Rosa Rubicondior: Unintelligent Design - The Heath-Robinson Machine That Keeps Rogue DNA Under Control

Unintelligent Design

The Heath-Robinson Machine That Keeps Rogue DNA Under Control

How a critical enzyme keeps potentially dangerous genes in check – lji.org

The human body, like those of most multicellular organisms, exhibits numerous instances of suboptimal design. These imperfections arise from evolutionary processes that balance competing demands, often prioritizing immediate reproductive success over long-term well-being and efficiency. As a result, many biological structures and functions are prone to errors, which tend to accumulate and manifest more prominently with age.

These inherent imperfections have driven the evolution of additional layers of complexity aimed at mitigating potential failures. Such complexity would likely be unnecessary if these biological systems had been optimally designed from the outset. Therefore, the presence of intricate mechanisms to counteract inherent errors serves as compelling evidence for evolution and challenges the notion of intelligent design. Examples of these compensatory complexities are abundant across all multicellular organisms.

A pertinent example involves the regulation of transposable elements (TEs), often referred to as "jumping genes." These DNA sequences can move within the genome, potentially causing significant disruptions if not properly controlled. In healthy cells, TEs are kept in check within heterochromatin — a tightly packed form of DNA that serves as a "prison" for these elements. Recent research led by Professor Anjana Rao, Ph.D., at the La Jolla Institute for Immunology, published in Nature Structural & Molecular Biology, has shed light on this control mechanism. The study reveals that the enzyme O-GlcNAc transferase (OGT) plays a crucial role in suppressing TE activity by restraining TET enzymes, thereby maintaining genomic stability.

This intricate system of checks and balances underscores the evolutionary arms race within our genomes, highlighting the complexity that arises from natural selection's ongoing efforts to mitigate the potential harms posed by transposable elements.

Tell me all about Heterochromatin and Transposable Elements, the harm they can do and the mechanisms for mitigating that harm. Can this be reconciled with the notion of Intelligent Design?

Heterochromatin and Transposable Elements: Overview

Heterochromatin is a tightly packed form of DNA that is generally transcriptionally inactive. It typically contains repetitive sequences, transposable elements, and structural regions like centromeres and telomeres. There are two main types:

Constitutive heterochromatin: Permanently compacted; found mainly in centromeres and telomeres.
Facultative heterochromatin: Temporarily compacted; its formation is regulated, such as during development (e.g., X chromosome inactivation).

Transposable Elements (TEs), or "jumping genes," are DNA sequences that can change positions within the genome. There are two major classes:

Class I (retrotransposons): Move by a "copy-and-paste" mechanism, involving RNA intermediates and reverse transcription (e.g., LINEs, SINEs, LTR retrotransposons).
Class II (DNA transposons): Move by a "cut-and-paste" mechanism without an RNA intermediate.

Harm Caused by Transposable Elements

Transposable elements can disrupt normal gene function in several ways:

Gene Disruption:

Insertion into genes can disrupt coding sequences, resulting in loss-of-function mutations or altered protein production.
Insertion into regulatory regions can disrupt gene expression levels or patterns.

Genomic Instability:

Recombination between repetitive TE sequences can cause genomic rearrangements, deletions, duplications, inversions, and translocations.
These rearrangements can lead to genomic instability, contributing to disease states, such as cancers and genetic disorders.

Epigenetic Dysregulation:

Activation of TEs can disrupt epigenetic control mechanisms, leading to abnormal gene expression and disease, including developmental disorders.

Metabolic Cost:

Expression and replication of TEs consume cellular resources and energy, imposing a metabolic cost to the host organism.

Mechanisms Mitigating the Harm of TEs

Cells have evolved various strategies to control the activity and harmful effects of TEs:

Epigenetic Silencing and Heterochromatin Formation:

DNA methylation: Methylation of cytosines in TE sequences suppresses their activity.
Histone modifications (e.g., H3K9 methylation): Recruit proteins like heterochromatin protein 1 (HP1), leading to formation of condensed heterochromatin, repressing TE expression.

RNA-Based Mechanisms (RNAi Pathways):

Small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs) specifically silence TE transcripts.
PiRNA pathways in germline cells are critical for safeguarding genetic integrity across generations.

Genomic Defences (KRAB-Zinc Finger Proteins):

KRAB-ZFP transcription factors specifically recognise and silence newly emerged TEs through epigenetic modifications.
This dynamic system adapts quickly to new TE invasions.

Selective Pressure and Natural Selection:

Natural selection eliminates organisms severely harmed by TEs, favouring mechanisms that reduce or neutralise TE activity.

Potential Beneficial Roles of TEs

Despite their harmful potential, TEs can occasionally benefit genomes:

Genomic Innovation:

TEs can provide regulatory elements, driving new gene expression patterns.
Occasionally, beneficial mutations arise, enhancing evolutionary adaptability.

Structural Roles:

TE sequences can form essential structural components (e.g., centromeres), crucial for proper chromosome segregation.

Evolutionary Drivers:

TEs facilitate genetic diversity, potentially increasing population adaptability under changing conditions.

Reconciling Heterochromatin and TEs with Intelligent Design
From an evolutionary biology standpoint, the presence of heterochromatin and TEs is easily explainable as the outcome of natural selection, genetic drift, mutation, and evolutionary history. Such genomic elements exemplify an "arms race," where genomes continually evolve defensive mechanisms against parasitic DNA.

However, reconciling these elements with Intelligent Design (ID) proves challenging:

Suboptimal Design and Harmful Effects:

The significant harm caused by uncontrolled TE activity suggests suboptimal genomic "design."
The existence of sophisticated defence mechanisms implies genomic conflict rather than intentional, beneficial "design."

Inefficiency and Wastefulness:

Genomic instability, increased mutation rates, and metabolic costs caused by TEs are inconsistent with an intelligently designed, streamlined genome.
The complexity of multiple overlapping defence mechanisms implies an evolutionary response rather than purposeful engineering.

Adaptation and Evolutionary Arms Race:

The rapidly evolving host-TE interactions exemplify an ongoing evolutionary process, challenging the notion of a static, intelligently created system.

Lack of Predictive Power in ID:

ID provides no explanation for the existence of harmful genomic parasites or their sophisticated control mechanisms.
Evolutionary theory not only explains but also predicts the presence, diversity, and mitigation strategies for TEs and heterochromatin dynamics.

Conclusion

Heterochromatin and TEs exemplify evolutionary processes rather than intelligent design. Their harmful potential, combined with complex, evolved mechanisms for mitigating damage, strongly supports evolutionary biology's view of genomes as dynamic, evolving systems shaped by selection pressures and genetic conflicts, rather than products of intentional, perfect design.

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The research teams findings are described in a La Jolla Institute for Immunology news item by Madeline McCurry-Schmidt:

How a critical enzyme keeps potentially dangerous genes in check
Meet OGT, your guardian enzyme on the dark side of the genome. You may have heard of the fantastic-sounding “dark side of the genome.” This poorly studied fraction of DNA, known as heterochromatin, makes up around half of your genetic material, and scientists are now starting to unravel its role in your cells.
For more than 50 years, scientists have puzzled over the genetic material contained in this “dark DNA.” But there’s a growing body of evidence showing that its proper functioning is critical for maintaining cells in a healthy state. Heterochromatin contains tens of thousands of units of dangerous DNA, known as “transposable elements” (or TEs). TEs remain silently “buried” in heterochromatin in normal cells—but under many pathological conditions they can “wake up” and occasionally even “jump” into our regular genetic code.

And if that change benefits a cell? How wonderful! Transposable elements have been co-opted for new purposes through evolutionary history — for instance the RAG genes in immune cells and the genes required for driving the development of the placenta and mammalian evolution have been derived from TEs.

But TEs may also wreak havoc on our health. In just the last few years, scientists have linked heterochromatin weakening to aging, premalignancy, cancer, and autoimmune disease.

You can think of heterochromatin as a prison for transposable elements. When heterochromatin loses its normal suppressive function, TEs escape and in parallel, the health of cells declines.

Professor Anjana Rao, Ph.D., lead author
Division of Signaling and Gene Expression
La Jolla Institute for Immunology, La Jolla, CA, USA.

The new study reveals a remarkable way that cells keep us safe from TEs gone wild. The researchers found that cells have taken advantage of an entire protein network to repress TE activity and keep themselves healthy.

Reactivated transposable elements can create a lot of genomic instability. Even just increased expression of these elements can affect the expression of nearby genes, as we show in our new paper. Abundant expression of transposable elements is a signature of many diseases, including cellular senescence, human aging, autoimmune disorders and many types of cancers.

Dr Hugo Sepulveda, Ph.D., first author.
Division of Signaling and Gene Expression
La Jolla Institute for Immunology, La Jolla, CA, USA.

How do cells keep transposable elements under control?

Meet O-GlcNAc transferase (OGT), an enzyme at the heart of many essential cellular functions. According to the new study, OGT is also a lead choreographer when it comes to suppressing TEs and keeping gene expression running smoothly.

For the new project, the researchers followed up on the fact that OGT interacts with important proteins called TET enzymes, discovered by the Rao Lab in 2009. TET proteins are part of the complex machinery that makes sure our DNA is correctly modified in our cells and that our cells activate the right transcriptional programs.

TET proteins are involved in the critical cycle of DNA modifications, where they play a role in a process that results in the removal of molecular markers that attach to DNA (an event called DNA demethylation). The most abundant DNA markers, called 5mC and 5hmC, are normally associated with transcriptional silencing and activation, respectively. Researchers have shown that 5mC is associated with genes turned “off” while 5hmC, mediated by TET proteins, is associated with gene expression turned “on.”

This “on/off” epigenetic system gives our cells the flexibility to respond to environmental changes and health threats. DNA demethylation helps our immune cells spring into action if they detect a threat.

DNA demethylation is normal, but cells also need balance. You can’t have TET proteins activating every gene at the same time. In normal cells, TET protein activity is restricted to the genes that need to be expressed in that particular cell type.

In the new study, the scientists harnessed Oxford Nanopore sequencing technology and other cutting-edge sequencing techniques to discover where OGT comes in. One especially important and new technique that they used is called duet evoC. This multiomics solution enabling the 6-base genome, developed by biomodal, was essential to establish that both 5mC and 5hmC were simultaneously changing at the same sites in the genome.

The researchers found that OGT protects cells by restraining TET activity. This is extremely important for controlling TE expression because it prevents the silencing modification 5mC from being converted to the activating modification 5hmC in heterochromatin.

Without OGT at the helm, TET proteins ramp up DNA demethylation in the wrong places, turning on too many genes at once, including intact TEs normally “buried” in our genetic material.

Next steps for understanding cancers, autoimmune disease, and more

This finding shows how the non-coding regions of our genome can turn active when TET functions are altered. The new understanding of the OGT-TET partnership shows that these proteins, their mediated marks, and TE expression can affect our cells in a big way.

We think of these elements as totally ‘silent,’ and therefore completely inert, but the reality is that cells have to make a huge—and constant—investment to keep TEs silent. We want to control that activity, and we may now have an option through OGT and TETs.

Dr Hugo Sepulveda, Ph.D.

This new research may also prove important for future drug development. Scientists have identified numerous genes linked to cancer, but controlling their expression remains a challenge. The new findings suggest we might stop cancer growth through interesting new avenues, such as by restraining TE activity in cancer cells.

Rao emphasizes that further studies are needed to investigate how OGT controls DNA modifications and TE expression—and how the dysregulation of this mechanism contributes to autoimmune disorders, cancers, and other diseases.

Additional authors of the study, “OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide,” include Leo J. Arteaga-Vazquez, Isaac F. López-Moyado, Melina Brunelli, Lot Hernandez Espinosa, Xiaojing Yue, J. Carlos Angel, Caitlin Brown, Zhen Dong, Natasha Jansz, Fabio Puddu, Aurélie Modat, Jamie Scotcher, Páidí Creed, Patrick Kennedy, and Cindy Manriquez.

Abstract
O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1–OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET–OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.

Sepulveda, H., Li, X., Arteaga-Vazquez, L.J. et al.
OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide. Nat Struct Mol Biol (2025). https://doi.org/10.1038/s41594-025-01505-9

© 2025 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

There is, of course, no logical way to reconcile these multiple layers of complexity — where each additional layer is needed to mitigate the failures of previous layers, which themselves arose to reduce the harmful effects of earlier poor design — with the notion of a supernatural, intelligent designer. The simplest and most coherent explanation is an unplanned, reactive evolutionary process driven by environmental selection pressures. Such a process inevitably settles for utilitarian solutions, provided they represent even slight improvements over what preceded them. With no overarching plan or ultimate objective, evolution has no gold standard to measure itself against; the only criterion for success is that something works adequately most of the time, and when it doesn't, it does not immediately lead to extinction.

What creationists fail to realise, or refuse to accept, is that these compromises and overly complex, inefficient solutions—solutions that would be inexplicable if devised by an omniscient, omnipotent creator—are pervasive throughout biology. Indeed, such complexity and imperfection are among the most significant drivers of biodiversity. Complexity is not evidence of intelligent design; rather, it provides compelling evidence against it.

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