F Rosa Rubicondior: Creationism in Crisis - How Genomic Imprinting Evolved - Unintelligently

Saturday 9 March 2024

Creationism in Crisis - How Genomic Imprinting Evolved - Unintelligently

Revealing the evolutionary origin of genomic imprinting 
Caenorhabditis elegans

Genomic imprinting is the process by which genes are suppressed by epigenetic settings that differ depending on whether the genes come from the father or the mother in a sexually-reproducing species.

This is an example of the sort of Heath Robinson machine which a natural, mindless evolutionary process can and does produce and which distinguishes evolved systems from intelligently designed processes. It comes from the fact that multicellular organism uses the same method to replicate their cells as their single-celled ancestors used, yet only need a small selection of the genes depending on how specialised the particular cells are.

But the reason for genomic imprinting involves something even more embarrassing to any creationists who understand it - it probably evolved out of an arms race not between the organism and a foreign parasite but between the organism and one of its genes that had gone rogue and turned into a 'jumping' gene or 'selfish genetic element':
What exactly are 'selfish genetic elements' and what do they do? Selfish genetic elements are DNA sequences that have evolved to enhance their own transmission to the next generation, often at the expense of the organism's overall fitness. These elements can manipulate various cellular and reproductive processes to increase their own propagation within a population, sometimes even if it is detrimental to the host organism.

One well-known example of selfish genetic elements is transposable elements, also known as jumping genes. These DNA sequences have the ability to move or copy themselves within the genome, potentially disrupting genes or regulatory sequences in the process. While transposable elements can sometimes contribute to genetic variation and evolution, they can also cause harmful mutations or genomic instability.

Another example of selfish genetic elements is meiotic drive elements. These elements bias their own transmission during meiosis, the process by which gametes (sperm and eggs) are formed. Meiotic drive can result in the preferential transmission of one allele (variant of a gene) over another, leading to distortions in genetic inheritance patterns within a population.

Selfish genetic elements can have significant implications for evolutionary processes, population genetics, and genome stability. They can influence patterns of genetic diversity, contribute to speciation, and even drive the evolution of complex biological systems. However, they can also pose challenges for organisms by causing genetic disorders or reducing overall reproductive success.
In the case of the nematode, Caenorhabditis elegans, this arms race has produced a truly bizarre result, and something only an unintelligent, mindless designer, or a malevolent designer, could come up with, known as toxic ascaris, or TAs:
Do you have any information on the selfish genetic elements known as TAs in the nematode C elegans? Yes, TAs, short for "Toxic Ascaris," are a class of selfish genetic elements found in the nematode Caenorhabditis elegans. They were first discovered in studies investigating the genetics of the nematode's reproductive system.

TAs are composed of two genetic components: the "toxin" gene and the "antidote" gene. The toxin gene encodes a protein that is toxic to sperm or embryos, while the antidote gene encodes a protein that neutralizes the toxin. These elements exploit the genetic machinery of C. elegans to bias their own transmission during reproduction.

The mechanism of action of TAs involves the preferential destruction of competing sperm or embryos that lack the antidote gene. This biased transmission allows TAs to spread through the population, even if they are harmful to the overall fitness of the organism.

TAs represent an intriguing example of the evolutionary arms race between selfish genetic elements and their hosts. While TAs can confer a reproductive advantage to themselves, they can also impose a fitness cost on the nematode population if left unchecked. Therefore, the evolutionary dynamics of TAs in C. elegans are of interest to researchers studying genetic conflict, reproductive biology, and evolutionary theory.

So any advantage for the "toxin" gene is only realised if the "antidote gene" is also inherited with it?

Yes, that's correct. The advantage conferred by the "toxin" gene of TAs is only realized if the "antidote" gene is inherited along with it. This is because the toxin produced by the "toxin" gene would harm the organism's reproductive cells or embryos unless it is neutralized by the antidote produced by the "antidote" gene.

The presence of both the toxin and antidote genes in the same individual allows the toxin to be produced and function without harming the organism itself. However, when the toxin gene is inherited without the antidote gene, the toxin can cause harm to the reproductive cells or embryos, potentially reducing the reproductive success of individuals lacking the antidote gene.

This scenario creates a selective pressure for the co-inheritance of both the toxin and antidote genes. Individuals that possess both genes will be more likely to successfully transmit the TAs to the next generation, while those lacking either gene may experience reduced reproductive success. As a result, the evolutionary fate of TAs depends on the balance between the advantages they confer and the potential costs they impose on the host population.

If any creationist can discern any intelligence behind the TAs in C. elegans, I'd like to know what it is.

But what has that to do with the evolution of genomic imprinting?

According to researchers at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences (IMBA), genomic imprinting likely evolved from and arms race between the organism and TA's, as they describe in an open access paper in Nature and in an IMBA news release:
Some of our genes can be expressed or silenced depending on whether we inherited them from our mother or our father. The mechanism behind this phenomenon, known as genomic imprinting, is determined by DNA modifications during egg and sperm production. The Burga Lab at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences uncovered a novel gene regulation process, associated with the silencing of selfish genes, that could represent the first step in the evolution of imprinting. Their discovery, reported in Nature, could begin to solve the mystery of how and why imprinting first evolved.

Alejandro Burga and his lab at IMBA, in collaboration with the lab of Eyal Ben-David at the Hebrew University, have reported the discovery of the first parent-of-origin effect in nematodes, in a study published in Nature on March 6, 2024.

In diploid organisms, one set of chromosomes is inherited from each parent. However, not all of the genes contained within will be expressed equally; instead, some may be silenced depending on whether they were inherited from the mother or the father. This phenomenon, known as genomic imprinting, depends on DNA methylation, an epigenetic signal that is erased and rewritten in every generation. Genomic imprinting arose independently in mammals and plants over 100 million years ago. However, how this mechanism evolved has, so far, remained largely a mystery. Key to solving this enigma is understanding how parent-of-origin effects, the substrate for the evolution of imprinting, evolved in the first place.

Thirty years ago, Denise Barlow, a pioneer in the study of imprinting working at the IMP, also located at the Vienna BioCenter, hypothesized that imprinting could be evolutionarily related to genome defense mechanisms that silence parasitic DNA elements called selfish genetic elements. Selfish elements and the defense mechanisms against them participate in an arms race: each evolves further to outcompete the other. Although much has been discovered about selfish element silencing in the thirty years since Denise Barlow postulated her theory, a direct connection between germline defense mechanisms and the origin of parent-of-origin effects was missing. 

The findings by the Burga lab provide the first clear example of how parent-of-origin effects can originate from the host small RNA genome defense pathway. Their findings point to the potential evolutionary origin of imprinting. 

Curiosity paves the way for a new discovery

Sometimes in science, curiosity and attention to surprising details can lead to unexpected paths and new discoveries. This was the case when first author Pinelopi Pliota was studying selfish genetic elements in a new nematode model organism called C. tropicalis, a close cousin of the more widely studied C. elegans. Pliota was investigating toxin-antidote elements (TAs), a type of selfish element that has evolved a fascinating mechanism to ensure its own inheritance: “When a mother carries the TA, it will “poison” its eggs with a toxin that can only be countered by an antidote which is also present in the TA,” she explains, “this way, all descendants that don’t inherit the TA will either die or be developmentally delayed.” 

To generate the mothers they were studying, the group always crossed a mother C. tropicalis carrying the TA with a father not carrying it. “Pinelopi asked me if we had ever done these crossings the other way around,” explains Alejandro Burga, corresponding author of the publication. Her curiosity led to an interesting discovery: “To our surprise, this reciprocal crossing produced mothers incapable of poisoning their eggs. All of a sudden, there was no effect at all,” explains Pliota. Fascinated by this unexpected result, the team decided to study how inheriting the TA from the mother or the father could lead to different effects. “We wanted to understand how this happens, what the molecular basis of this parent-of-origin effect is,” says Burga. 

Inhibiting the inhibitor: maternal mRNA licenses toxin expression 

To figure out the mechanism of the observed parent-of-origin effect, the Burga group decided to study the main germline defense mechanism against selfish genetic elements, known as the piRNA pathway. In the piRNA pathway, a coordinated effort of different small RNA molecules and proteins silences the expression of selfish elements during germline development to ensure genome stability in reproduction. 

The group, collaborating with the lab of Julius Brennecke, also at IMBA, were able to identify the piRNA molecules and proteins involved in silencing the toxin-antidote element. However, all these factors alone didn’t explain the parent-of-origin-specific results they were observing. The researchers were missing a piece in this puzzle.

Fortunately, the Burga group had one last trick up their sleeve: “We knew from previous research that worms have evolved various ingenious ways to discriminate their own genes from foreign elements like a virus or a selfish element.” Burga says. “We realized that, in this case, the key missing element was maternal mRNA which is loaded into eggs.”  

They proved that, in maternal inheritance, the TA is accompanied by the toxin mRNA, which is expressed in the germline of the mother and loaded into the egg. The Burga group showed that this mRNA marks the TA as “own”, avoiding its silencing by the piRNA pathway. “This process is called epigenetic licensing, and its balance with the piRNA pathway determines whether a gene is expressed or not”. 

On the other hand, when the TA is inherited paternally, the lack of maternal mRNA means there is no licensing, leading to a strong repression of the toxin gene and very low levels of toxin being expressed. “By default, the piRNA pathway will silence the toxin gene,” explains Burga. “Unless there’s maternal mRNA that licenses it by repressing the piRNA pathway. This inhibition of the inhibitor is what causes the toxin gene to be active, and the eggs to be poisoned.”. 

Interestingly, this silencing pattern was observed to last for several generations, meaning that lack of licensing in one generation can even affect their great-grand-daughters. This is not the case in genomic imprinting, which gets reset in each generation. 

Explaining the evolution of imprinting 

The results from the Burga group cement the evolutionary link between parent-specific gene expression and host defence mechanisms, tracing the origins back to organisms that lack DNA methylation and canonical imprinting. Despite the differences between these processes in worms and mammals, the Burga group believes that the mechanism they described could represent an evolutionary first step for more advanced forms of inherited silencing. These more advanced forms of silencing ended up regulating the expression of the cell's endogenous genes, leading to the evolution of genomic imprinting
And more technical detail and background is given in the open access paper in Nature:

Genomic imprinting—the non-equivalence of maternal and paternal genomes—is a critical process that has evolved independently in many plant and mammalian species1,2. According to kinship theory, imprinting is the inevitable consequence of conflictive selective forces acting on differentially expressed parental alleles3,4. Yet, how these epigenetic differences evolve in the first place is poorly understood3,5,6. Here we report the identification and molecular dissection of a parent-of-origin effect on gene expression that might help to clarify this fundamental question. Toxin-antidote elements (TAs) are selfish elements that spread in populations by poisoning non-carrier individuals7,8,9. In reciprocal crosses between two Caenorhabditis tropicalis wild isolates, we found that the slow-1/grow-1 TA is specifically inactive when paternally inherited. This parent-of-origin effect stems from transcriptional repression of the slow-1 toxin by the PIWI-interacting RNA (piRNA) host defence pathway. The repression requires PIWI Argonaute and SET-32 histone methyltransferase activities and is transgenerationally inherited via small RNAs. Remarkably, when slow-1/grow-1 is maternally inherited, slow-1 repression is halted by a translation-independent role of its maternal mRNA. That is, slow-1 transcripts loaded into eggs—but not SLOW-1 protein—are necessary and sufficient to counteract piRNA-mediated repression. Our findings show that parent-of-origin effects can evolve by co-option of the piRNA pathway and hinder the spread of selfish genes that require sex for their propagation.


Diploid organisms carry two copies of each gene: one inherited from their mother and the other one from their father. Typically, these copies are functionally interchangeable. Imprinted genes are the exception to this rule. They keep an epigenetic memory of their gametic provenance, making maternal and paternal genomes non-equivalent, which has a large effect on embryonic development, species hybridization and human disease10. Multiple theories have been put forward to explain the evolution of imprinting. The most accepted theory—kinship conflict—states that imprinting arises when there are conflicting interests between maternal and paternal genomes owing to differential investment in their offspring3,4. Notably, this theory presupposes the existence of mechanisms that establish differences in the expression of maternal and paternal alleles—otherwise, there would be nothing to select on3. This raises the critical question of how parent-of-origin effects on gene expression evolve in the first place.

The discovery of the first imprinted loci in mammals led to the hypothesis that imprinting evolved from host defence mechanisms that use DNA methylation to keep viruses and parasitic genes at bay11,12. This is in line with the close proximity of many imprinted loci to transposable elements in plants13,14 and piRNA-induced DNA methylation of a retrotransposon being critical for the paternal imprinting of mouse Rasgrf1 (ref. 15). However, the evolutionary origins of imprinting remain poorly understood at the molecular level. More recently, histone modifications, such as H3K27me3, have been reported to act as imprinting marks independently of DNA methylation in mice16. These observations have raised the possibility that a link between parent-of-origin-dependent gene expression and host defence mechanisms can also be found in organisms that lack DNA methylation but are rich in small regulatory RNAs, such as Caenorhabditis elegans and related nematodes17. Here we dissect the mechanism behind a parent-of-origin effect on gene expression and provide a physiological context for the emergence of imprinting.

A TA with a parent-of-origin effect

C. tropicalis is a hermaphroditic nematode that—unlike its more widely distributed relative C. elegans—inhabits exclusively equatorial regions18. While studying genetic incompatibilities between the two C. tropicalis wild isolates NIC203 (Guadeloupe, France) and EG6180 (Puerto Rico, USA), we uncovered a maternal-effect TA, which we named slow-1/grow-1 (ref. 9). This selfish element is located in NIC203 chromosome III and comprises three tightly linked genes: a maternally expressed toxin, slow-1, and two identical and redundant antidotes, grow-1.1 and grow-1.2, which are expressed zygotically. For simplicity, we will refer to the two antidotes collectively as grow-1 unless specifically noted (Extended Data Fig. 1a and Supplementary Discussion). Slow-1 transcripts are maternally loaded into eggs prior to fertilization and remain stable in embryos, at least until the 20-cell stage. However, from the comma stage until hatching, slow-1 transcripts are found only in the germline precursor cells9. SLOW-1 is homologous to nuclear hormone receptors, whereas the antidote GROW-1 has no homology to known proteins. In crosses between TA carrier and non-carrier strains, heterozygous mothers poison all their eggs but only progeny that inherit the TA can counteract the toxin by zygotically expressing its antidote (Extended Data Fig. 1b). Whereas wild-type worms typically take two days to develop from the L1 stage to the onset of egg laying, embryos poisoned by maternal SLOW-1 take on average four days. This developmental delay imposes a high fitness cost and favours the spread of the selfish element in the population9.

To study the inheritance of slow-1/grow-1 TA, we previously generated a near-isogenic line strain (hereafter referred to as ‘NIL’) containing the slow-1/grow-1 NIC203 chromosome III locus in an otherwise EG6180 background9. As expected, slow-1 mRNA was detected in the NIL but not in EG6180 (Extended Data Fig. 1c). As previously reported, in crosses between NIL hermaphrodites and EG6180 males, the toxin induced developmental delay in all the F2 homozygous non-carrier (EG/EG) individuals9 (100% delay, n = 34; Fig. 1a). However, we noticed an unexpected pattern of inheritance when performing the reciprocal cross. If EG6180 hermaphrodites were mated to slow-1/grow-1 NIL males, most of their F2 EG/EG progeny were not developmentally delayed but phenotypically wild type (9.4% delay, n = 53; P  ≤  0.0001; Fig. 1a,b). This was surprising, because known TAs—including C. elegans peel-1/zeel-1 and sup-35/pha-1, the Medea locus in Tribolium, and the mouse homogeneously staining region (HSR) locus—affect non-carrier individuals regardless of whether the element is inherited from the maternal or paternal lineage8,19,20,21 (Extended Data Fig. 1d).
Fig. 1: slow-1/grow-1, a selfish element with a parent-of-origin effect.
a, Reciprocal crosses between the slow-1/grow-1 TA NIL and the EG6180 parental strain. Maternal (M) or paternal (P) inheritance refers to the slow-1/grow-1 locus. Worms with a significant developmental delay or larval arrest were categorized as delayed, otherwise they were classified as wild type (WT). Sample sizes (n) are shown for each phenotypic class. Error bars indicate 95% binomial confidence intervals calculated with the Agresti–Coull method. Each cross was performed independently at least twice with identical results (see Supplementary Table 1 for raw data). b, Activity of the NIC203 chromosome II TA in reciprocal crosses. Penetrance of the toxin, the percentage of F2 non-carrier individuals that are phenotypically affected, is used as a proxy for TA activity (slow-1/grow-1 TA: M, n = 34; P, n = 53; P < 0.0001, NIC chromosome II TA: M, n = 44; P, n = 50; P = 0.27; two-sided Fisher’s exact test; data are mean ± 95% confidence interval). Chr., chromosome; NS, not significant. c, Reciprocal crosses between the NIL and EG6180 followed by RNA-seq of their F1 progeny indicate that slow-1 transcripts are more abundant when maternally inherited (two-sided unpaired t-test; M, n = 7; P, n = 6; P = 0.0092; data are mean ± s.e.m.).
We also investigated the inheritance pattern of two recently discovered maternal-effect TAs in C. tropicalis and C. briggsae that cause developmental delay9,22. However, we found no evidence of a parent-of-origin effect, indicating that this is not a general feature of non-lethal toxins (Fig. 1b and Extended Data Fig. 1e). Mito-nuclear incompatibilities could not explain the observed pattern because both parental lines carry the same mito-genotype (Extended Data Fig. 1f). Moreover, C. tropicalis, like all nematodes of the Rhabditida group, lacks de novo methyltransferases, making the involvement of mammalian-like epigenetic imprinting unlikely23. Because parent-of-origin effects are extremely rare in nematodes and all reported cases involve transgenic reporters, we set out to investigate this phenomenon24,25.
Can a creationists suggest a reason why any intelligent designer would design a selfish gene that ensures its own survival by killing carriers of the alleles that don't include the antidote to itself, and a species having what looks like an arms race with one of its own genes that have gone 'rogue' in this way?

Or will they have to abandon the pretense that intelligent design is not Bible literalism in disguise and invoke the biblical myth of 'The Fall' to blame it on?

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