Refuting Creationism
Students Discover How The Mammalian Immune System Evolved.
Students Discover How The Mammalian Immune System Evolved.
Nebraska undergrads uncover ancient secrets of human immunity | Nebraska Today
(C–F) Expanded views of the interaction interface between STAT2 CCD and IRF9 IAD for mouse (C), human (D), Hypanus sabinus (E), and Stegostoma tigrinum (F). The interactions are observed in the crystal structure of the mouse STAT2-IRF9 complex (PDB ID: 5OEN) [19]. For humans and the two cartilaginous fishes, the interactions are based on the modeled structures of the STAT2-IRF9 complex. The key residues involved in the interface are labeled. The phenylalanine (F) on the STAT2 protein is colored in green. The four residues forming the cleft on the IRF9 protein are colored in magenta. The corresponding sequences of the interface area and other details are found in Supporting Information S1: Figure S3.
These findings offer robust evidence supporting the theory of evolution by demonstrating the gradual and adaptive changes in genetic material that have led to sophisticated immune functions in humans. The identification of a pseudogene's integration into primate DNA and its subsequent role in immunity exemplifies natural selection's influence on genetic composition over millions of years. Such evidence challenges creationist perspectives by providing concrete examples of evolutionary processes shaping complex biological systems, underscoring the dynamic nature of genetic evolution in response to environmental pressures.
During the course of evolution, these factors have evolved as additional layers of complexity to improve and refine a system which, as the product of an unplanned, utilitarian evolutionary process was a suboptimal compromise between the tendencies to over-react to some infections and fail to respond to others. An intelligently-designed sytem would need no such regulatory mechanisms. This is how we can tell that such overly-complex systems were not intelligently designed.
What are interferon regulatory factors (IRFs), what role do they play in the human immune system and why are they needed?In addition to the two papers in Medical Virology the students' work is explained in Nebraska Today, from The University of Nebraska - Lincoln:Interferon Regulatory Factors (IRFs) are a family of transcription factors that play crucial roles in regulating immune responses, particularly those involving interferons—proteins critical for defence against viral infections and other pathogens. They act as molecular switches that turn genes on or off in response to signals indicating infection or cellular stress.
In the human immune system, IRFs orchestrate antiviral responses by controlling the production of interferons and cytokines, coordinating both innate (non-specific, immediate) and adaptive (specific, long-term) immunity. When a virus infects cells, certain IRFs (such as IRF3 and IRF7) become activated, triggering the expression of interferons. These interferons then warn neighbouring cells, enhancing their antiviral defences and activating immune cells like macrophages, dendritic cells, and natural killer (NK) cells.
IRFs are essential because they help maintain a delicate balance in immune responses—ensuring pathogens are efficiently cleared while limiting excessive inflammation, which can cause severe tissue damage or autoimmune conditions. The evolutionary conservation and complexity of IRFs highlight their importance in adaptive evolution, demonstrating how intricate molecular mechanisms evolved to defend against diverse and continually changing microbial threats.
Nebraska undergrads uncover ancient secrets of human immunityThe August 2024 paper:
Three Husker students under the mentorship of Luwen Zhang, a leading University of Nebraska–Lincoln virologist, have achieved a rare feat for undergraduates.
Vanessa Hubing, a junior biological sciences major from Castle Pine, Colorado; Avery Marquis, a senior pre-veterinary medicine student from Omaha; and Chanasei Ziemann, a recent biological sciences graduate from Hickman, Nebraska; are first authors of two recently published scientific research articles that describe significant findings about how human immune systems evolved.
Undergraduates are often participants in research as part of a larger group — but first authorship is very rare. The three of them made a major contribution to this work.
Luwen Zhang, lead author (both papers)
School of Biological Sciences
University of Nebraska, Lincoln, Nebraska, USA.
All three students worked in Zhang’s laboratory through the university's Undergraduate Creative Activities and Research Experience program, which provides stipends for students to gain research experience while they pursue their bachelor’s degree.
Both studies have to do with how interferon regulatory factors (IRFs) orchestrate innate immune system and inflammatory responses. In one article, published last month in the Journal of Medical Virology, the three young scientists traced how vertebrate organisms developed more sophisticated immune regulation when they evolved to acquire jaws.
In a previous article, published in August, also in the Journal of Medical Virology, the team described how a “pseudogene” — a gene that doesn’t make a protein — may have hitchhiked into the DNA of higher primates via a retrovirus 60 million years ago. They hypothesize that this DNA fragment gave the human ancestors an edge against certain germs — and may continue to play a role in fine-tuning human immune response.
Coached by Zhang, a professor of biological sciences, and his fellow professor Etsuko Moriyama, who specializes in bioinformatics, the student researchers used cutting-edge computer technology to analyze genetic sequences and build phylogenetic trees for organisms including lampreys, sharks, ray-finned fish, birds and humans.
Zhang selected the research topic, and Moriyama helped train the students to do the analysis.
They have never done this kind of computational analysis before. They handled it very well. We guided them how to do it, and they did the work. They also did a very good job for time management.
Luwen Zhang
Hubing and Marquis said mastering the bioinformatics presented a big learning curve. It was not something either of them had experienced before.
As the process is happening, you don’t realize what all the work amounts to — but when you see the article, it makes you feel really accomplished. That really motivates me to pursue a career in science, because I see what all the work can do.
Avery Marquis, first author of the first paper and co-author of the second.
School of Biological Sciences
University of Nebraska, Lincoln, Nebraska, USA.
In addition to shedding light on humanity’s ancient defenses against disease, Zhang said his students’ work offers important hints about how to tackle immune-related diseases. He and Moriyama are actively pursuing grant support to continue the line of research.
This work is very important for all of the fields of immunity, and it drew a lot of attention in the field. One reason is how it relates to chronic human autoimmune diseases.
Luwen Zhang
IRF5, one of a family of nine interferon transcription factors, figured prominently in both studies. It provides a general pathway for immune response to many viruses, including COVID-19 — but overactivation of IRF5 also has been linked to illnesses such as systemic lupus erythematosus, or lupus for short.
An important facet of Zhang’s research is understanding how the immune system balances itself. The first to discover IRF7, another factor in the IRF gene family and critical to viral transformation and innate immunity, he uses a blend of virology, molecular and cellular biology, immunology and pathology to understand virus-host interactions.
The February 2025 paper:Abstract
Interferon regulatory factor 5 (IRF5) is a key transcription factor in inflammatory and immune responses, with its dysregulation linked to autoimmune diseases. Using bioinformatic approaches, including Basic Local Alignment Search Tool (BLAST) for sequence similarity searches, BLAST-Like Alignment Tool (BLAT) for genome-wide alignments, and several phylogenetics software, such as Multiple Alignment using Fast Fourier Transform (MAFFT), for phylogenetic analyses, we characterized the structure, origin, and evolutionary history of the human IRF5 pseudogene 1 (IRF5P1). Our analyses reveal that IRF5P1 is a chimeric processed pseudogene containing sequences derived from multiple sources, including IRF5-like sequences from disparate organisms. We find that IRF5P1 is specific to higher primates, likely originating through an ancient retroviral integration event approximately 60 million years ago. Interestingly, IRF5P1 resides within the triple QxxK/R motif-containing (TRIQK) gene, and its antisense strand is predominantly expressed as part of the TRIQK pre-messenger RNA (mRNA). Analysis of publicly available RNA-seq data suggests potential expression of antisense IRF5P1 RNA. We hypothesize that this antisense RNA may regulate IRF5 expression through complementary binding to IRF5 mRNA, with human genetic variants potentially modulating this interaction. The conservation of IRF5P1 in the primate lineage suggests its positive effects on primate evolution and innate immunity. This study highlights the importance of investigating pseudogenes and their potential regulatory roles in shaping lineage-specific immune adaptations.
1 INTRODUCTION
Interferon regulatory factor 5 (IRF5) is a transcription factor that plays a key role in the regulation of inflammatory and immune responses. IRF5 is a member of the IRF family of transcription factors, which contain a conserved DNA-binding domain that binds to interferon-stimulated response elements found in the promoters of interferon target genes.1-5 Upon activation, IRF5 translocates to the nucleus where it regulates expression of downstream target genes involved in type I interferon signaling, cytokine production, cell proliferation, and apoptosis. Dysregulation of IRF5 has been implicated in several autoimmune and inflammatory diseases.2, 6 The mechanisms by which IRF5 genetic variants contribute to autoimmunity and inflammation continues to be an important avenue of research, as IRF5 may represent a promising therapeutic target for treating these diseases.6 The primate immune system has evolved unique features in response to specific pathogenic challenges over millions of years. Notable examples of primate-specific immune adaptations include the expansion and diversification of killer cell immunoglobulin-like receptor genes, which play a crucial role in natural killer cell function and have undergone significant changes in different primate lineages.7, 8 Similarly, interferon-stimulated genes have adapted in primates showing primate-specific variants or expression patterns.9, 10 The evolution of primate-specific tripartite motif-containing protein 5 alpha isoforms in different primate species provides varying degrees of protection against various viral pathogens.11-13 Pseudogenes are DNA sequences that resemble functional genes but are generally thought to have lost their protein-coding ability or gene expression potential.14 Pseudogenes are ubiquitous in genomes across taxa and they arise primarily from gene duplication or retrotransposition.14, 15 Although initially thought of as nonfunctional genetic elements, recent research has uncovered diverse functional roles for pseudogenes. For example, some retain the ability to produce RNAs that regulate expression levels of functional progenitor genes or even produce truncated proteins with novel activities.16, 17 Other pseudogenes play roles in regulating gene expression by acting as decoys for microRNAs (miRNAs) that would otherwise suppress messenger RNAs (mRNAs) from related coding genes.18-20 There is also evidence that pseudogene transcription may elicit autoimmune responses in some diseases.20, 21 Therefore, pseudogenes exhibit functionality ranging from gene expression regulation to generation of immunological epitopes. To investigate the potential role of IRF5 pseudogene 1 (IRF5P1) in primate innate immunity, we systematically analyzed the IRF5P1 gene. Our results reveal that IRF5P1 has high DNA sequence similarity to two mRNA sequences in the functional domains of IRF5. The DNA sequences of IRF5P1 exhibit a mixed origin and likely originated approximately 60 million years ago. Because IRF5P1 antisense RNA are at least transiently expressed, evolutionary conservation in primate genomes implies selection for functional noncoding roles. Studying IRF5P1 may reveal noncoding regulatory functions or novel peptide products relevant to IRF5 biology and human diseases.
Marquis, Avery; Hubing, Vanessa; Ziemann, Chanasei; Moriyama, Etsuko N.; Zhang, Luwen
The primate-specific presence of interferon regulatory factor-5 pseudogene 1 Journal of Medical Virology 96 (8) e29879 DOI: 10.1002/jmv.29879
Copyright: © 2024 The authors.
Published by John Wiley & Son]. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
In the immune system, we observe multiple layers of complexity accumulating over time, each responding to the limitations of earlier configurations—a clear signature of evolution. As shown by recent research, changes such as the evolution of jaws and subsequent dietary shifts introduced new environmental pressures, necessitating further adaptations. Despite this continuous refinement, our immune system still struggles to fully protect us from parasites, many of which have simultaneously evolved sophisticated strategies to evade our improved defences in a relentless evolutionary arms race. Moreover, the immune system often overreacts, mistakenly attacking the body itself, resulting in autoimmune diseases.ABSTRACT The emergence of jaws in early vertebrates introduced a novel feeding apparatus and powerful oral defenses, but it also increased the risk of physical injury and pathogen exposure. Interferon regulatory factors (IRFs) play critical roles in orchestrating innate immunity and inflammation in response to invading microbes and tissue damage, with their subcellular localization being essential to some IRFs' function. Our results indicate that IRF members underwent independent expansion and diversification in two distinct vertebrate lineages: jawed and jawless vertebrates. The jawed vertebrate-specific factor, IRF5, has maintained conserved nuclear export sequences throughout evolution, while newly diversified IRF members in jawed vertebrates have acquired cytoplasmic localization. This cytoplasmic shift particularly affected IRFs involved in type I interferon (IFN) signaling (IRF3, IRF5, IRF7, and IRF9), suggesting co-evolution with the development of the type I IFN system in jawed animals. Interestingly, although IRF9 is inherently nuclear, its association with Signal Transducer and Activator of Transcription 2 (STAT2) has led to its cytoplasmic localization. Additionally, IRF6, another jawed vertebrate-specific factor, plays a crucial role in jaw development, reflecting an evolutionary adaptation that aligns structural innovations with immune function. Our findings suggest that the evolution of jaws coincided with the adoption of cytoplasmic localization in IRF members, potentially enhancing rapid immune responses to meet the immunological challenges posed by the predatory lifestyle of early jawed vertebrates.
1 Introduction
The evolution of jaws marked a transformative innovation in early vertebrates, fundamentally altering their interaction with the environment. This transition from filter feeding to active predation not only enabled access to new food resources but also introduced novel immunological challenges: powerful jaws increased risks of physical injury while consuming larger prey exposed early jawed vertebrates to more diverse pathogen communities. These new environmental pressures likely drove the evolution of more sophisticated immune defenses. The innate immune system and inflammation, constituting the first line of defense against pathogens, injury, and stress, play crucial roles in both immediate protection and broader physiological functions, suggesting their potential co-evolution with jaw-related innovations. Interferon regulatory factors (IRFs), a family of transcription factors, are key orchestrators of innate immune and inflammatory responses. These transcription factors share a conserved DNA-binding domain (DBD) in their N-terminus that recognizes specific DNA sequences [1]. The IRF-association domain (IAD) at the C-terminus determines specific biological functions (Supporting Information S1: Figure S1). A distinctive feature of several IRF family members, particularly those involved in interferon (IFN) signaling (IRF3, 5, 7, and 9), is their cytoplasmic localization in unstimulated cells. This spatial regulation through nuclear-cytoplasmic shuttling serves as a crucial control mechanism for their function [2-6]. Among these cytoplasmic IRFs, IRF5 exemplifies the importance of spatial regulation in immune function. Expressed in immune cells including macrophages and dendritic cells, IRF5 responds to pattern recognition receptor activation by translocating from its cytoplasmic location to the nucleus, where it induces pro-inflammatory cytokines and type I IFNs [7, 8]. Through this regulated trafficking, IRF5 influences both innate and adaptive immunity, and its dysregulation is linked to autoimmune conditions such as systemic lupus erythematosus [9, 10]. While significant advances have been made in understanding IRF biology, the evolution of their nuclear-cytoplasmic trafficking mechanisms remains poorly characterized [11-15]. Here, we conducted phylogenetic and sequence analyses of IRF proteins focusing especially on the transition from jawless to jawed vertebrates. Our findings revealed that this jawless-to-jawed transition was accompanied by both lineage-specific expansion of the IRF family and acquisition of cytoplasmic localization by key IRFs, suggesting an evolutionary innovation that enhanced immune response regulation through spatial control of these transcription factors.
Hubing, Vanessa; Marquis, Avery; Ziemann, Chanasei; Moriyama, Hideaki; Moriyama, Etsuko N.; Zhang, Luwen
Cytoplasmic Shift of Interferon Regulatory Factors Co-Evolved With Jawed Vertebrate Innate Immunity
Journal of Medical Virology 97 (2); DOI: 10.1002/jmv.70247
Published by John Wiley & Son]. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
To creationists, this intricate layering and complexity is perceived as evidence of a purposeful, intelligent creator. However, from a scientific perspective, these observations strongly support evolution as a natural, undirected process driven by environmental pressures and adaptation. The absence of a coherent, optimally designed plan underscores that these adaptations arise from an unguided, utilitarian mechanism, rather than from the foresight of a supreme intelligence.
Complexity is evidence of evolution, not intelligent design. Intelligently designed objects and processes are minimally complex.
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Last Modified: Mon Mar 31 2025 00:18:05 GMT+0000 (Coordinated Universal Time)
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