mRNA of their parent genes. After mRNAs of the parent genes are transcribed in the usual fashion by RNA polymerases, they are reverse transcribed and integrated into genomic DNA by reverse transcriptases and endonucleases encoded by long interspersed nuclear elements (LINEs) in primates and humans [14, 15, 5, 16, 17]. Because these pseudogenes are generated through mRNA intermediates, they are notable for their lack of introns, spliced out during mRNA maturation. On the other hand, duplicated pseudogenes are generated via direct DNA-to-DNA duplication followed by integration into genomic DNA and eventual disablement . They retain most of the exon-intron arrangements with possible duplication of upstream and downstream regions.
We have developed computational methods for cataloguing processed and duplicated pseudogenes [19, 3, 4, 20, 2]. First we identify pseudogene candidates by aligning the genome in all six frames of the translated amino acid sequences to the known proteins in the organism . Then we distinguish pseudogenes from their parent genes by identifying disablements such as insertions, deletions, and nonsense mutations, as these would interfere with the potential transcription and translation of the pseudogenes into a fully functional protein.
Because pseudogenes are released from the pressures of natural selection, they capture the sequences of genes at points in time and are subsequently subject to mutations at a neutral rate . Understanding the subtleties of pseudogenes that effect their inactivation would aid in predicting genes de novo from genome sequences [23–25]. In addition to their passive role as genetic fossils, the functional roles of pseudogenes are still being characterized. Pseudogenes have been found to interact with the mRNA of their parent gene [26–28]. Some pseudogenes have also been implicated in chromosomal recombination and gene conversion events leading to diseases because of high sequence homology to their parent genes [7, 29]. Others have been reactivated and become fully expressed variants of their parent genes .
In order to characterize the factors influencing the generation of pseudogenes, it is useful to study a selected set of genes that are common to multiple species and have many associated pseudogenes . We identified such a set that encodes the enzymes in glycolysis, a fundamental metabolic pathway conserved since ancient anaerobic prokaryotes. Using our pseudogene pipeline, we assembled the first detailed catalog of the processed and duplicated pseudogenes of glycolytic enzymes in the well-annotated eukaryotic genomes: human, chimpanzee, mouse, rat, chicken, zebrafish, pufferfish, fruitfly, and worm genomes [20, 31–39]. By comparing pseudogenes of orthologous genes in multiple genomes, we are able to identify general characteristics as well as species-specific characteristics. The dates of species divergence can be used as landmarks in the temporal evolution of the glycolytic pseudogenes.
From this analysis, we found that the number of processed and duplicated pseudogenes of GAPDH, as well as its spermatogenic isozyme, far exceeded the numbers of other glycolytic pseudogenes, and for this reason, most of the present work focuses on GAPDH specifically. In order to look for an evolutionary explanation for the large number of GAPDH pseudogenes, we matched orthologous regions by extensive synteny analysis, using genomes that had sufficiently complete and intact annotations and significant numbers of GAPDH pseudogenes, namely the human, mouse, and rat genomes. After considering various methods that aligned large genomic segments by nucleotide sequences , we decided to align the genomes using orthologous genes as anchors. Then, after applying Kimura's two-parameter model for neutral evolution , we calculated a burst in retrotranspositional activity dating to about 26 million years ago. This relative recentness is consistent with the low numbers of GAPDH pseudgenes syntenic between the primate and rodent lineages. Our study documents a careful analysis of a group of pseudogenes in multiple organisms, contrasting against recent studies devoted to draft pseudogene annotation of individual genomes and attempting to date the burst in retrotransposition [28, 42].
Genomic sequences and annotated genes
The human (Homo sapiens) NCBI 35 assembly, the chimpanzee (Pan troglodytes) 4× shotgun assembly released on November 13th 2003 from the Chimpanzee Sequencing Consortium, the mouse (Mus musculus) NCBI m34 assembly, the rat (Rattus norvegicus) assembly version 3.4 November 2004 update from the Rat Genome Project, and the chicken (Gallus gallus) first draft assembly were downloaded from ENSEMBL release 33. The zebrafish (Danio rerio) assembly version 7 (Zv7) released on 13 July 2007, the pufferfish (Tetraodon nigroviridis) assembly version 7, the fruitfly (Drosophila melanogaster) BDGP assembly release 5, and worm (Caenorhabditis elegans) WormBase 180 frozen database were downloaded from ENSEMBL release 49. Gene annotations, their intron and exon positions, and their protein sequences were also obtained from ENSEMBL. The segmental duplications for the human NCBI 35 assembly were obtained from http://eichlerlab.gs.washington.edu/database.html.
Computer programs were written in Perl and GNU Bash to collect and process data. The Perl API provided by ENSEMBL was used to query releases 33, 36, and 49 of its genome databases.
We used a pseudogene pipeline containing separate routines to identify processed and duplicated pseudogenes. The pipeline had been tested on large parts of the human genome [3, 4, 28, 20, 43]. On one hand, protein sequences were used to query each genome for processed pseudogenes. Minimal thresholds for identifying processed pseudogenes were optimized at 40% sequence identity and 70% alignment without an insertion longer than 60 nucleotides. Pseudogene candidates that did not meet the second criterion were considered pseudogene fragments. On the other hand, nucleotide sequences spanning a parent gene's exons with 50-nucleotide extensions in both 5' and 3' directions were used to query each genome for duplicated pseudogenes. Repetitive sequences and exons were masked in all candidate matches for processed and duplicated pseudgenes. Please see the methods section of Zheng and Gerstein (2006) for thorough specifications of the pseudogene pipeline .
To examine the sensitivity of the pseudogene pipeline, we varied both the percent identity and e-value threshold used for the identification of the pseudogenes in the mouse genome. The total number of pseudogenes varied from 16,963 to 15,884 while the degree of similarity to the parent protein was incremented from 25% to 50%, which constituted a dramatic range. This showed that the number of pseudogenes did not change significantly with the sequence identity parameter, about 40 pseudogenes per 1% increase in sequence similarity. We used an identity threshold of 40%, which yielded 16,730 pseudogenes. We performed similar sensitivity analyses for other parameters and present those results in Additional File 1.
Total Nucleotides Aligned
human ⇔ mouse
human ⇔ rat
mouse ⇔ rat
Kimura model parameters
7.15 × 10-4
4.90 × 10-4
7.28 × 10-4
8.02 × 10-4
2.75 × 10-4
1.17 × 10-4
1.81 × 10-4
3.77 × 10-4
1.84 × 10-3
1.20 × 10-3
1.94 × 10-3
2.06 × 10-3
5.22 × 10-4
4.14 × 10-4
3.83 × 10-4
6.24 × 10-4
where α is taken to be the averaged transition rate for genes and pseudogenes and β is taken to be the averaged transversion rate for genes and pseudogenes.
in order to accomodate the nucelotide substitution rates in the common ancestor of mouse and rat.
In these calculations, we derive different rates of nucleotide substitution in genes and pseudogenes because genes are subject to pressures of natural selection whereas pseudogenes are not. Although Kimura's model assumes neutral rates of nucleotide substitutions, we use it as an approximation of the mutation rates of the GAPDH genes for the sake of consistency, perhaps yielding conservative estimates or upper bounds on the ages of pseudogenes.
Evolutionary analysis with synteny and mutation
Number of syntenic pseudogene pairs
Number of Syntenic Pseudogene Pairs
human ⇔ chimp
human ⇔ mouse
human ⇔ rat
mouse ⇔ rat
As a central pathway in metabolism, glycolysis has been highly conserved across multiple species from archaea to humans. The omnipresence of the glycolytic enzymes makes for a crude but standardized genomic measuring stick, comprising an ideal platform for studying pseudogenes.
Despite the high degree of conservation in the glycolytic enzymes, there is much more variation in their pseudogene abundances. Some genomes, like chicken, zebrafish, pufferfish, fruitfly, and worm, have very few or none, while others, like mouse and rat, have hundreds. The differences in pseudogene abundances alone suggests significant differences in the processes of gene expression, duplication, and retrotransposition in the different genomes. Previous studies have suggested that the difference lies in the prolonged lampbrush stage of oogenesis in mammalians as compared to non-mammalian organisms [48, 49].
As a coincident finding, GAPDH has many more biological roles outside glycolysis as compared to the other glycolytic enzymes. For example, GAPDH functions in DNA repair, telomeric DNA binding, transcriptional regulation, nuclear RNA export, apoptosis, membrane fusion, phosphorylation, tubulin bundling, and sperm motility [53–59]. Because the molecular processes of retrotransposition are separate from the enzymatic functionalities, we can only speculate that the preponderance of non-glycolytic roles may be correlated to the enrichment of GAPDH pseudogenes.
In an intergenomic analysis, GAPDH pseudogenes have about five- to six-fold greater abundance in the rodent genomes as in the primate genomes even though overall the mouse genome was found to have about half as many pseudogenes as the human genome . The mouse genome has higher rates of nucleotide substitution, insertion, and deletion  than the human genome, leading to a higher rate of pseudogene decay. However, the higher rate of pseudogene decay seems to have preferentially spared the GAPDH pseudogenes.
To further characterize the molecular history of pseudogenes in the human, chimpanzee, mouse, and rat genomes, it was necessary to identify the pseudogenes that were most likely present prior to the primate-rodent ancestral divergence. We used orthologous genes to identify regions of synteny between primate-rodent genome pairs. This approach is based on the assumption that gene-coding regions are much less variable than intergenic regions because of functional constraints and are therefore more reliably matched between genome pairs.
The scarcity of GAPDH pseudogenes syntenic between the primate and rodent genomes suggests an increase in retrotranspositional activity after the primate-rodent divergence 91 million years ago, which is consistent with the findings of previous investigators . In order to achieve more detail in the timeline and provide further corroboration, we used Kimura's two-parameter model of nucleotide substitution to estimate the rates of change in the GAPDH genes and pseudogenes and thereby calculate the insertion date of each pseudogene. The creation dates formed three distinct distributions centered at 42.0, 36.3, and 25.9 million years ago in the human, mouse, and rat genomes, respectively, signifying a burst in retrotranspositional activity around those times. Kimura's model assumes neutrally evolving sequences, as in many pseudogenes , but some may initially be subject to natural selection  and the ages of these pseudogenes may be underestimated. In the human genome, the bursts in retrotranspositional activity may coincide with the "Alu burst" that occurred about 40 million years ago in primate genomes [60, 1, 5, 61]. By examining the sensitivity of our pseudogene pipeline, as decribed under Methods, we found that the number of pseudogenes does not vary significantly with the threshold for sequence identity or BLAST score when compared to the parent gene. Thus, we believe this dating method accurately reflects all GAPDH pseudogenes and is not significantly biased towards longer and therefore younger pseudogenes.
The ubiquitous nature of glycolytic enzymes rendered their pseudogenes most appropriate for comparing retrotransposition among multiple genomes. There was no evidence for preferential distribution of GAPDH pseudogenes in relation to individual chromosomes and to the location of the parent genes. We were able to calculate synteny using orthologous genes as anchors between two genomes. Whereas retrotransposition and gene annotation have been previously characterized on an individual genome basis, our syntenic method allowed us to perform a careful analysis of one pseudogene family across multiple genomes. This and a molecular clock analysis indicated that three distinct bursts in the insertion of GAPDH pseudogenes occurred at approximately 42, 36, and 26 million years ago in the human, mouse, and rat genomes, respectively, with evidence that most were created within the last 50 million years, subsequent to the divergence of rodent and primate lineages.
We would like to acknowledge financial support from grants from the NIH and from the Yale University School of Medicine Summer Research Grant. The authors would also like to acknowledge Rajkumar Sasidharan and Hugo Lam for helpful discussion.
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