F Rosa Rubicondior: Creationism in Crisis - How A Small Mutation Made Us Human - And Shows Our Common Origin With Other Apes

Friday 19 April 2024

Creationism in Crisis - How A Small Mutation Made Us Human - And Shows Our Common Origin With Other Apes

A regulatory variant impacting TXB1 expression contributes to the morphology at the base of the skull. (SNP = single nucleotide polymorphisms).
Genetic Variant Identified that Shaped the Human Skull Base|Tokyo Medical and Dental University, National University Corporation

Creationists like Michael J Behe try to fool their fellow cultists that all mutations are 'devolutionary' and move the organism away from some notional idea of created perfection, although perfection for what is never stated. It is left to the parochial ignorance of the reader to fill the gap and conclude that the religious superstition of 'The Fall' must be true, so he can claim his absurd notion is not really Christian fundamentalism in a lab coat like his 'intelligent design' notion, but real science.

The same parochial, ignorant religious fundamentalists will also assume that somehow humans represent the supreme created perfection (how could it be otherwise for those who, with the 'humility' of a religious fundamentalist, see themselves as the perfect creations of a perfect creator?).

So how does that square with the many examples of mutations being what makes humans different to other species, as shown by any comparison of our genome with that of apes such as chimpanzees or bonobos?

Of course, it's biological nonsense to talk of perfection without reference to the environment and how a mutation affects fitness in that environment, and fitness is what the process of natural selection produces. There is no perfect pattern against which to compare what evolution produces, so both Homo sapiens and Pan troglodytes (common chimpanzee) are perfect at being human or common chimpanzee respectively, as is are African elephants, a cabbages, or a bacteria, perfect at being what they are.

And this was demonstrated a few days ago with publication of a paper by a team from Tokyo Medical Dental University (TMDU), the University of Helsinki, and the University of Barcelona who have analysed the genetics of the shape of the base of the human skull and found it to be due to a mutation in a single gene called TBX1. The mutation is a single nucleotide polymorphism (SNP), which means a change in a single letter in the DNA 'code' for a single amino acid. The SNP (“rs41298798”) is in the DNA involved in the regulation of TXB1.

This single mutation allowed the base of our skull to change shape as our brain enlarged as we became more intelligent and more dependent on technology and the cognitive abilities that enabled us to become Homo sapiens.

The team have published their findings, open access, in the Cell Press, American Journal of Human Genetics, the journal of the American Society for Human Genetics, and explain it in a TMDU News release:
Researchers from Tokyo Medical and Dental University (TMDU) and the Universities of Helsinki and Barcelona have identified a single nucleotide change key in the evolution of human skull morphology, affecting TXB1 gene expression and skull base development
Tokyo, Japan – Humans, Homo sapiens, have unique features compared with other closely related hominin species and primates, including the shape of the base of the skull. The evolutionary changes underlying these features were significant in allowing the evolution of our increased brain size. Now, in a study recently published in the American Journal of Human Genetics, a team from Tokyo Medical and Dental University (TMDU), the University of Helsinki, and the University of Barcelona has analyzed a genomic variant responsible for this unique human skull base morphology.

Most of the genomic changes that occurred during human evolution did not occur directly to genes themselves, but in regions responsible for controlling and regulating the expression of genes. Variants in these same regions are often involved in genetic conditions, causing aberrant gene expression throughout development. Identifying and characterizing such genomic changes is therefore crucial for understanding human development and disease.

The development of the basicranial region, the base of the skull where it joins the bones of the neck, was key in the evolution of Homo sapiens, as we developed a highly flexed skull base that allowed our increased brain size. Therefore, variants that affect the development of this region are likely to have been highly significant in our evolution.

First, the team searched for variants in just a single letter of the DNA code, called single nucleotide polymorphisms (SNPs), that caused different regulation of genes in the basicranial region in Homo sapiens compared with other extinct hominins. One of these SNPs stood out, located in a gene called TXB1.

They then used cell lines to show that the SNP, called “rs41298798”, is located in a region that regulates the expression levels of the TXB1 gene, and that the “ancestral” form of the SNP, found in extinct hominins, is associated with lower TXB1 expression, while the form found in Homo sapiens gives us higher levels of TXB1.

“We then employed a mouse model with lower TXB1 expression,” explains lead author Noriko Funato, “which resulted in distinct alterations to the morphology at the base of the skull and premature hardening of a cartilage joint where the bones fuse together, restricting the growth ability of the skull.” The changes in the Tbx1-knockout mice were reminiscent of the known basicranial morphology of Neanderthals.

These morphological changes are also reflected in human genetic conditions associated with lower TXB1 gene dosage, such as DiGeorge syndrome and velocardiofacial syndrome, further indicating the significance of this genetic variant in the evolution of our unique skull base morphology.

The identification of this genomic variant sheds light on human evolution, as well as providing insight into common genetic conditions associated with lower expression of the TXB1 gene, paving the way for greater understanding and management of these conditions.
Technical details and background to the research are given in the team's open access paper:

Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TXB1, implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TXB1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TXB1 expression levels compared to the ancestral allele. Tbx1-knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TXB1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TXB1 contributes to the formation of skull base and vertebral structures found in Homo sapiens.

Graphical abstract


Genetic variants that distinguish Homo sapiens from closely related extinct hominins, for whom high-coverage genomes are available, are predominantly located in the noncoding regions of the genome.1,2,3,4 These noncoding variants, particularly in regulatory regions, have the potential to affect gene expression.5,6,7 Changes in this regulatory program are likely to have had a significant impact on human evolution, with evidence suggesting that these changes underlie morphological differences between our closest relatives.2,8,9,10 Noncoding single-nucleotide polymorphisms (SNPs) often affect gene expression by altering the function of enhancer elements and are under evolutionary pressure.6,7,11,12 In addition, these noncoding SNPs have also been implicated in human disease by playing a critical role in controlling the expression of target genes during development,13 although most noncoding variants associated with disease susceptibility are unlikely to be strongly deleterious.14 To improve our understanding of the genetic and molecular basis of morphological differences in Homo sapiens, the identification of causal variants and the interpretation of the biological impact of regulatory divergence on human evolution are essential.9,15 However, pinpointing these causal variants remains extremely challenging.16

The skull of Homo sapiens has acquired unique cranial features among primates, including a highly flexed skull base, with an increase in absolute and relative brain size during hominin evolution.17,18 Compared to modern humans (Homo sapiens), closely related extinct hominins and other great apes have different skull base phenotypes, including a flatter basicranium, a shorter length of the posterior skull base, and an anteroposteriorly elongated foramen magnum.16,17,19,20 It is hypothesized that the distinctive morphology and evolution of the human skull are influenced, at least in part, by changes in brain development and embryonic brain-skull interactions.18,21 The synchondroses of the skull base play a critical role in embryonic and postnatal skull elongation.22 To retain their capacity for accelerated fetal and postnatal growth, synchondroses must remain unmineralized as cartilage.22,23 In particular, the spheno-occipital synchondrosis (SOS) persists in the endochondral basicranium and does not ossify until 16–18 years of age in humans, contributing to the longitudinal growth of the skull.22 In the vertebral column, dysmorphic vertebrae and platyspondyly are frequently observed in our closest extinct relatives.24,25

Studying the mechanisms driving human diseases and pathological conditions in skeletal morphology can provide clues to evolutionary anatomical changes.16 Chromosome 22q11.2 deletion is one of the most common genetic microdeletions in humans.26 A 1.5 Mb hemizygous deletion of 22q11.2 causes most craniofacial phenotypes of DiGeorge syndrome (DGS [MIM: 188400]) and velocardiofacial syndrome (VCFS [MIM: 192430]). TXB1 (MIM: 602054), located at 22q11.21, encodes T-box transcription factor 1. Heterozygous loss-of-function mutations in TXB1 also cause DGS, VCFS, and conotruncal anomaly face syndrome (MIM: 217095).26,27,28,29 Some individuals with DGS/VCFS show changes in the structure of the skull base and the vertebral column.30,31,32,33,34 Tbx1 (GenBank: 21380) knockout (KO) mice exhibit cardiac and craniofacial phenotypes that mirror those observed in individuals with DGS/VCFS.35,36,37,38 During mouse embryonic development, TXB1 is localized in the cartilaginous primordium of the posterior skull base and plays a critical role in maintaining the undifferentiated phenotype of chondroprogenitors in the SOS.39 In Tbx1-KO mice, the SOS in the skull base is completely mineralized at birth,39 and the anterior arch of the first cervical vertebra is aplastic.35,37,38 Using the similar skeletal phenotypes of Tbx1-KO mice and DGS/VCFS to investigate the morphological effects of Tbx1 and TXB1 dosage may provide a basis for understanding morphological changes in modern human lineage.

In the present study, we identified an ancestral allele within the TXB1 locus that may contribute to the basicranial morphology found in Homo sapiens. To elucidate how the TXB1 locus influences basicranial morphology, we identified the target genes regulated by SNP rs41298798 and the mechanism by which this SNP controls TXB1 expression. Furthermore, we analyzed the effects of TXB1 dosage on the basicranial morphology found in Homo sapiens.
So, it would seem we owe the main difference between us and the other apes, and between us and our closes extinct ancestor, the Neanderthals, to a 'single nucleotide polymorphism', i.e., the smallest possible genetic mutation, being a single change in the triplet code for an amino acid.

And as a further disappointment to creationists, the authors have no doubt that evolution provides the only logical explanation for this observation, despite the assurances their cult leaders have been giving them for the last 20 or more years that mainstream biologists are about to abandon the TOE in favour of their childish, magic-based superstition, and so prove them right all along.

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