Friday, 8 November 2024

Unintelligent Design - How Evolution Rescued an Unintelligent Heath-Robinson Design Blunder


A WashU researcher hand pollinates Arabidopsis.

Photo: Joe Angeles/WashU
How plants evolved multiple ways to override genetic instructions - The Source - Washington University in St. Louis

The thing about evolution that distinguishes it from intelligent design is that evolution is utilitarian. It settles for something that works better than what preceded it, which is different from designing a perfect solution to a problem. Near enough is good enough because anything which is an improvement gets pushed up the frequency listing in the gene pool. So, organisms over time have accumulated sub-optimal systems that sometimes fail and cause other problems.

One of those systems is the way DNA is replicated - which is so error prone that error correction mechanisms have evolved over time, but they don't always work either, so we have the phenomenon of the 'jumping genes' that get inserted in the wrong place in the genome, sometime in the middle of a functional gene or in a control section adjacent to a functional gene, causing genetic defects.

So, in the best Heath-Robinson approach to design, rather than abandoning that design and starting again, the way any intelligent designer would do, another layer of complexity is needed to try to mitigate the occasion when the system fails.

So, what organisms have evolved over the years is a process for neutralising these 'jumping genes' by attaching methyl groups to one of the bases which prevents it being transcribed. This is a part of the epigenetic system by which the specialised cells of multicellular organisms turn of unwanted genes and only allow the genes for their speciality to be active - a layer of complexity needed because the way cells replicate was inherited from their single-celled ancestors where the whole genome needs to be included in every daughter cell.

Animals, such as mammals have two enzymes which attach this methyl group depending on the DNA 'context', but plants have multiple enzymes for doing the same thing. The question is why do plants need these multiple enzymes?

This was the question a research group at Washington University in St. Louis set out to answer, and the answer turned out to be something that creationists tell us is impossible - new genetic information arising by gene duplication and mutation. The research centred around two enzymes (CMT3 and CMT2). CMT3 adds a methyl group to parts of the DNA sequence known as CHG, while CMT2 adds methyl groups to CHH DNA sequences. Despite having different functions, these two enzymes are part of the same chromomethylase (CMT) family which evolved by duplication events, with the duplicate then being free to mutate without loss of function, eventually hitting on a new function while retaining the existing function of the original gene.

What can you tell me about the enzymes CMT2 and CMT3 found in plants; their function how they evolved, etc? CMT2 and CMT3 are plant-specific enzymes that play essential roles in DNA methylation, a key process in gene expression regulation and genome stability. Both CMT2 and CMT3 belong to the *Chromomethylase* (CMT) family, which are methyltransferases that add methyl groups to DNA. They are unique to plants and are primarily responsible for maintaining methylation patterns in non-CG (CHG and CHH) contexts, which is distinct from the CG methylation often maintained by DNA methyltransferases in animals.

Here’s an overview of their functions and evolution:

Functions of CMT2 and CMT3
  1. CMT3: This enzyme is primarily responsible for maintaining CHG methylation. CHG methylation is one of the main methylation contexts in plants, alongside CG and CHH. CMT3 plays a role in silencing transposable elements (TEs) and repetitive sequences, helping protect the genome from instability caused by transposition. It binds to regions of the genome marked with histone H3 methylation at lysine 9 (H3K9me), which helps direct CMT3 to specific targets and maintain methylation across cell divisions.
  2. CMT2: Unlike CMT3, CMT2 is mostly responsible for adding methylation in the CHH context, especially within regions dense in TEs and other repetitive sequences. CHH methylation is generally more dynamic and needs to be actively maintained across the plant lifecycle. CMT2 also targets regions associated with H3K9me, similar to CMT3, but with a bias for longer and more heavily methylated TEs, which are common in plant genomes.

Evolution of CMT Enzymes

The CMT family of methyltransferases appears to have evolved as an adaptation to plant-specific needs for genome stability. Unlike animals, which rely mostly on CG methylation, plants face unique challenges with transposable elements and must maintain a high degree of epigenetic control across their large, repetitive genomes. The CMT enzymes evolved to fill this role by allowing non-CG methylation (CHG and CHH) to be maintained without relying solely on RNA-directed DNA methylation pathways, which can be energy-intensive.

The evolution of CMT enzymes likely diverged from a common ancestral DNA methyltransferase in the early land plants, coinciding with the expansion of TEs in plant genomes. Over time, CMT enzymes specialized, with CMT3 focusing on CHG methylation and CMT2 emerging later to help manage CHH methylation in regions where TEs are densely packed.

Role in Plant Development and Adaptation

CMT2 and CMT3 play roles beyond genome defense; they help regulate genes involved in stress responses and development. By modulating methylation patterns, plants can "turn off" sections of their genome under stress conditions or in response to environmental changes, a flexibility that has been key in plant evolution. This methylation plasticity, regulated by CMT2 and CMT3, is thought to contribute to the adaptability of plants in diverse habitats.

These enzymes, therefore, highlight how plants have evolved unique solutions for managing large and complex genomes while responding to environmental pressures, setting them apart from the DNA methylation systems found in other kingdoms like fungi and animals.

So, TEs are design 'errors' in DNA that need a layer of complexity to compensate for?

Transposable elements (TEs) are indeed often considered "genomic parasites" or "selfish DNA" because they can duplicate and insert themselves randomly within the genome. This activity can disrupt genes, regulatory regions, or create instability, posing a risk to an organism's overall fitness. So, yes, they can be seen as sources of "design errors," as their unchecked movement could cause harmful mutations. However, plants (and other organisms) have evolved mechanisms to manage and even harness these elements to some extent, so it’s a more nuanced relationship than just error correction.

Why TEs Are Not Just Errors
  1. Evolutionary Innovation: TEs can introduce genetic diversity, which, while potentially harmful, also fuels evolution. By moving within the genome, they sometimes create new gene combinations, regulatory elements, or gene expression patterns that can lead to beneficial traits. In plants, this has been particularly advantageous because TEs have helped shape adaptation to different environmental conditions.
  2. Regulation and Defense: DNA methylation systems, like those involving CMT2 and CMT3, manage TEs by silencing them to prevent unchecked transposition. This layer of regulation isn’t just compensatory; it’s an integral part of genome structure in plants and helps to maintain balance. Over time, plants evolved robust regulatory networks that include TEs, using DNA methylation and histone modification to keep them inactive in most cases.
  3. Functional Adaptations: In some cases, TEs have been co-opted to perform useful functions. They can donate regulatory sequences to nearby genes, enabling responses to stress or other environmental cues. Some TEs even carry gene fragments or regulatory elements from other locations in the genome, which can be beneficial if inserted near a relevant gene. For example, in plants, certain TEs contribute to drought resistance or other adaptive traits.

So, while TEs do represent a kind of "imperfection" from a structural viewpoint, they also act as a force of genetic novelty, which plants have leveraged over millions of years. DNA methylation machinery like CMT2 and CMT3 reflects the evolutionary compromise: keep the TEs mostly silent but retain their capacity to introduce genetic variation when advantageous.
The reason there was a niche for CMT3 is because CMT2 lost its ability to methylate CHG sequence DNA because an amino acid, arginine was substituted by valine, which is important to that function, because arginine carries a positive electrical charge which can form bonds with, for example, negatively charged DNA. But, with arginine being replaced by valine, this charge was lost. The team found that by substituting arginine back into CMT2 in place of valine, CMT2 was able to methylate both CHG and CHH DNA sequences.

So, what evolution has produced is an additional layer of complexity (two slightly different enzymes) to get around the fact that one of the enzymes got broken so it could only do half its job. In fact, the probability is that CMT3 originally evolved by gene duplication to lighten the load of a single enzyme for both DNA sequences, then, when CMT2 mutated to lose its arginine, it was still able to cope with CHG DNA, while CMT3 was taking care of the CHH sequences. In other words, evolution had solved the problem of a ramshackle 'design'.

The biologists at Washington University who discovered this have recently published their findings open access in Science Advances and explained it in a Washington University new release by Maddy Frank:
How plants evolved multiple ways to override genetic instructions
WashU biologists investigate inner workings of DNA methylation in plants

Biologists at Washington University in St. Louis have discovered the origin of a curious duplication that gives plants multiple ways to override instructions that are coded into their DNA. This research could help scientists exploit a plant’s existing systems to favor traits that make it more resilient to environmental changes, like heat or drought stress.

The study led by Xuehua Zhong, a professor of biology in Arts & Sciences, was published Nov. 6 in Science Advances.

Zhong’s new research focuses on DNA methylation, a normal biological process in living cells wherein small chemical groups called methyl groups are added to DNA. This activity controls which genes are turned on and off, which in turn affects different traits — including how organisms respond to their environments.

Part of this job involves silencing, or turning off, certain snippets of DNA that move around within an organism’s genome. These so-called jumping genes, or transposons, can cause damage if not controlled. The entire process is regulated by enzymes, but mammals and plants have developed different enzymes to add methyl groups.

Mammals only have two major enzymes that add methyl groups in one DNA context, but plants actually have multiple enzymes that do that in three DNA contexts, this is the focus of our study. The question is — why do plants need extra methylation enzymes?

Certain genes or combinations of genes are contributing to certain features or traits. If we find precisely how they are regulated, then we can find a way to innovate our technology for crop improvement.

Professor Xuehua Zhong, lead author
The Dean’s Distinguished Professorial Scholar
Department of Biology
Washington University in St. Louis, St. Louis, MO, USA.

Looking forward, Zhong’s research could pave the way for innovations in agriculture by improving crop resilience.

Evolving different functions

The new study is centred around two enzymes specifically found in plants: CMT3 and CMT2. Both enzymes are responsible for adding methyl groups to DNA, but CMT3 specializes in the parts of DNA called the CHG sequences, while CMT2 specializes in different parts called CHH sequences. Despite their functional differences, both enzymes are a part of the same chromomethylase (CMT) family, which evolved through duplication events that provide plants with additional copies of genetic information.

Using a common model plant called Arabidopsis thaliana, or thale cress, Zhong and her team investigated how these duplicated enzymes evolved different functions over time. They discovered that somewhere along the evolutionary timeline, CMT2 lost its ability to methylate CHG sequences. This is because it’s missing an important amino acid called arginine.

Arginine is special because it has charge. In a cell, it’s positively charged and thus can form hydrogen bonds or other chemical interactions with, for example, the negatively charged DNA. [However, CMT2 has a different amino acid — valine.] Valine is not charged, so it is unable to recognize the CHG context like CMT3. That’s what we think contributes to the differences between the two enzymes.

Jia Gwee, co-first author Department of Biology
Washington University in St. Louis, St. Louis, MO, USA.
To confirm this evolutionary change, the Zhong lab used a mutation to switch arginine back into CMT2. As they expected, CMT2 was able to perform both CHG and CHH methylation. This suggests that CMT2 was originally a duplicate of CMT3, a backup system to help lighten the load as DNA became more complex:

But instead of simply copying the original function, it developed something new. This is one of the ways plants evolved for genome stability and to fight environmental stresses.

Professor Xuehua Zhong.


This research also provided insights about CMT2’s unique structure. The enzyme has a long, flexible N-terminal that controls its own protein stability. “” Zhong said. This feature may explain why CMT2 evolved in plants growing in such a wide variety of conditions worldwide.

Much of the data for this study came from the 1001 Genomes Project, which aims to discover whole-genome sequence variation in A. thaliana strains from around the globe.

“We’re going beyond laboratory conditions,” Zhong said. “We’re looking at all of the wild accessions in plants using this larger data set.” She believes part of the reason A. thaliana has evolved to thrive despite environmental stresses is because of the diversification that happens during the methylation process, including those jumping transposons: “One jump might help species deal with harsh environmental conditions.”
Jia Gwee, co-first author of the new study in Science Advances, created this comic to illustrate the duplication event in evolutionary history that led to the extra DNA methylation enzymes found in today’s plants.
Courtesy image.
Abstract
DNA methylation is an important epigenetic mechanism essential for transposon silencing and genome integrity. Across evolution, the substrates of DNA methylation have diversified between kingdoms. In plants, chromomethylase3 (CMT3) and CMT2 mediate CHG and CHH methylation, respectively. However, how these two methyltransferases diverge on substrate specificities during evolution remains unknown. Here, we reveal that CMT2 originates from a duplication of an evolutionarily ancient CMT3 in flowering plants. Lacking a key arginine residue recognizing CHG in CMT2 impairs its CHG methylation activity in most flowering plants. An engineered V1200R mutation empowers CMT2 to restore CHG and CHH methylations in Arabidopsis cmt2cmt3 mutant, testifying a loss-of-function effect for CMT2 during evolution. CMT2 has evolved a long and unstructured amino terminus critical for protein stability, especially under heat stress, and is plastic to tolerate various natural mutations. Together, this study reveals the mechanism of chromomethylase divergence for context-specific DNA methylation in plants and sheds important lights on DNA methylation evolution and function.

INTRODUCTION
DNA methylation is an important gene regulatory mechanism and plays critical roles in many biological processes such as development, transposon silencing, and genome integrity (1, 2). Dysregulation of DNA methylation can lead to pleiotropic developmental defects in plants and the development of diseases such as cancer in mammals (3, 4). While most methylated DNA in mammals is found in the CG context, DNA methylation in plants occurs in CG, CHG, and CHH (H = A, T, C). In Arabidopsis thaliana, this complex nature of substrate preference is facilitated by multiple DNA methyltransferases including DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2), METHYLTRANSFERASE 1 (MET1), CHROMOMETHYLASE 3 (CMT3), and CMT2 (5, 6).

Chromomethylases are plant-specific DNA methyltransferases containing a chromo domain, a bromo-adjacent homology (BAH) domain, and a catalytic methyltransferase domain (7, 8). In A. thaliana, there are three CMT genes, CMT1, CMT2, and CMT3, that emerged from duplication events through the evolution of green plants (9). Genome duplication events such as whole genome duplication and small-scale duplication are abundant in plants and are thought to be a driving force for diversity and speciation (10). While most duplicated genes become silenced or pseudogenes, functional diversifications such as subfunctionalization and neofunctionalization serve as potential mechanism behind duplicate retention (11). In the case of A. thaliana, the CMT1 gene is dispensable for DNA methylation, while CMT2 and CMT3 appear to have diversified for the labor division for non-CG methylation (1214). However, how the two CMTs have diversified to confer the increasing complexity of non-CG methylation during plant evolution remains unknown.

Functionally, CMT3 maintains symmetric CHG methylation on transposable elements (TEs) and repetitive sequences in the heterochromatin (13, 14). Recent studies have also shown that CMT3 is involved in the de novo establishment of gene-body methylation (9, 15, 16). On the other hand, CMT2 maintains the asymmetric CHH methylation alongside DRM2, with CMT2 methylating DNA within long TEs in heterochromatic regions whereas DRM2 mediates methylation within short TEs and at the edges of long TEs (13). CHH methylation plays important roles in TE silencing and environmental adaptation, and both CMT2 and DRM2 pathways enable a “double-lock mechanism,” indicated by the conversion of CMT2 targets to DRM2 targets during the loss of remodeler DDM1, for ensuring maintenance of CHH methylation and genome integrity (1719). CMT2 is also capable of maintaining CHG methylation alongside CMT3, suggesting a partial redundancy between the two chromomethylases to ensure maintenance of methylation in the heterochromatin for genome stability (14).

Although CMT2 and CMT3 have distinct DNA substrate preferences, both proteins recognize and bind to methylated histone 3 lysine 9 (H3K9me) through both chromo and BAH domains to methylate DNA substrate (12, 14, 20). The substrate specificity of CMT3 has recently been illustrated in its functional homolog in maize, ZMET2, where the enzyme is activated by allosteric recognition of H3K9me2 and histone 3 lysine 18, and the base-specific interactions of the methyltransferase domain with the hemimethylated CHG site and deformation of the DNA around the target cytosine for methylation (21).

CMTs are present in major green plant lineages ranging from green algae to angiosperms. Physcomitrella patens CMT (PpCMT) from the homologous β (hCMTβ) clade can methylate DNA in the CHG context, suggesting that CHG methylation is a conserved function of CMTs predating angiosperm CMTs (22, 23). In angiosperms, CMTs are further evolved via whole genome duplication event resulting in the CMT2 subclade and the CMT1/3 subclade in eudicots, ZMET subclade in monocots and magnoliids, and CMT subclade in Amborella trichopoda (9). However, not all angiosperm species have both CMT2 and CMT3; Zea mays lost CMT2 although its close relative Sorghum bicolor retains it, while two close Brassicaceae relatives of A. thaliana, Eutrema salsugineum and Conringia planisiliqua, lost their CMT3 (9, 13, 16). Furthermore, some angiosperm species such as Oryza sativa contain multiple copies of CMT3 (24), yet the basis and consequence behind the variation and retention of CMTs in various angiosperm species remain unknown.

Here, we investigated the molecular mechanism underlying the divergence of CMT2 and CMT3 by carrying out a comprehensive structural, functional, and evolutionary study. We noted that an arginine residue crucial for the recognition of CHG by CMT3 (R745) showed great variations in CMT2, explaining its loss of CHG specificity. Mutation of the corresponding residue in CMT2 to arginine in Arabidopsis (V1200R) gained CHG methylation activity and resilenced a subset of TEs in cmt2 cmt3 mutant with CMT3-like function. While CMT3 has a short N terminus, CMT2 contains a long and disordered N terminus, which is a common characteristic among many plant species. This long N terminus regulated CMT2 stability and mediated heat-induced CMT2 degradation. Furthermore, CMT2 N terminus is more plastic and tolerant to mutations as various CMT2 variations at the N terminus are observed in nature. Together, this study reveals the mechanism of chromomethylase divergence and provides important insights into DNA methylation function and evolution in plants.

As a clunky workaround for a basic design flaw, this is exactly the sort of multi-layered complexity to make the best of a suboptimal solution to an earlier problem that we expect evolution to produce. It is, of course, precisely the opposite of the minimally complex, error free design we would expect if an omniscient designer had intelligently designed it.
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