Rosa Rubicondior: Unintelligent Design - How The Human Genome Has Mutation-Prone Weak Spots

If the outcome is pre-ordained, what are all the other sperms for?

New mutation hotspot discovered in human genome | EurekAlert!

Creationists and other religious fundamentalists claim that their god deliberately fashions each human life according to a divine plan — that every individual is personally designed, even down to the genes they inherit from their parents. But this raises a perpetually unanswered question: why produce so many sperm cells, all competing to reach the egg, if the outcome is pre-ordained?

Creationists also insist that our DNA is a “code”, equivalent to a computer program that must have been created by an intelligent designer or programmer.

If that were true, we would expect the genes bestowed on each individual to be robustly designed and immutable.

However, new research by scientists at the Centre for Genomic Regulation, Barcelona, Catalunya, Spain, just published in Nature Communications, shows that this is not the case — and once again, a prediction of fundamentalist creationism has been falsified by science.

The researchers found that the human genome is especially vulnerable to mutations in the first 100 base pairs of genes, particularly during the earliest rounds of cell division in embryo development. Each division introduces mutations with the potential to cause disease, including cancer. Because these mutations do not appear in every cell of the early embryo, the resulting individual becomes a genetic mosaic, with some cells and tissues carrying certain mutations while others do not. But if the mutated cells give rise to germ cells — eggs or sperm — the mutation can be passed to the next generation, whose members will carry it in all their cells and may develop disease as a result.

Unless creationism’s designer god intended this outcome, or is incompetent, there is no coherent way to present this as the deliberate work of an intelligent designer. It is, however, entirely consistent with an unintelligent, utilitarian evolutionary process that settles for sub-optimal solutions based on a single criterion: what produces the most descendants who themselves reproduce?

Mutations in Early embryos. Mosaicism and Early Embryo Mutations

Mosaicism occurs when an individual develops from a mixture of genetically different cells. These differences arise because mutations can appear during early embryonic cell divisions, long before specialised tissues form. As a result, some tissues may carry certain mutations while others do not.

Why Early Embryos Are Especially Vulnerable

During the first few rounds of cell division:

DNA is copied at extremely high speed.
Proofreading systems are less effective than in later development.
Each new mutation is proportionally amplified because the embryo contains so few cells.
A single mutated cell can give rise to a whole lineage of differentiated tissues.

This makes the earliest stages of development a hotspot for new mutations — a natural and unavoidable feature of biology.

Somatic vs Germline Mutations

Most early mutations are somatic, meaning they affect only the body of the individual and are not passed on. However, if a mutated cell goes on to form part of the germline (the cells that become sperm or eggs), the mutation becomes heritable, appearing in every cell of the next generation.

This blurring of the boundary between somatic and germline changes is a key mechanism by which new genetic variation enters populations.

How Many Mutations Do We Inherit?

Every person is born with roughly 50–100 new mutations that were not present in either parent. Most have no noticeable effect, a few may be harmful, and a very small number can be beneficial. This steady influx of mutations provides the raw material on which evolution works.

The work of the Centre for Genomic Regulation team is summarised in a news release from EurekAlert!

New mutation hotspot discovered in human genome
Gene starting points are vulnerable to mutations which can be passed on to future generations, finds new study
Researchers have discovered new regions of the human genome particularly vulnerable to mutations. These altered stretches of DNA can be passed down to future generations and are important for how we study genetics and disease.

The regions are located at the starting point of genes, also known as transcription start sites. These are sequences where cellular machinery starts to copy DNA into RNA. The first 100 base pairs after a gene’s starting point are 35% more prone to mutations compared with what you’d expect by chance, according to the study published today in Nature Communications.

These sequences are extremely prone to mutations and rank among the most functionally important regions in the entire human genome, together with protein-coding sequences.

Dr. Donate Weghorn, corresponding author
Centre for Genomic Regulation (CRG)
The Barcelona Institute of Science and Technology
Barcelona, Spain.

The study found that many of the excess mutations appear immediately after conception, during the first few rounds of cell division in the human embryo. Also known as mosaic mutations, these changes to the DNA sequence end up in some cells but not others and are part of the reason the mutational hotspot has gone undiscovered until now.

A parent can carry disease-contributing mosaic mutations without symptoms because the change ends up in some cells or tissues only. However, they can still pass the mutation on through their eggs or sperm. The child then carries the mutation in all their cells, which could cause disease.

The researchers made the discovery by looking at transcription start sites across 150,000 human genomes from the UK Biobank and 75,000 from the Genome Aggregation Database (gnomAD). They compared the results with data that included information about mosaic mutations from eleven separate family studies.

They found that many gene starting sites across the human genome experienced excess mutations. When the researchers looked more closely, they found the most affected regions were the starting points of sets of genes linked to cancer, brain function and defective limb development.

The mutations are likely to be harmful. The study found a strong excess of mutations near start sites when looking at extremely rare variants, which are normally very recent mutations. That excess shrunk when looking at older, more common variants, suggesting natural selection is filtering the mutations out. In other words, families with mutations in gene starting sites, particularly those linked to cancer and brain function, are less likely to pass them on. Over generations, the mutations do not stick around.

Avoiding false conclusions and finding missed clues

The study can help avoid false conclusions from mutational models. These are tools which help geneticists determine how many mutations are to be expected in specific regions of the genome if nothing special is going on. Clinically, that baseline is used to determine which variants should be paid attention to and which deprioritised.

Knowing that gene starting points are natural mutational hotspots means the true baseline in these regions is higher than previously thought and models need to be recalibrated to take that into account.

If a model doesn’t know this region is naturally mutation-rich, it might expect, say, 10 mutations but observe 50. If the correct baseline is 80, then 50 means fewer than expected and is a sign harmful changes are being removed by natural selection. You would completely miss the importance of that gene.

Dr. Donate Weghorn.

The study also has implications for genetic studies which only look for mutations present in the child and completely absent in parents. This works well for mutations that are present in every cell, but not for mosaic mutations which end up in a patchwork of different tissues. These studies are filtering out mosaic mutations and inadvertently losing important information about potential contributors to disease.

There is a blind spot in these studies. To get around this, one could look at the co-occurrence patterns of mutations to help detect the presence of mosaic mutations. Or look at the data again and revisit discarded mutations that occur near the transcription starts of genes most strongly affected by the hotspot.

Dr. Donate Weghorn.

A new source of mutations

The process of transcribing DNA into RNA is hectic. The study explains the mutational hotspot exists because the molecular machinery involved often pauses and restarts near the start line. It can even fire in both directions. At the same time, short-lived structures can form that briefly leave one strand of DNA exposed to possible damage.

All of this, the authors argue, makes transcription start sites more prone to mutations during the rapid cell divisions that follow conception. Cells can usually repair these alterations, but under the pressure of needing to grow fast, cells leave some mutations unpatched like scars on the human genome.

The discovery adds a previously missing piece on how mutations arise in the first place. The obvious culprits, like errors during DNA replication or damage from ultraviolet rays, have been known about for decades.

Finding a new source of mutations, particularly those affecting the human germline, doesn’t happen often.

Dr. Donate Weghorn.
Publication:
Cortés Guzmán, M., Castellano, D., Serrano Colomé, C. et al.
Transcription start sites experience a high influx of heritable variants fueled by early development.
Nat Commun 16, 10120 (2025). https://doi.org/10.1038/s41467-025-66201-0

Abstract
Mutations drive evolution and genetic diversity, with the most consequential mutations occurring in coding exons and regulatory regions. However, the impact of transcription on germline mutagenesis remains poorly understood. Here, we identify a mutational hotspot at transcription start sites (TSSs) in the human germline, spanning several hundred base pairs in both directions. Notably, the hotspot is absent in de novo mutation data. We reconcile this by showing that TSS mutations are significantly enriched with early mosaic variants, many of which are excluded from de novo mutation calls, indicating that the hotspot partly arises during early embryogenesis. We associate the TSS mutational hotspot with divergent transcription, RNA polymerase II stalling, R-loops, and mitotic—but not meiotic—double-strand breaks, suggesting a recombination-independent mechanism distinct from known processes. Our findings are reinforced by mutational signature analysis, which highlights alternative double-strand break repair and transcription-associated mutagenesis. These insights reveal a germline mutational phenomenon with evolutionary and biomedical implications, particularly affecting genes linked to cancer and developmental phenotypes.

Introduction
The mutation rate in human cells is influenced by DNA sequence composition and epigenetic factors^1,2,3. Although germ cells and somatic tissue cells share many of these factors, there are fundamental differences in the observed distribution and nature of mutations, particularly due to exogenous and disease-related mutational processes active in the soma⁴. In addition to replication time, which is one of the most important determinants of mutation rate, transcription and the directionality of its effects are also debated^5,6. Transcription affects mutation rate in at least two important ways: (1) via the joint effects of transcription-associated mutagenesis (TAM) and transcription-coupled repair (TCR) on the transcribed sequence itself and (2) via the effects of transcription factor (TF) binding in the regulatory sequence elements⁷.

The balance of TAM and TCR on expressed genes is a topic of great interest. In the soma, gene expression is often thought to correlate negatively with observed mutation density, likely due to a dominant role of TCR, especially in tumours with a strong influx of mutation-inducing DNA damage^2,8. In the germline, the consensus is not as clear. A recent study reported an overall negative correlation between transcription and mutation density, similar to that observed in the soma^9,10. However, this effect was not observed in another study⁴ and reversed when some potential confounding factors were taken into account¹¹, consistent with previous reports^12,13. Hence, it is currently uncertain how large the actual impact of transcription on mutation rates in the germline is when all important covariates of mutation rate are taken into account. Regarding the influence of TFs, it has been shown that promoter-proximal TF binding sites in the soma exhibit an increased mutation density, especially in melanomas and binding sites belonging to CTCF^14,15,16. This effect is likely due to a combination of limited DNA repair and, in particular, increased DNA damage^17,18. Interestingly, Perera & Poulos et al. (2016) found that TF binding alone cannot be the sole reason for the increased mutagenicity at DNAse I hypersensitive sites (DHSs) and speculated that transcription initiation must play an important role16. In the germline, an excess of mutations around testis-active promoter-proximal TF binding sites, especially for T > G mutations, was recently found^19,20.

To shed more light on these open questions, we investigated the effects of transcription on mutation rate by examining the variability of observed mutation density in transcribed regions and their genomic neighbourhood. Using extremely rare variants (ERVs) from two large human whole-genome sequencing cohorts, we uncovered a pronounced mutational hotspot of non(CpG > TpG) mutations near the transcription start site (TSS) in the human germline, extending several hundred base pairs in both directions. Surprisingly, the hotspot is not detectable in de novo mutations (DNMs) from family sequencing data. We show that this apparent discrepancy is resolved by a significant enrichment of the TSS with early mosaic mutations, many of which are removed in family sequencing mutation calling pipelines, unveiling early development as a key factor in TSS mutagenesis. Consistently, analysis of the mechanistic factors driving TSS mutagenesis showed no association with meiotic double-strand breaks, but instead revealed that the hotspot is associated with divergent transcription, stalling of RNA polymerase II (RNAP II), R-loops and mitotic double-strand breaks. Mutational signature decomposition further corroborates the role of mosaic variants occurring during mitotic cell divisions and suggests involvement of non-canonical double-strand break repair, transcription-dependent mutational processes, and a process typically associated with clustered mutations that arise in the female human germline.

Cortés Guzmán, M., Castellano, D., Serrano Colomé, C. et al.
Transcription start sites experience a high influx of heritable variants fueled by early development.
Nat Commun 16, 10120 (2025). https://doi.org/10.1038/s41467-025-66201-0

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

What this research underscores, yet again, is the profound gap between the world as creationists insist it must be and the world as we actually find it. If human beings were the product of a meticulous designer who hand-selects every gene, we should see stability, precision, and a degree of foresight reflected in our biology. Instead, we see a system that is inherently error-prone, full of compromises, and reliant on a developmental process in which chance plays a central role.

The early human embryo is not the showcase of flawless design that Intelligent Design advocates would have us believe. It is a vulnerable, rapidly dividing cluster of cells in which mutations are not only common but inevitable. Many remain harmless, some seed diseases that may emerge decades later, and a few slip into the germline to shape the genomes of future generations. This pattern does not speak of a designer implementing a perfect plan; it speaks of a natural process in which variation arises blindly and selection acts only on the outcomes that happen to be viable.

Once more, the predictions of creationism fail when confronted with evidence. The predictions of evolution, meanwhile, are borne out with striking consistency. A system shaped by natural selection is expected to be messy, contingent, and imperfect — but functional enough to produce descendants who can themselves reproduce. That is exactly what we observe, from embryonic mosaicism to the steady accumulation of new mutations in every generation.

In short, the real world looks nothing like the product of an intelligent designer and everything like the outcome of an unguided, utilitarian evolutionary process. Science continues to reveal the intricacies of that process; creationism merely continues to ignore them.

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