Unitary Pseudogenes Have Function! Part 2
In part one of this two-part series, I discussed the context for an exciting discovery that demonstrates that unitary pseudogenes play a role in regulating gene expression—thus providing evidence in favor of design/creation models. In this installment, I will describe the work of the Oxford scientists who made the find and the implications for the creation-evolution debate.
Shout it from the rooftops! Researchers from Oxford University have discovered that unitary pseudogenes play a role in regulating gene expression. As I predicted in my book Who Was Adam?, if Reasons To Believe’s human origins model is correct, scientists would eventually find that unitary pseudogenes possess functional utility
Up until this discovery, evolutionary biologists maintained that identical (or nearly identical) unitary pseudogene sequences found in the human genome and in corresponding locations in genomes of the great apes provide compelling evidence that humans and chimpanzees must have evolved recently from a shared ancestor. Now the presence of shared unitary pseudogenes no longer demands an evolutionary interpretation. These pseudogenes can be understood as common design features.
Researchers from Oxford supplied one of the first tests of the competitive endogenous RNA hypothesis by examining unitary pseudogenes’ potential regulatory roles in rodents.1 These rodent pseudogenes have counterparts in the human genome, except the human genes are intact.
The team studied 48 regions that encode unitary pseudogenes. They demonstrated that the pseudogenes are transcribed even though the pseudogenes don’t produce functional proteins. In fact, the tissue profiles for the expression of these transcripts in rodents is comparable to that found in the corresponding human tissues.
The investigators determined that each unitary pseudogene is part of a distinct regulatory network of genes defined by shared microRNA response elements. They also learned that the gene expressions in the networks correlate with each other. This means that the transcripts in the networks are all functioning as molecular decoys for one another and that the unitary pseudogenes are vital components of the networks. When a unitary pseudogene is not transcribed, it causes the expression of other genes in the network to be downregulated. When it is transcribed, it causes the other genes in the network to be upregulated.
To fully appreciate the role that unitary pseudogenes play, some background information is in order.
Regulation of Gene Expression: Transcriptional Control
Gene expression refers to the process employed by the cell’s machinery to read the information harbored in DNA and to use it to make proteins. Some genes are expressed throughout the cell cycle. Biochemists call these housekeeping genes because they specify the production of proteins required for the life-essential biochemical activities that operate continually inside the cell. Other genes are expressed only at certain points in the cell cycle, when the proteins they specify are needed. When not required, these genes are turned off.
However, gene expression involves more than simply turning genes on and off. It also entails regulating the amount of proteins produced. That is, some genes are expressed at high levels and others at low levels. By way of analogy, gene expression can be thought of as both the on-off switch and volume control knob for each gene in the organism’s genome.
Traditionally, biochemists and molecular biologists believed that the primary mechanism for regulating gene expression involved controlling the frequency and amount of mRNA produced during transcription. In other words, mRNA is produced continually for housekeeping genes, while for genes that specify situational proteins it is produced only when needed. Along these lines, more mRNA is produced for highly expressed genes and limited amounts for genes expressed at low levels.
Researchers long thought that once the mRNA was produced, it would be translated into proteins—but recent discoveries indicate this is not the case. Instead, an elaborate mechanism exists that selectively degrades mRNA transcripts before they can be used to direct the production of proteins at the ribosome. This mechanism dictates the amount of protein produced by permitting or preventing mRNA from being translated. The selective degradation of mRNA plays a role in gene expression, functioning in a complementary manner to the transcriptional control of gene expression.
Regulation of Gene Expression: MicroRNAs and Post-Transcriptional Control
Another class of RNA molecules, called microRNAs, mediates the selective degradation of mRNA. In the early 2000s, biochemists recognized that by binding to mRNA (in the 3′ untranslated region of the transcript), these molecules play a crucial role in gene regulation. The binding of microRNAs to mRNA flags the mRNA for destruction by a protein complex called RNA-induced silencing complex (RISC).
There are a number of distinct microRNA species in the cell that bind to specific sites in the 3′ untranslated region of mRNA transcripts. (These binding locations are called microRNA response elements.) The selective binding by the population of microRNA molecules explains the role that duplicated pseudogenes play in regulating gene expression.
The sequence similarity between the duplicated pseudogene and the corresponding “intact” gene means that the same microRNAs will bind to both mRNA transcripts. (It is interesting to note that most duplicated pseudogenes are transcribed.) When microRNAs bind to the transcript of the duplicated pseudogene, it allows the transcript of the “intact” gene to escape degradation by RISC. To say it another way, the transcript of the duplicated pseudogene is serving as a molecular decoy, preventing the “intact” gene from being degraded. By eschewing degradation, the mRNA transcript can be translated and, hence, the “intact” gene is expressed.
The Competitive Endogenous RNA (ceRNA) Hypothesis
Insights into duplicated pseudogenes’ capability of regulating gene expression via a decoy mechanism prompted Pier Paolo Pandolfi and collaborators from Harvard University to propose the competitive endogenous RNA hypothesis in 2011.2 Pandolfi and his team also noted that it is not merely “intact” and duplicated pseudogenes that harbor the same microRNA response elements. A number of other genes share the same set of microRNA response elements in the 3′ untranslated region of the transcripts and, consequently, will bind the same set of microRNAs. These genes, in effect, are part of a network that, when transcribed, will influence the expression of all the genes in the network. This relationship means that all the mRNA transcripts in the network can function as decoys, binding microRNAs and allowing the other member genes of the network to be expressed.
One important consequence of this hypothesis is that mRNA has dual functions inside the cell:
- It encodes information needed to make proteins.
- It plays a role in regulating the expression of other transcripts that are part of its network, defined by microRNA response elements in the 3′ untranslated region of the transcript.
The ceRNA Hypothesis and the Case for Intelligent Design
It is remarkable to note that in the last decade biochemists and molecular biologists have come to recognize that all three classes of pseudogenes are functional. Processed pseudogenes code for functional proteins. Also, the function of both unitary and duplicated pseudogenes finds explanation in the competitive endogenous RNA hypothesis. These pseudogenes take part in gene regulatory networks along with intact genes by serving as molecular decoys, binding microRNAs, and permitting the translation of intact genes.
This important new insight means that shared pseudogenes in the genomes of humans and the great apes does not demand an evolutionary interpretation (shared ancestry). Instead, from a design/creation standpoint, one could maintain that the unitary and duplicated pseudogenes shared among the genomes of humans and the great apes reflect common design.
- Ana C. Marques et al., “Evidence for Conserved Post-Transcriptional Roles of Unitary Pseudogenes for Frequent Bifunctionality of mRNAs,” Genome Biology 13, no. 11 (2012): R102, doi:10.1186/gb-2012-13-11-r102.
- Ana C. Marques et al., “Wrangling for microRNAs Provokes Much Crosstalk,” Genome Biology 12, no. 11 (2011): 132; Leonardo Salmena et al., “A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language?” Cell 146 (August 5, 2011): 353–58.