'Preparing the popular film of a Taube soaring above Rheims cathedral'
W. Heath-Robinson (1915)
Creationism's putative designer is like William Heath Robinson but without the competence.
Like creationism's putative designer, William Heath Robinson's 'irreducibly complex' designs are ludicrously over-complicated solutions to simple problems, but at least Heath-Robinson's machines look as though they would work if ever anyone constructed one.
Designed by creationism's supposed omniscient, omnipotent designer the bits of knotted string used to connect things together, and originally designed for a different purpose altogether, would have knots that came undone, or they would be made of elastic, or the chair used to stand something on to make it tall enough would have a broken leg.
The problem starts with the clunky workaround for the problem caused by using the same method for replicating cells in a multicellular organism that is used in single-celled organisms where the entire genome has to be duplicated in each daughter cell. But in a multicellular organism, where there is cell specialisation to gain any benefit from multicellularity, each specialist cell only needs a few genes, so the rest have to be switched off. Creationism's divine incompetence came up with the usual overly complex solution to this problem of its own making in the form of the epigenetic system, adding an unnecessary layer of complexity when the simple solution would have been to give each specialist cell just the genes it needs and no more.
And this become even more complicated when, during the life of a multicellular organism, specialist cells need to change slightly according to the needs of the organism as a whole, so a system of signals had been devised to tell the cells when to switch on some genes and switch off others. Another layer of complexity, and this is where things start to go wrong - the equivalent of Heath-Robinson's knotted string coming undone or stretching, or the chair supporting the entire structure starting to buckle.
Scientists at the Wellcome Sanger Institute's Wellcome Genome Campus, Hinxton, Cambridgeshire, UK, Cambridge University and AstraZeneca have discovered that genes are sometimes active when they should be switched off, even in healthy people.
Researchers have recently found that some human genes remain active when they should be inactive* What are some of the diseases caused by this misexpression of genes? Misexpression of genes, where genes are active when they should be inactive, can contribute to a variety of diseases. Here are some of the diseases and conditions caused by this phenomenon:The human genome contains about 19,000 genes and, although only about 0.07% of these misexpress at any one time, this amounts to 96% of sampled individuals have active genes that should be inactive. Misexpression of genes has been linked to a number of rare diseases.
- Cancer: Aberrant activation of oncogenes (genes that have the potential to cause cancer) can lead to uncontrolled cell growth and tumor development. Examples include:
- Breast Cancer: Overexpression of the HER2 gene.
- Colorectal Cancer: Activation of the Wnt signaling pathway.
- Leukemia: Activation of the BCR-ABL fusion gene in chronic myeloid leukemia.
- Autoimmune Diseases: Genes that regulate the immune system, if misexpressed, can cause the immune system to attack the body's own tissues.
- Systemic Lupus Erythematosus (SLE): Overactivity of genes involved in immune response.
- Rheumatoid Arthritis: Misexpression of genes that lead to inflammation and joint damage.
- Neurological Disorders: Misexpression of genes in the brain can lead to various neurological conditions.
- Alzheimer’s Disease: Abnormal expression of genes involved in amyloid precursor protein processing.
- Schizophrenia: Dysregulation of genes involved in neurotransmission and synaptic function.
- Developmental Disorders: Improper expression of genes during development can cause congenital anomalies and developmental delays.
- Down Syndrome: Overexpression of genes on chromosome 21.
- Fragile X Syndrome: Dysregulation of the FMR1 gene.
- Cardiovascular Diseases: Genes regulating heart and blood vessel function, if misexpressed, can lead to heart disease.
- Hypertrophic Cardiomyopathy: Overexpression of genes involved in cardiac muscle growth.
- Metabolic Disorders: Genes involved in metabolic pathways, if improperly regulated, can result in metabolic diseases.
- Diabetes: Misexpression of genes that regulate insulin production and glucose metabolism.
Understanding the specific genes and pathways involved in these diseases is crucial for developing targeted therapies and interventions.
The research team's findings are published, open access, in Cell Press American Journal of Human Genetics, and are explained in a Welcome Sanger Institute news release:
New insights into the prevalence and mechanisms of gene misexpression in a healthy population could help in diagnosing and developing treatments for complex diseases.
Scientists have uncovered that ‘gene misbehaviour’ – where genes are active when they were expected to be switched off – is a surprisingly common phenomenon in the healthy human population.
The team also identify several mechanisms behind these gene activity errors. This may help inform precision medicine approaches and enable the development of targeted therapies to correct expression.
Researchers from the Wellcome Sanger Institute, the University of Cambridge and AstraZeneca studied the activity of inactive genes in a large, healthy population for the first time. While rare at the individual gene level, they revealed misexpression is widespread across samples and involved more than half of the genes that should be inactive.
The findings, published today (24 July) in the American Journal of Human Genetics, shed new light on how our genetic code operates. The approach could be used in future research to investigate various complex diseases.
The human genome contains about 19,900 genes. These genes form part of the instruction manual for our bodies, encoding proteins needed to carry out cell functions. Proper gene regulation involves turning these gene instructions on and off as needed, depending on a cell’s specific role or environmental factors. When this regulation fails and a typically inactive gene is activated, or ‘expressed’, it can disrupt normal cell function1.1.
While gene misexpression has previously been linked to several rare diseases, such as congenital limb syndromes2.1, it is not known how often or why this may happen in the general population.
In this new study, researchers analysed blood samples from 4,568 healthy individuals from the INTERVAL study3.1. They used advanced RNA sequencing techniques to measure gene activity and whole genome sequencing to identify genetic changes behind irregular gene activity.
The team found that while misexpression events were rare at the individual gene level –occurring in only 0.07 per cent of genes – nearly all samples – 96 per cent – had some misexpression, with over half of the normally inactive genes showing misexpression. They also found these events can be caused by rare structural changes in the DNA4.1.
While these findings show that gene misbehaviour is common, it may not always lead to health issues. This new understanding of the prevalence and mechanisms of gene misexpression provides a valuable tool for further investigation into the complexities of human genetics and disease. This could help in diagnosing and developing treatments for conditions caused by misexpression.
Until now, we have been looking at disease risk through the lens of highly active genes. Our study reveals ‘unusual’ gene activity is far more usual than previously thought and we need to consider the full picture, including genes that shouldn’t be active but sometimes are. This is a big step towards more personalised healthcare, enabling a more comprehensive understanding of all the ways our genes impact our health.
”Thomas Vanderstichele, first author
Wellcome Sanger Institute,
Wellcome Genome Campus, Hinxton, UK.
Interestingly, while over half of genes occasionally misexpress, we find certain critical genes, particularly those governing development, rarely make such mistakes. This suggests that when these essential genes do misexpress, the consequences for health and disease are likely to be more severe.
Dr Katie L. Burnham, co-author
Wellcome Sanger Institute,
Wellcome Genome Campus, Hinxton, UK.
The work of this pioneering large-scale study is testament to the incredible ‘genomics ecosystem’ in Cambridge that brought together experts from the Sanger Institute, the University of Cambridge and AstraZeneca. The findings open avenues for research into gene misexpression across different tissues, to understand its role in various diseases and potential treatments.
Dr Emma E. Davenport, senior author
Wellcome Sanger Institute,
Wellcome Genome Campus, Hinxton, UK.
Summary
Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL study blood donors. We found that while individual misexpression events occur rarely, in aggregate they were found in almost all samples and a third of inactive protein-coding genes. Using 2,821 paired whole-genome and RNA sequencing samples, we identified that misexpression events are enriched in cis for rare structural variants. We established putative mechanisms through which a subset of SVs lead to gene misexpression, including transcriptional readthrough, transcript fusions, and gene inversion. Overall, we develop misexpression as a type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression.
Introduction
Temporal and spatial regulation of gene expression is essential for the functioning of multicellular eukaryotes. Gene regulation involves the context-specific activation and maintenance of transcription, as well as gene silencing to avoid aberrant transcription interfering with normal cellular function. The aberrant transcription of a gene in a context where it is usually inactive is termed gene misexpression (also referred to as ectopic expression) (Figure 1A).1 Gene misexpression can occur either via the transcription of a single inactive gene or via the production of a novel transcript derived in part from an inactive gene. We refer to these different types of events as non-chimeric and chimeric misexpression, respectively.
Gene misexpression can have profound phenotypic consequences, as evidenced by the development of ectopic eyes across different tissues in Drosophila melanogaster upon targeted misexpression of eyeless.2 In humans, gene misexpression has been implicated in cancers3,4 and several rare diseases, for example, congenital limb malformations,5 congenital hyperinsulinism,6 and monogenic severe childhood obesity.7 These studies have identified gain-of-function genetic variants that lead to both chimeric and non-chimeric gene misexpression. For example, chimeric misexpression can be caused by transcript fusions7 and non-chimeric misexpression via rearrangements in 3D chromatin architecture8 or loss of silencer function.6 However, these studies have predominantly focused on a limited number of disease-related loci.
- Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. In this schematic, the majority of individuals have negligible or no expression of gene A (inactive, gray), with only a handful of individuals showing high expression (misexpression, red).
- Distribution of gene activity across 29,614 genes within the INTERVAL whole-blood RNA-seq dataset. For each gene, activity is quantified as the percentage of samples where the gene has a TPM >0.1 (x axis). Inactive genes are defined as having a TPM >0.1 in less than 5% of samples (vertical dashed line).
- Proportion of 39,513,200 gene-sample pairs (8,650 inactive genes across 4,568 samples) that are misexpressed (y axis) across different misexpression Z score thresholds (x axis). Text labels indicate the total number of misexpression events at each misexpression Z score threshold.
- Enrichment of gene-level features within 4,437 genes that are misexpressed (Z score >2 and TPM >0.5) versus 4,213 non-misexpressed genes. The 15 features with the highest absolute log odds passing Bonferroni correction are shown. Lines indicate 95% confidence intervals for the fitted parameters using the standard normal distribution.
- Human Phenotype Ontology (HPO) terms by -log10(adjusted p value) on the x axis, underrepresented within 1,070 misexpressed protein-coding genes using 3,092 inactive protein-coding genes as the custom background. The top 10 most significant results are shown.
Recent large-scale RNA sequencing (RNA-seq) studies analyzing transcriptional outliers in humans have demonstrated that outliers are enriched for rare single-nucleotide variants (SNVs), indels, and structural variants (SVs) in cis9,10,11,12 and that these outlier-associated genetic variants can contribute to complex disease risk.11,13 However, these studies focused on outliers in highly expressed genes within the tissue(s) under study, overlooking misexpression of inactive genes. Consequently, the prevalence of gene misexpression in humans, the genes whose misexpression can be tolerated, and their associated properties are unknown. Furthermore, the types of genetic variants associated with misexpression and their mechanisms remain underexplored.
To address these gaps in our understanding, we conducted a genome-wide analysis of gene misexpression using bulk RNA-seq data from 4,568 blood donors from the INTERVAL study.14,15 We assessed the prevalence of gene misexpression across genes and samples and the characteristics of genes that tolerate misexpression. Additionally, we established the types of genetic variants associated with gene misexpression as well as their putative mechanisms of action using 2,821 paired whole-genome sequencing (WGS) and RNA-seq samples.
Vanderstichele, Thomas; Burnham, Katie L.; de Klein, Niek; et al.
Misexpression of inactive genes in whole blood is associated with nearby rare structural variants. The American Journal of Human Genetics (2024); DOI: 10.1016/j.ajhg.2024.06.017.
Copyright: © 2023 The authors.
Published by Cell Press. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
Traditionally, creationists will cite Michael J. Behe's biologically nonsensical excuse of 'genetic entropy' for things going wrong, but sadly for them, this isn't a case of genes going wrong - they're doing what they're supposed to do - the problem is with the next layer of complexity - the control mechanism that should deactivate them but sometimes doesn't work properly and leaves them active.
So far, no-one at the Discovery Institute has managed to invent an excuse for this failure, just as they have never been able to invent a plausible excuse for these over-complex layers of Heath-Robinson work-arounds for basic design errors. The best they can do is claim that complexity, rather than the evidence of poor, unintelligent design, is evidence of intelligent design, and hope their dupes are too ignorant and gullible to see through the deception.
The last thing they will ever do is to admit that the most plausible explanation is the unintelligent, mindless evolutionary process that all leading biologists accept. Admitting that science is right is diametrically opposed to the basic objective of the Discovery Institute - to fool people into believing that science is all wrong and the best explanation is god-magic, so priests and theologians should control all levels of government and impose Christian fundamentalism on the population.
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