Competitive Endogenous RNA Hypothesis Supports the Case for Creation

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BY FAZALE RANA – MAY 15, 2019

When Francis Crick, codiscoverer of the DNA double helix, first conceived of molecular biology’s organizing principle in 1958, he dubbed it the central dogma. He soon came to regret the term. In his autobiographical account, What Mad Pursuit, Crick writes:

I called this idea the central dogma, for two reasons, I suspect. I had already used the obvious word hypothesis in the sequence hypothesis, and in addition I wanted to suggest that this new assumption was more central and more powerful….As it turned out, the use of the word dogma caused almost more trouble than it was worth. Many years later Jacques Monod pointed out to me that I did not appear to understand the correct use of the word dogma, which is a belief that cannot be doubted. I did apprehend this in a vague sort of way but since I thought that all religious beliefs were without foundation, I used the word the way I myself thought about it, not as most of the world does, and simply applied it to a grand hypothesis that, however plausible, had little direct experimental support.1

Even though Crick rued labeling his idea as “dogma,” the term seems to fit, all the connotations aside, because of its singular importance to molecular biology.

The Central Dogma of Molecular Biology

The central dogma of molecular biology describes the directional flow of information in the cell, which moves from DNA to RNA to proteins. Information can flow from DNA to DNA during DNA replication, from DNA to RNA during transcription, and from RNA back to DNA during reverse transcription. However, biochemical information can’t flow from proteins to either RNA or DNA.

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Figure 1: The Central Dogma of Molecular Biology. Image credit: Shutterstock

Is There a New Dogma in Molecular Biology?

In my opinion as a biochemist, if there is an idea that has the potential to rival the significance of the central dogma, it just might be the competitive endogenous RNA (ceRNA) hypothesis. This newer model provides a comprehensive description of the role messenger RNA (mRNA) molecules play in regulating gene expression, thereby influencing the flow of information from DNA to proteins.

The ceRNA hypothesis also provides an elegant rationale for why the genomes of eukaryotic organisms contain pseudogenes (including unitary pseudogenes) and encode long noncoding RNA molecules. Additionally, it explains why duplicated pseudogenes resemble corresponding intact genes. In doing all this, the ceRNA hypothesis provides support for the RTB’s genomics model—which interprets the structure and activities associated with genomes from a creation or design standpoint. (An overview of the RTB genomics model can be found in the updated and expanded 2nd edition of Who Was Adam?)

The Competitive Endogenous RNA Hypothesis

I discuss the ceRNA hypothesis in a previous article. So, I’ll offer just a brief description here. According to the central dogma, the final step in the flow of biochemical information is the production of proteins at the ribosome, directed by the information housed in mRNA. Biochemists have discovered an elaborate mechanism that selectively degrades mRNA transcripts before they can reach this point. This degradation process controls gene expression by dictating the amount of protein produced.

Molecules called microRNAs bind to the mRNA’s 3′ untranslated region, which flags the transcript for destruction by RNA-induced silencing complex (RISC). A number of distinct microRNA species exist in the cell. Each microRNA species bind to specific sites in the 3′ untranslated region of mRNA transcripts. (These binding locations are called microRNA response elements or MREs.)

A network of genes shares the same set of MREs and, consequently, will bind to the same set of microRNAs. When one gene is transcribed, it will influence the expression of all the other genes in its network. And when one gene in the network becomes up-regulated (leading to increased transcription of that gene), the expression of all the genes in the network increases. Why? Because the increased level of that particular transcript exerts a “sponge effect” that consumes more of the microRNAs that would otherwise target other transcripts for degradation.

The Competitive Endogenous RNA Hypothesis and the Role of Junk DNA

The ceRNA hypothesis elegantly explains the functional utility of three classes of junk DNA: duplicated and unitary pseudogenes, plus long noncoding RNAs. As it turns out, the transcripts produced from these types of so-called junk DNA also harbor MREs. None of these transcripts codes for proteins yet they play an indispensable role in regulating gene expression. In fact, all three are much better suited for the role of molecular sponges precisely because they aren’t translated into proteins.

Of particular utility are duplicated pseudogenes due to their close structural resemblance to the corresponding coding genes. Duplicated pseudogenes not only exert a sponge effect but also serve as decoys that allow the transcripts of the intact genes to escape degradation and to be translated into proteins.

Is the Competitive Endogenous RNA Hypothesis Valid?

This question has generated a minor scientific controversy. Some studies provide experimental support for this idea while others question the physiological relevance of ceRNAs. In light of this debate, a team of researchers headed by investigators from Columbia University sought to validate this hypothesis on a large-scale.They discovered that ceRNA interactions can disrupt the expression of thousands of genes. The team concluded that “ceRNA regulation is the norm not the exception…and that ceRNA interactions have genome-wide effects on gene expression.”3

These researchers think that this insight sheds light on tumor biology because dysregulation of ceRNAs have been implicated in some cancers. Their work also has theological significance because it undermines one of the most significant challenges to design arguments and, in turn, can be marshaled in support of the RTB genomics model.

The Competitive Endogenous Hypothesis and the Case for a Creator

Evolutionary biologists have long maintained that identical (or nearly identical) junk DNA sequences (such as pseudogene sequences) found in corresponding locations in genomes of organisms that naturally cluster together (such as humans and the great apes) provide compelling evidence that these organisms must have evolved from a shared ancestor. This interpretation was compelling because junk DNA sequences seemed to be useless vestiges of evolutionary history.

Creationists and intelligent design proponents had little to offer by way of evidence for the intentional design of genomes. But research in recent years has revealed that virtually every class of junk DNA has function. It seems, then, that shared junk DNA sequences can be understood as shared designs, which is what the RTB genomics model predicts.

Additionally, the ceRNA hypothesis supports the RTB genomics even further. This hypothesis provides an elegant explanation for the widespread existence of pseudogenes in genomes and their structural similarity to intact genes.

Could it be that the idea of religious dogma affirming a Creator’s role in life’s design and history has merit?

Resources

Endnotes
  1. Francis Crick, What Mad Pursuit (New York: Basic Books, 1988), 109.
  2. Hua-Sheng Chiu et al., “High-Throughput Validation of ceRNA Regulatory Networks,” BMC Genomics 18 (2017): 418, doi:10.1186/s12864-017-3790-7.
  3. Chiu et al., 418.

Reprinted with permission by the author
Original article at:
https://www.reasons.org/explore/blogs/the-cells-design/read/the-cells-design/2019/05/15/competitive-endogenous-rna-hypothesis-supports-the-case-for-creation

Pseudogene Discovery Pains Evolutionary Paradigm

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BY FAZALE RANA – MAY 8, 2019

It was one of the most painful experiences I ever had. A few years ago, I had two back-to-back bouts of kidney stones. I remember it as if it were yesterday. Man, did it hurt when I passed the stones! All I wanted was for the emergency room nurse to keep the Demerol coming.

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Figure 1: Schematic Depiction of Kidney Stones Moving through the Urinary Tract. Image Credit: Shutterstock

When all that misery was going down, I wished I was one of those rare individuals who doesn’t experience pain. There are some people who, due to genetic mutations, live pain-free lives. This condition is called hypoalgesia. (Of course, there is a serious downside to hypoalgesia. Pain lets us know when our body is hurt or sick. Because hypoalgesics can’t experience pain, they are prone to serious injury, etc.)

Biomedical researchers possess a keen interest in studying people with hypoalgesia. Identifying the mutations responsible for this genetic condition helps investigators understand the physiological processes that undergird the pain sensation. This insight then becomes indispensable to guiding efforts to develop new drugs and techniques to treat pain.

By studying the genetic profile of a 66-year-old woman who lived a lifetime with pain-free injuries, a research team from the UK recently discovered a novel genetic mutation that causes hypoalgesia.1 The mutation responsible for this patient’s hypoalgesia occurred in a pseudogene, a region of the genome considered nonfunctional “junk DNA.”

This discovery adds to the mounting evidence that shows junk DNA is functional. At this point, molecular geneticists have demonstrated that virtually every class of junk DNA has function. This notion undermines the best evidence for common descent and, hence, undermines an evolutionary interpretation of biology. More importantly, the discovery adds support for the competitive endogenous RNA hypothesis, which can be marshaled to support RTB’s genomics model. It is becoming more and more evident to me that genome structure and function reflect the handiwork of a Creator.

The Role of a Pseudogene in Mediating Hypoalgesia

To identify the genetic mutation responsible for the 66-year-old’s hypoalgesia, the research team scanned her DNA along with samples taken from her mother and two children. The team discovered two genetic changes: (1) mutations to the FAAH gene that reduced its expression, and (2) deletion of part of the FAAH pseudogene.

The FAAH gene encodes for a protein called fatty acid amide hydrolase (FAAH). This protein breaks down fatty acid amides. Some of these compounds interact with cannabinoid receptors. These receptors are located in the membranes of cells found in tissues throughout the body. They mediate pain sensation, among other things. When fatty acid amide concentrations become elevated in the circulatory system, it produces an analgesic effect.

Researchers found elevated fatty acid amide levels in the patient’s blood, consistent with reduced expression of the FAAH gene. It appears that both mutations are required for the complete hypoalgesia observed in the patient. The patient’s mother, daughter, and son all display only partial hypoalgesia. The mother and daughter have the same mutation in the FAAH gene but an intact FAAH pseudogene. The patient’s son is missing the FAAH pseudogene, but has a “normal” FAAH gene.

Based on the data, it looks like proper expression levels of the FAAH gene require an intact FAAH pseudogene. This is not the first time that biomedical researchers have observed the same effect. There are a number of gene-pseudogene pairs in which both must be intact and transcribed for the gene to be expressed properly. In 2011, researchers from Harvard University proposed that the competitive endogenous RNA hypothesis explains why transcribed pseudogenes are so important for gene expression.2

The Competitive Endogenous RNA Hypothesis

Biochemists and molecular biologists have long believed that the primary mechanism for regulating gene expression centered around controlling the frequency and amount of mRNA produced during transcription. For housekeeping genes, mRNA is produced continually, while for genes that specify situational proteins, it is produced as needed. Greater amounts of mRNA are produced for genes expressed at high levels 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 protein production at the ribosome. This mechanism dictates the amount of protein produced by permitting or preventing mRNA from being translated. The selective degradation of mRNA also plays a role in gene expression, functioning in a complementary manner to the transcriptional control of gene expression.

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), microRNAs play a crucial role in gene regulation. Through binding, microRNAs flag the mRNA for destruction by RNA-induced silencing complex (RISC).

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Figure 2: Schematic of the RNA-Induced Silencing Mechanism. Image Credit: Wikipedia

Various distinct microRNA species in the cell 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 microRNAs 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. In other words, the transcript of the duplicated pseudogene is a decoy. The mRNA transcript can then be translated and, hence, the “intact” gene expressed.

It is not just “intact” and duplicated pseudogenes that harbor the same microRNA response elements. 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 form a network that, when transcribed, will influence the expression of all genes in the network. This relationship means that all the mRNA transcripts in the network can function as decoys. This recognition accounts for the functional utility of unitary pseudogenes.

One important consequence of this hypothesis is that mRNA has dual functions inside the cell. First, it encodes information needed to make proteins. Second, it helps regulate the expression of other transcripts that are part of its network.

Junk DNA and the Case for Creation

Evolutionary biologists have long maintained that identical (or nearly identical) pseudogene sequences found in corresponding locations in genomes of organisms that naturally group together (such as humans and the great apes) provide compelling evidence for shared ancestry. This interpretation was persuasive because molecular geneticists regarded pseudogenes as nonfunctional, junk DNA. Presumably, random biochemical events transformed functional DNA sequences (genes) into nonfunctional garbage.

Creationists and intelligent design proponents had little to offer by way of evidence for the intentional design of genomes. But all this changed with the discovery that virtually every class of junk DNA has function, including all three types of pseudogenes (processed, duplicated, and unitary).

If junk DNA is functional, then the sequences previously thought to show common descent could be understood as shared designs. The competitive endogenous RNA hypothesis supports this interpretation. This model provides an elegant rationale for the structural similarity between gene-pseudogene pairs and also makes sense of the widespread presence of unitary pseudogenes in genomes.

Of course, this insight also supports the RTB genomics model. And that sure feels good to me.

Resources

Endnotes
  1. Abdella M. Habib et al., “Microdeletion in a FAAH Pseudogene Identified in a Patient with High Anandamide Concentrations and Pain Insensitivity,” British Journal of Anaesthesia, advanced access publication, doi:10.1016/j.bja.2019.02.019.
  2. Ana C. Marques, Jennifer Tan, and Chris P. Ponting, “Wrangling for microRNAs Provokes Much Crosstalk,” Genome Biology 12, no. 11 (November 2011): 132, doi:10.1186/gb-2011-12-11-132; Leonardo Salmena et al., “A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language?”, Cell 146, no. 3 (August 5, 2011): 353–58, doi:10.1016/j.cell.2011.07.014.

Reprinted with permission by the author
Original article at:
https://www.reasons.org/explore/blogs/the-cells-design/read/the-cells-design/2019/05/08/pseudogene-discovery-pains-evolutionary-paradigm