Rosa Rubicondior: Unintelligent Design - How Creationism's Heath-Robinson Designer Muddles Through But Still Messes Up.

Quality control during splicing: When an error in the precursor mRNA is detected, the spliceosome is blocked, the recruited control factors interrupt the “normal” cycle, and a molecular short circuit causes the spliceosome to disassemble.

Spliceosome: How Cells Avoid Errors When Manufacturing mRNA

Q. How can you tell when something is designed by a supreme intelligence with the inerrant ability of foresight?

A. It works perfectly, without errors and does exactly what it was intended to do, nothing more and nothing less.

Q. How can you tell when something is 'designed' by a natural, utilitarian process like evolution by natural selection?

A. It works most of the time, even if not very efficiently, is over-complex and so prone to errors and doesn't anticipate change. It also frequently requires additional layers of complexity to compensate for its errors and inefficiency.

Sadly for intelligent design advocates, structures and processes found in nature are almost never perfect and free from errors and, when examined closely, are seen to be error-prone, suboptimal and requiring additional complexity to compensate for the errors and inefficiencies. And these error-correction mechanisms are themselves error-prone and prone to failure.

One such mechanism, the details of which have just been worked out by researchers at the Heidelberg University Biochemistry Center (BZH) in collaboration with colleagues from the Australian National University, is the system of spliceosomes found in eukaryote cells, that correct the errors in messenger RNA (mRNA) before they are transcribed into functional proteins.

The reason these large nuclear proteins are required is because the DNA the mRNA is transcribed from is contains 'introns' - small sequences that are not part of the gene being coded for. Imagine a computer database of words, which, when a retrieved, inserts random letters in the middle of the word.

Tell me all you know about the spliceosomes found in eukaryote cells. Spliceosomes in Eukaryotic Cells

Overview
The spliceosome is a large and dynamic ribonucleoprotein (RNP) complex found in the nuclei of eukaryotic cells. Its primary function is to remove introns (non-coding sequences) from precursor messenger RNA (pre-mRNA) and ligate the remaining exons (coding sequences) to form a mature mRNA transcript. This process is called RNA splicing and is a crucial step in gene expression.

Structure and Composition
The spliceosome is one of the most complex molecular machines in the cell, rivalling the ribosome in size and complexity. It consists of:

Small Nuclear Ribonucleoproteins (snRNPs)

These are complexes of small nuclear RNAs (snRNAs) and proteins. The major snRNAs involved are:

U1 snRNA
U2 snRNA
U4 snRNA
U5 snRNA
U6 snRNA

Additional Splicing Factors

These include various RNA-binding proteins, helicases, and regulatory proteins that facilitate the splicing reaction.

Each snRNP has a set of proteins that help recognize the splicing sites and catalyse the reactions necessary for intron removal.

Spliceosome Assembly and Splicing Mechanism
Spliceosome assembly is a stepwise and dynamic process that involves multiple conformational changes. The splicing process occurs in the following stages:

Recognition of the Splice Sites

U1 snRNP binds to the 5' splice site (GU sequence at the start of the intron).
U2 snRNP binds to the branch point sequence within the intron, aided by accessory proteins.

Pre-Spliceosome Formation (A Complex)

U2 binding causes a bulging of the branch point adenosine (A), which is crucial for the catalytic reaction.

B Complex Formation

The U4/U6.U5 tri-snRNP complex is recruited.
U4 and U6 snRNAs form base pairs, keeping U6 inactive until the proper conformation is achieved.

Catalytic Activation (C Complex)

U1 and U4 snRNPs are displaced.
U6 snRNA base-pairs with the 5’ splice site and U2 snRNA, forming the catalytic core.
The branch point A attacks the 5’ splice site, forming a lariat intermediate.

Exon Ligation and Intron Release

The 3' OH of the released exon attacks the 3' splice site, leading to exon ligation.
The intron lariat is released and degraded.

Types of Spliceosomes

Major Spliceosome

Processes most introns and uses U1, U2, U4, U5, and U6 snRNPs.

Minor Spliceosome

Processes a rare class of introns (U12-type) and uses U11, U12, U4atac, U6atac, and U5 snRNPs.

Alternative Splicing and Regulation
Spliceosomes enable alternative splicing, which allows a single gene to produce multiple protein isoforms by selecting different exon combinations. This is a major mechanism for increasing proteomic diversity in eukaryotes. Splicing is regulated by splicing factors such as:

SR proteins (Serine/Arginine-rich proteins) that enhance exon recognition.
hnRNPs (Heterogeneous nuclear ribonucleoproteins) that can repress or modulate splicing.
Evolutionary Significance

Spliceosomes are found only in eukaryotes, indicating that intron-exon architecture evolved after the divergence of prokaryotes and eukaryotes.
Some scientists propose that self-splicing Group II introns (found in bacteria and archaea) were evolutionary precursors to the modern spliceosome.
Medical Relevance

Splicing mutations can lead to diseases such as spinal muscular atrophy (SMA), retinitis pigmentosa, and certain cancers.
Drugs targeting splicing (e.g., Spinraza for SMA) are emerging as potential therapies.

The function of the spliceosomes is to run along the length of the immature mRNA molecule, snipping out the introns and joining the remaining 'exons' into a contiguous mature mRNA sequence that codes for a functional protein. The research team also found that if the spliceosome finds the immature mRNA is too badly damaged, it locks it to prevent it being transcribed. If this process fails, it can cause various genetic conditions and cancers.

The research team's findings are described in the journal Nature Structural & Molecular Biology and in a news release from Heidelberg University:

Structural biologists provide a first-time look at the atomic level into the quality control mechanism of this complex molecular machine
A complex molecular machine, the spliceosome, ensures that the genetic information from the genome, after being transcribed into mRNA precursors, is correctly assembled into mature mRNA. Splicing is a basic requirement for producing proteins that fulfill an organism’s vital functions. Faulty functioning of a spliceosome can lead to a variety of serious diseases. Researchers at the Heidelberg University Biochemistry Center (BZH) have succeeded for the first time in depicting a faultily “blocked” spliceosome at high resolution and reconstructing how it is recognized and eliminated in the cell. The research was conducted in collaboration with colleagues from the Australian National University.
The genetic information of all living organisms is contained in the DNA, with the majority of genes in higher organisms being structured in a mosaic-like manner. So the cells are able to “read” the instructions for building proteins stored in these genetic mosaic particles, they are first copied into precursors of mRNA, or messenger RNA. The spliceosome then converts them into mature, functional mRNA. To do this, this large protein-RNA complex, which is located in the cell nucleus, removes non-coding sections (introns) from mRNA precursors and links the coding sections (exons) to form a continuous strand of information. Errors in this process, also known as splicing, are one of the main causes of inheritable genetic disorders and are associated with neurodevelopmental disorders and diseases such as cancer. It was known that the spliceosome has quality control mechanisms, but the mechanistic details were not understood.

For their experiments, the Heidelberg researchers led by BZH director Prof. Dr Irmgard Sinning used the fission yeast Schizosaccharomyces pombe, a model organism frequently used in cell biology. Using molecular markers, defective spliceosomes were identified, purified, and structurally examined via cryo-electron microscopy.

The largely stable structure of the spliceosome center enabled us to obtain high-resolution information. This means that a spliceosome discarded during cellular quality control can be represented at the atomic level for the first time.

Professor Dr. Irmgard Sinning, co-corresponding author
Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany

However, analyzing the components flexibly bound to the periphery of the spliceosome was a major challenge for our work.

Dr Komal Soni, first author
Biochemistry Center (BZH)
Heidelberg University, Heidelberg, Germany

Based on this structural information, the scientists were able to understand which errors occur during splicing, how the spliceosome recognizes faulty processes and subsequently aborts the splicing, thereby sorting out the faulty complex. Using the detailed structures, the researchers were also able to model the underlying molecular mechanisms. The proteins involved in this process of cellular quality control are conserved in eukaryotic organisms from fission yeast to humans. The scientists therefore assume that the mechanisms for recognizing and sorting out faulty spliceosomes have remained largely unchanged over the course of evolution.

The research was carried out as part of a long-term collaboration between the teams of Prof. Sinning and Prof. Dr Tamas Fischer, who specializes in RNA surveillance at the Australian National University in Canberra. Prof. Dr Henning Urlaub’s research group at the Max Planck Institute for Multidisciplinary Sciences in Göttingen also participated. The work was funded by the German Research Foundation and the Australian Research Council. The results of the research were published in “Nature Structural & Molecular Biology”.

Original publication
K. Soni, A. Horvath, O. Dybkov, M. Schwan, S. Trakansuebkul, D. Flemming, K. Wild, H. Urlaub, T. Fischer & I. Sinning:
Structures of aberrant spliceosome intermediates on their way to disassembly.
Nature Structural & Molecular Biology (20 January 2025), DOI: 10.1038/s41594-024-01480-7

Before looking at the team's findings, it's worth trying to understand what these introns are and why they need to be snipped out in the first place, because there is very little sign of any intelligence being involved in their evolutionary origins. Why would any intelligent designer design things that are just a nuisance that has to be overcome?

What is the origin of the 'introns' that need to be snipped out? The origin of introns is a topic of considerable debate in molecular evolution, with two major competing hypotheses:

The Intron Early Hypothesis
This hypothesis suggests that introns were present in the earliest genes and played a fundamental role in the evolution of complex genomes. Key points:

The earliest genes may have consisted of small, modular exons separated by introns.
Introns could have facilitated the shuffling of exons, promoting the evolution of new proteins.
Over time, prokaryotes lost introns due to selective pressure for genome efficiency, while eukaryotes retained them.
Supporting Evidence:

Some modern genes show "exon shuffling," where exons from different genes appear to have been recombined.
Some protein domains correspond to individual exons, suggesting early modular assembly of genes.
Weaknesses:

Prokaryotes, which evolved first, lack spliceosomal introns.
No clear evidence that introns were widespread in the earliest genes.

The Intron Late Hypothesis
This hypothesis suggests that introns appeared later in evolution, after prokaryotes and eukaryotes diverged. Key points:

Introns were inserted into genes after eukaryotes evolved, possibly through mobile genetic elements like transposons or self-splicing elements.
Prokaryotes never had them (or rapidly removed them) to maintain small, efficient genomes.
Supporting Evidence:

Introns in eukaryotes resemble Group II self-splicing introns found in bacteria, suggesting a horizontal gene transfer event.
The spliceosome may have evolved from these self-splicing introns, adapting to a more complex genome.
Weaknesses:

If introns were introduced late, how did they become so widespread in eukaryotic genes?

Group II Introns: The Evolutionary Link?
A leading theory proposes that introns originated from self-splicing Group II introns, which are found in modern-day bacteria and archaea.

Group II introns can cut themselves out and reinsert elsewhere, much like a primitive version of the spliceosome.
These elements may have entered an ancestral eukaryote via endosymbiosis (possibly when mitochondria were acquired).
Over time, eukaryotic cells co-opted these introns, leading to the evolution of spliceosomal introns and the modern spliceosome.
Supporting Evidence:

Group II introns use a lariat mechanism similar to spliceosomes.
The snRNAs of the spliceosome (U6 and U2) show sequence similarities to Group II intron RNA structures.

Why Do Eukaryotes Still Have Introns?

Evolutionary inertia: Once spliceosomal introns became widespread, they persisted.
Alternative splicing: Introns allow for the production of multiple proteins from a single gene.
Regulation: Some introns contain regulatory elements affecting gene expression.

Conclusion: An Intron-Mediated Evolution?
The Group II intron hypothesis is currently the most widely accepted explanation for the origin of introns in eukaryotes. These mobile elements, likely inherited from bacteria or archaea, were domesticated into the modern spliceosomal machinery.

Abstract
Intron removal during pre-mRNA splicing is of extraordinary complexity and its disruption causes a vast number of genetic diseases in humans. While key steps of the canonical spliceosome cycle have been revealed by combined structure–function analyses, structural information on an aberrant spliceosome committed to premature disassembly is not available. Here, we report two cryo-electron microscopy structures of post-Bact spliceosome intermediates from Schizosaccharomyces pombe primed for disassembly. We identify the DEAH-box helicase–G-patch protein pair (Gih35–Gpl1, homologous to human DHX35–GPATCH1) and show how it maintains catalytic dormancy. In both structures, Gpl1 recognizes a remodeled active site introduced by an overstabilization of the U5 loop I interaction with the 5′ exon leading to a single-nucleotide insertion at the 5′ splice site. Remodeling is communicated to the spliceosome surface and the Ntr1 complex that mediates disassembly is recruited. Our data pave the way for a targeted analysis of splicing quality control.

K. Soni, A. Horvath, O. Dybkov, M. Schwan, S. Trakansuebkul, D. Flemming, K. Wild, H. Urlaub, T. Fischer & I. Sinning:
Structures of aberrant spliceosome intermediates on their way to disassembly.
Nature Structural & Molecular Biology (20 January 2025), DOI: 10.1038/s41594-024-01480-7

Copyright: © 2025 The authors.
Published by Springer Nature, open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Apart from the muddle creationism's intelligent designer seems to have gotten itself into over what should be a simple matter of transcribing the DNA sequences into mRNA sequences to produce the right proteins, there is another matter that would embarrass creationists if they understood the subject well enough to see the flaw in William A. Dembski's 'proof of intelligent design', this paper reveals.

Dembski argues that the genetic information in DNA is so highly 'specified' to produce exactly the right proteins that it must have been provided by an intelligence in the form of 'specified information'. Although, in keeping with intelligent design creationism, he never explains the process involved nor where in evolving organisms this insertion of 'specified information' occurred, but we now see that it isn't very well specified and needs a complex, error-prone process to correct the mistakes in it.

Presumably, Dembski's intelligent designer lacked the competence to get it right first time and needed to include an overly-complex process to correct its errors.

And when that too fails, we get genetic diseases and cancers, because the intelligent designer wasn't capable of designing a simpler, error-free process and getting it's 'specified information' right.

The scientific explanation of the mindless process of evolution suffers from no such defects, nor does it require unexplained, undetectable supernatural entities using a methodology that remains a mystery having never been observed.

Advertisement

Amazon