Creationism in Crisis - How A 700-Million-Year-Old Chance Mutation Could Explain Why We Have Limbs

New research suggests a mistake in DNA millions of years ago could explain why the human body is so complex today.

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A graphic representation of the DNA sequence

How a 700-million-year-old DNA glitch could explain why humans have limbs | National Post

700 million years ago in a remote ancestor of all terrestrial tetrapods - which includes all amphibians, reptiles, birds and mammals, a mutation in a gene happened. To begin with this made no difference because the mutation was neutral - neither deleterious nor advantageous.

But later on, it became the mutation that made the evolution of limbs possible, in an illustration of how redundant or neutral DNA can later be exapted for new functions and structures.

This may seem highly improbable to anyone who doesn't understand how natural selection ensure that beneficial traits accumulate and increase in the species gene pool but in fact, there have been several such chance mutations that opened up the possibility of a new direction in evolution in human genetic history.

Can you give me a list of chance mutations that have played a significant part in human evolutionary history, with approximate dates, please? Certainly! Here's a list of significant chance mutations that have played a key role in human evolutionary history, along with their approximate dates:

1. FOXP2 Gene Mutation (Language and Speech)
   • Date: Around 100,000-200,000 years ago
   • Significance: This mutation is associated with the development of complex language and speech abilities in humans.
2. LCT Gene Mutation (Lactase Persistence)
   • Date: Around 7,500-10,000 years ago
   • Significance: This mutation allows adults to digest lactose, providing a nutritional advantage in populations with domesticated dairy animals.
3. SLC24A5 Gene Mutation (Skin Pigmentation)
   • Date: Around 10,000 years ago
   • Significance: This mutation affects skin pigmentation, leading to lighter skin in populations that migrated to higher latitudes with less sunlight.
4. EDAR Gene Mutation (Hair and Teeth)
   • Date: Around 35,000 years ago
   • Significance: This mutation is associated with thicker hair and changes in teeth morphology, common in East Asian populations.
5. CCR5-Δ32 Mutation (HIV Resistance)
   • Date: Around 5,000-10,000 years ago
   • Significance: This mutation provides resistance to HIV infection and possibly to smallpox, found mainly in European populations.
6. Sickle Cell Trait (HBB Gene)
   • Date: Around 5,000-7,000 years ago
   • Significance: This mutation provides resistance to malaria, common in regions with high malaria prevalence.
7. AMY1 Gene Duplication (Starch Digestion)
   • Date: Varies, likely within the last 10,000 years
   • Significance: Increased copies of the AMY1 gene allow for better starch digestion, advantageous in agricultural societies.
8. EPAS1 Gene Mutation (High Altitude Adaptation)
   • Date: Around 3,000 years ago
   • Significance: This mutation allows for better adaptation to low oxygen levels, found in Tibetan populations.
9. MYH16 Gene Mutation (Jaw Muscle Size)
   • Date: Around 2.4 million years ago
   • Significance: This mutation results in smaller jaw muscles, potentially allowing for the development of a larger brain.
10. MC1R Gene Mutation (Red Hair and Fair Skin)
    • Date: Around 20,000-40,000 years ago
    • Significance: This mutation affects hair and skin color, providing an advantage in regions with low UV radiation.

These mutations highlight the role of genetic variation in human adaptation to diverse environments and lifestyles throughout our evolutionary history.

For example, nearly five million years ago a mutation allowed our jaw muscles to weaken, which in turn made our skull and brain expand, and almost three million years ago, a gene accidentally duplicated, which helped the neurons in our brain to form more connections, which might have actually made us smarter.

The discovery of the mutation that later enabled limbs to evolve by an international team co-led by Dr. Maria Ina Arnone of Stazione Zoologica Anton Dohrn, Villa Comunale, Napoli, Italy; Dr. Jordi Garcia-Fernàndez of the Department of Genetics, School of Biology, and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona, Spain, and Dr. Manuel Irimia of Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain, was the subject of a 2017 open-access paper in the journal Nature Communications and a press release reported in National Post:

How a 700-million-year-old DNA glitch could explain why humans have limbs

A fluke mutation having such an impact on humans may seem highly unlikely, but it's not uncommon. We're the product of many such accidents

Figuring out how humans evolved to be the complex creatures we are today is no easy feat. But a recent study found that a tiny mistake in DNA that occurred 700 million years ago could be part of the puzzle.

Researchers discovered a DNA mutation that was initially “silent”; in other words, it didn’t change the way an organism looked or acted, so it seemed meaningless. But years later, this tiny mistake triggered several genes to work together, which eventually led to the development of organs and other important structures like limbs.

It was very surprising to see that a mutation which is normally neutral, actually enabled everything that resulted in humans. If that one mutation hadn’t occurred, the story of (human development) could have been very different.

We know now that this process is very relevant in humans, but nobody ever asked the question of how did this evolve or how did this originate.

Dr. Manuel Irimia, co-author
Centre for Genomic Regulation (CRG)
Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

One gene can be cut many ways to create different proteins, which each serve their own function. Say for example you have a gene which is cut at point A and point B. This creates a protein that helps your body fight off infections. Say that same gene is cut at points Y and Z instead. Now, this creates a protein that helps deliver oxygen to your blood.

This is how the human body is so complex — a single gene can code for many different things. And the 700-million-year-old mutation was partially responsible for creating this phenomenon.

The findings were published in Nature Communications and prove how something that might at first seem irrelevant, could actually be important from an evolutionary perspective.

I think what’s fascinating is that a single mutation can change so many things. And it’s also interesting how a mutation can be silent for a long time and then suddenly cause changes in organisms.

Dr. Maria Ina Arnone, co-author
Stazione Zoologica Anton Dohrn
Villa Comunale, Napoli, Italy.

This “genetic flexibility” is part of the reason why humans have evolved to be so complex. But this process doesn’t just happen in humans. The researchers also found the ancient mutation in many animals, including sea urchins and fish. Irimia explains that even a fish’s fin and a human’s arm are related, but eventually each diversified to adapt to their environment. Irimia says that looking at several animals is important when studying evolution.

By studying different animals we can see what features they share,” he said. “You need to think of a gene as a tool in the tool box. It can be used for many things such as creating different organs in different animals.

It’s really interesting to know how we actually became humans, and this (gene mutation) is just one of the many processes involved.

Dr. Maria Ina Arnone.

While the thought of a fluke mutation having such an important impact on humans might seem rare, it’s actually not uncommon. Humans are often considered to be the product of many accidental mutations that ended up benefiting us in the long run.

Nearly five million years ago a mutation allowed our jaw muscles to weaken, which in turn made our skull and brain expand. Almost three million years ago, a gene accidentally duplicated, which helped the neurons in our brain to form more connections, which might have actually made us smarter.

Irimia says learning about these evolutionary mutations gives us more clues about the mysteries of human development.

Abstract
Epithelial-mesenchymal interactions are crucial for the development of numerous animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control interplays between these tissues is key to understanding morphogenetic evolution. Here, we study Esrp genes, which regulate extensive splicing programs and are essential for mammalian organogenesis. We find that Esrp homologs have been independently recruited for the development of multiple structures across deuterostomes. Although Esrp is involved in a wide variety of ontogenetic processes, our results suggest ancient roles in non-neural ectoderm and regulating specific mesenchymal-to-epithelial transitions in deuterostome ancestors. However, consistent with the extensive rewiring of Esrp-dependent splicing programs between phyla, most developmental defects observed in vertebrate mutants are related to other types of morphogenetic processes. This is likely connected to the origin of an event in Fgfr, which was recruited as an Esrp target in stem chordates and subsequently co-opted into the development of many novel traits in vertebrates.

Introduction
During embryo development, tissues proliferate and differentiate in a coordinated manner to build a whole organism through a genome-guided process. Different cell types express distinct transcriptomes to control cellular identity and physiology, and to establish differential interaction capabilities between embryonic tissues. Final morphology is thus achieved by cell-specific transcriptomic responses to external and internal stimuli within each tissue. Therefore, changes in the genetic networks involved in morphogenesis are ultimately responsible for both the modification of organs and, at a macroevolutionary scale, the origin of new structures^1,2.

In particular, epithelial-mesenchymal interplays are essential to many organogenetic processes in vertebrates^3,4. These tissues often interact in morphogenetic interfaces through the exchange of cells and signaling molecules^5,6. Despite the great diversity of cell types across the embryo, the majority can be classified as showing either mesenchymal or epithelial characteristics. This broad distinction, which is independent of tissue origin, has also been shown to be reflected in the patterns of gene expression and alternative splicing (AS)⁷. Those transcriptomic programs confer partly antagonistic morphogenetic properties to epithelial and mesenchymal tissues by modulating certain cellular features, such as adhesion, motility and polarity.

Of particular importance for mammalian morphogenesis is a mutually exclusive exon skipping event found in members of the FGF receptor (Fgfr) gene family⁸. Exons IIIb and IIIc encode a region of the third immunoglobulin domain (IgIII) of the FGFR1, FGFR2, and FGFR3 proteins, and are differentially included in transcripts from epithelial or mesenchymal cells, respectively. Importantly, their mutually exclusive inclusion has a dramatic effect on the affinity of the receptors for FGF ligands⁹, providing epithelial cells specificity for FGF signals secreted by the mesenchyme, and vice versa. Consistent with the importance of this regulatory system in development, disruption of the Fgfr2-IIIb isoform leads to severe defects during mice organogenesis¹⁰.

These and other morphogenesis-associated AS events are directly regulated by the Epithelial Splicing Regulatory Protein (Esrp) genes in mammalian species¹¹. Esrp1 and Esrp2 were originally identified as positive regulators of IIIb exon inclusion of the Fgfr2 gene¹². They encode RNA-binding proteins that are dynamically expressed mainly in a subset of epithelial tissues during mouse development¹³, although mesenchymal expression has also been reported in chicken¹⁴. Recently, double knockout (DKO) mice for both Esrp genes were shown to display severe organogenetic defects and a complete shift to exon IIIc inclusion in Fgfr1, Fgfr2, and Fgfr3¹⁵. In addition, many Esrp exon targets were identified in genes involved in cell–cell adhesion, cell polarity, and migration¹⁶. However, the origin and evolution of Esrp morphogenetic functions and its regulated AS programs remain largely unknown.

Here, to investigate the evolution of Esrp functions and associated transcriptomic programs, we performed Esrp loss-of-function or gain-of-function experiments in several deuterostome species. Within bony vertebrates, Esrp genes play conserved roles in the development of numerous homologous organs. Consistently, Esrp regulates a core set of homologous exons in the three studied vertebrate species, including the mutually exclusive exons in the Fgfr family. Study of three non-vertebrate deuterostomes showed that Esrp is involved in a wide variety of morphogenetic processes in multiple unrelated structures in these species, and that, among others, it likely played an ancestral role in regulating specific mesenchymal-to-epithelial transitions (METs) in the deuterostome ancestor. However, transcriptomic analyses showed that most exons present clade-restricted differential regulation. In particular, no Esrp-dependent alternative exons were found conserved between studied species belonging to different phyla. Exemplifying this split, we show that the Fgfr event affecting the IgIII domain originated from a Bilateria hotspot of recurrent AS evolution that was co-opted as an Esrp target at the base of chordates.

Fig. 1

Expression and developmental roles of esrp1 and esrp2 in zebrafish. a WMISH for esrp1 and esrp2 in Danio rerio WT embryos. At 14 h.p.f., esrp1 transcripts were observed in embryonic epidermis, while esrp2 expression was only detected in the polster (po). At 16 h.p.f., esrp1 was restricted to the posterior and tailbud (tb) epidermis, whereas esrp2 persisted in the hatching gland rudiment (hr) and mild expression started to be detected in the otic placode (ot). By 20 h.p.f., esrp1 was found in the tailbud epidermis and more subtly in the olfactory placode (ol), while esrp2 appeared in new territories, such as pronephros (pn) and ectodermal cells of tailbud fin fold (ff). At 24 h.p.f., expression of both paralogs presented a similar pattern including olfactory and otic placodes, cloaca (cl), and epidermis (ep), although esrp2 was also observed in the hatching gland (hg). By 36 h.p.f., both genes were detected in the inner ear epithelium (ie), notochord (nt), and phanynx (ph), and esrp2 was also observed in the heart (he). At 48 h.p.f., expression was found predominantly in inner ear and pharynx. b Schematic representation of the genomic and transcriptomic impact of the selected esrp1 and esrp2 mutations. Blue boxes/lines represent genomic deletions in the mutants, while the red line depicts an altered splice junction in the esrp1 mutant allele. TSS, transcription start site; PTC, premature termination codon; del, deletion. Standard and fluorescent (green dot) primers used during genotyping are represented by arrows. c Left: genotyping of embryos by fluorescent PCR readily distinguished between WT and MUT alleles. Right: Representative 5 d.p.f. larvae for wild type (WT), esrp1 mutant (esrp1^MUT/MUT), esrp2 mutant (esrp2^MUT/MUT), and double mutant (DMUT) genotypes. Deflated swim bladder in the DMUT embryo is indicated by a red asterisk. d–i Phenotypic differences between 6 d.p.f. WT (top) and DMUT (bottom) embryos in different embryonic structures. DMUT larvae showed impaired fin formation (arrows) and cleft palate (arrowhead) d, including malformation of the ethmoid bone, as shown by Alcian blue staining e. f–i Transversal histological sections stained with hematoxylin and eosin showing structural differences in pectoral fin f, esophagus g, inner ear h and olfactory epithelium i. Black arrowheads mark the dorso-lateral septum between semicircular canals in h. Proximal (pr) and distal (dl) parts of the fin are indicated in f. Scale bars: 1 mm a, 2 mm c–e, 100 µm f–h, 50 µm i

Burguera, D., Marquez, Y., Racioppi, C. et al.
Evolutionary recruitment of flexible Esrp-dependent splicing programs into diverse embryonic morphogenetic processes. Nat Commun 8, 1799 (2017). https://doi.org/10.1038/s41467-017-01961-y

Copyright: © 2024 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

This finding is exactly what the Theory of Evolution predicts. A mutant gene which, in the environment of a remote ancestor millions of years ago was neutral so free to drift in allele frequency over time, later proved to be significantly advantageous and placed the descendants of that organism on a new evolutionary trajectory, in this case the evolution of limbs and the eventual colonization of land by vertebrates.

The idea that creationists find hard to grasp here is that the eventual outcome we see today was not an intended outcome at all; it is simply what a series of chance mutations, selected for by the prevailing environment, produced over time. There was no plan, not even one to produce them, shocking as that may seem to a creationist, or even those who claim to believe in evolution but insist a god must have guided it to produce them.

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