F Rosa Rubicondior: Malevolent Design - How The Malaria Parasite is 'Designed' To Evolve And Outwit Medical Science

Tuesday 12 March 2024

Malevolent Design - How The Malaria Parasite is 'Designed' To Evolve And Outwit Medical Science

The malaria parasite generates genetic diversity using an evolutionary ‘copy-paste’ tactic | EMBL

Devotees of creationism’s divine malevolence would be conflicted by this news if they understood it, because it shows the creative genius of any intelligent designer who could come up with this system, but, it looks like it did so (if you believe it couldn't happen naturally) by setting up an evolutionary process that creationists are obliged by dogma to believe doesn't work.

The news is that the organisms that causes malaria, Plasmodium falciparum, is 'designed' to quickly find a way to overcome the anti-malarial drugs medical science has developed to cure people suffering from it and to prevent others from getting malaria, by evolving very quickly.

The discovery was by researchers at European Molecular Biology Laboratory's (EMBL’s) European Bioinformatics Institute who have identified a mechanism of ‘copy-paste’ genetics that increases the genetic diversity of the parasite at accelerated time scales. This helps solve a long-standing mystery regarding why the parasite displays hotspots of genetic diversity in an otherwise unremarkable genetic landscape. Copy-paste' is a way of doing something creationists insist is impossible without the aid of god-magic of increasing the genetic information in a genome and making it available for evolution by mutation and selection without any loss of function in the original copied genes.

The team have recently published their finding in the open access journal PLOS Biology and describe it in an EMBL news item:
The malaria parasite generates genetic diversity using an evolutionary ‘copy-paste’ tactic

Plasmodium falciparum, a malaria parasite, uses gene conversion to produce genetic diversity in two surface protein genes targeted by the human immune system
  • All modern Plasmodium falciparum, the deadliest malaria parasite in humans, are descendants of one initial infection and so are very closely related, with relatively limited genetic differences.
  • A long-standing mystery in the field has revolved around a very few locations in the P. falciparum genome where there are ‘spikes’ of mutations – far more than anywhere else.
  • Researchers at EMBL-EBI have identified two genes in which these unusual mutation spikes result from DNA being copied and pasted from one gene to another.

By dissecting the genetic diversity of the most deadly human malaria parasite – Plasmodium falciparum – researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI) have identified a mechanism of ‘copy-paste’ genetics that increases the genetic diversity of the parasite at accelerated time scales. This helps solve a long-standing mystery regarding why the parasite displays hotspots of genetic diversity in an otherwise unremarkable genetic landscape.

Malaria is most commonly transmitted through the bites of female Anopheles mosquitoes infected with P. falciparum. The latest world malaria report states that in 2022, there were an estimated 249 million malaria cases and over 600,000 malaria deaths across the globe. 94% of malaria cases and 95% of malaria deaths are found in Africa, with infants, pregnant women, travellers, and people with HIV/AIDS being at higher risk.

The new study, published in the journal PLOS Biology, provides key insights into the evolutionary history of P. falciparum through the analysis of two genes that encode surface proteins critical to immune evasion. The genes in question are DBLMSP and DBLMSP2.

These findings deepen our understanding of how the malaria parasite has evolved and could help to inform new approaches to vaccine development, offering hope for more effective prevention methods against a disease that continues to impact millions globally.

Copy-paste genetics

Usually, the sequence of an individual’s gene is inherited from their parents, but in some circumstances, part of a gene sequence can be copied between different genes on the same DNA molecule – this is known as non-allelic gene conversion. This process has been linked to the evolution of important gene families, including those involved in the functioning of the human immune system.

One of this study’s key discoveries is that gene conversion takes place between the P. falciparum DBLMSP and DBLMSP2 genes and results in increased genetic diversity within the surface proteins of the parasite. Since these proteins are exposed to, and interact with our immune system, they are potential vaccine targets, and a fuller understanding of their genetic diversity could be very valuable for vaccine design.

“The discovery of ‘copy-paste’ genetics within malaria’s DNA reveals the impact of an underestimated evolutionary mechanism,” said Brice Letcher, Postdoctoral Researcher at the Laboratory for Biology and Modelling of the Cell (LBMC, France) and former PhD student at EMBL-EBI. “Here we show that gene conversion was a potentially important strategy behind malaria’s ability to adapt and thrive in humans, including possibly to evade the human immune system. Understanding this genetic flexibility offers new perspectives on malaria’s persistence in and adaptation to the human host.”

Mapping hidden genetic diversity in malaria parasites

Any immune-interacting protein is potentially a vaccine target, but knowledge of global genetic diversity is an important requirement for vaccine development. For example, influenza and SARS-CoV-2 vaccines are developed based on the knowledge of how their genomes have evolved. However, the very unusual hotspots of genetic diversity in the P. falciparum DBLMSP and DBLMSP2 genes are so extreme that current algorithms for mapping genetic variants failed to capture them, leaving researchers unaware of a large proportion of the variation in these genes.

To address this, the researchers developed new bioinformatics software that uses genome graphs and analysed a broad sample of parasites from 29 countries. This new approach revealed a wide range of previously hidden variants, and with these, they were able to demonstrate that multiple gene conversion events had occurred. These new variants, available for download from the website linked to the study, provide a valuable resource for the malaria research community.

Genome graphs are a great bioinformatics method to help us decode the complex genetic landscapes arising from the interplay between pathogens and human hosts. They allow us to take into account a broader spectrum of genetic diversity and obtain new insights into how pathogens like P. falciparum evolve and evade our immune defences.

Dr. Sorina Maciuca, co-author
Genomics Data Scientist at Genomics England, London, UK.
What are genome graphs?

The traditional approach in genomics is to define one reference genome and describe any other genome as a set of small differences from this reference. This does not work well when genomes differ too much. Genome graphs take a population of genomes and build an ensemble reference which is aware of all of the genetic variation in the species.

This research provides a comprehensive map of genetic diversity of these two fascinating genes in P. falciparum. We have been trying to understand the unusual patterns in these genes for almost a decade now, and our best hypothesis had been that the really different "versions" of the gene were being preserved by natural selection, for unknown reasons. We have shown here that, in fact, this copying mechanism – gene conversion – has been repeatedly creating these anomalous different "versions" of the genes. This data not only enhances our grasp of malaria’s biology, but also will be valuable to researchers across the world studying these genes and their interaction with our immune system.

Professor Zamin Iqbal, co-corresponding author
Group Leader at EMBL-EBI
and Professor of Algorithmic and Microbial Genomics
University of Bath, Somerset, UK

While the malaria parasite Plasmodium falciparum has low average genome-wide diversity levels, likely due to its recent introduction from a gorilla-infecting ancestor (approximately 10,000 to 50,000 years ago), some genes display extremely high diversity levels. In particular, certain proteins expressed on the surface of human red blood cell–infecting merozoites (merozoite surface proteins (MSPs)) possess exactly 2 deeply diverged lineages that have seemingly not recombined. While of considerable interest, the evolutionary origin of this phenomenon remains unknown. In this study, we analysed the genetic diversity of 2 of the most variable MSPs, DBLMSP and DBLMSP2, which are paralogs (descended from an ancestral duplication). Despite thousands of available Illumina WGS datasets from malaria-endemic countries, diversity in these genes has been hard to characterise as reads containing highly diverged alleles completely fail to align to the reference genome. To solve this, we developed a pipeline leveraging genome graphs, enabling us to genotype them at high accuracy and completeness. Using our newly- resolved sequences, we found that both genes exhibit 2 deeply diverged lineages in a specific protein domain (DBL) and that one of the 2 lineages is shared across the genes. We identified clear evidence of nonallelic gene conversion between the 2 genes as the likely mechanism behind sharing, leading us to propose that gene conversion between diverged paralogs, and not recombination suppression, can generate this surprising genealogy; a model that is furthermore consistent with high diversity levels in these 2 genes despite the strong historical P. falciparum transmission bottleneck.

Fig 2. Deeply diverged private and shared lineages in DBLMSP1/2.

We built a hierarchical clustering tree of all unique DBL-spanning protein sequences (see Methods). The inner ring colours sequences by gene of origin (DBLMSP, DBLMSP2), and the outer ring shows species of origin, for P. falciparum and its 3 most closely related species. Three main lineages exist in the tree, labelled A, B, and C: Lineages A and C contain only representatives of DBLMSP2 and DBLMSP, respectively (“private lineages”), and lineage B contains representatives of both (“shared lineage”). The data and code to generate this Figure can be found at https://zenodo.org/doi/10.5281/zenodo.7677547.

Plasmodium falciparum is a single-celled eukaryotic parasite causing malaria disease in humans. Malaria burden remains high worldwide, with 241 million cases and 627,000 deaths in 2020 according to WHO [1]. The high burden is in part due to P. falciparum’s ability to evade the human immune system, mediated by 2 main mechanisms [2]. Firstly, cell-surface–exposed antigens targeted by the immune system are produced by functionally redundant gene families. For example, merozoites, the parasite life stage infecting human red blood cells (RBCs), use different members of the Rh and EBA families for invasion [2], and different members of the var, rifin, and stevor families enable infected RBCs to bind to the host microvasculature [3]. Secondly, surface antigens are highly diverse at the sequence and immunological levels. In the var family, diversity is mainly generated by frequent recombination and gene conversion (sequence copy-pasting) events, occurring both between orthologs during sexual reproduction, and paralogs on the same genome during asexual replication [47].

Historically, several cell-surface antigens called merozoite surface proteins (MSPs) were found to display unusual genealogies, with exactly 2 deeply diverged lineages: This includes MSP1, MSP2, MSP3, and MSP6 [811]. Such deep divergence suggests ancient origins and possible maintenance by balancing selection for immune escape [12,13], but Roy and colleagues showed that neither this nor neutral evolution should produce exactly 2 lineages, and with such a deep most recent common ancestor [14]. In addition, loci with such extreme diversity levels are at odds with P. falciparum’s overall low diversity levels, likely due to its very recent origin (10,000 to 50,000 years ago) in humans from a common ancestor with gorilla-infecting P. praefalciparum [1517].

In this study, we focussed on 2 MSPs called DBLMSP and DBLMSP2, both among the most diverse genes in P. falciparum [18], and both encoding cell-surface–exposed antigens recognised by the human immune system [19,20]. They are part of an 8-gene tandemly arrayed family of paralogs, as identified from sequence sharing: All 8 genes possess an N-terminal signal sequence, 6 (including DBLMSP and DBLMSP2) possess a C-terminal SPAM domain, and DBLMSP and DBLMSP2 further uniquely possess a DBL domain [20] (illustrated in S1 Fig). DBL domains mediate a number of important malarial host–pathogen interactions, including between erythrocyte binding antigen (EBA) gene products and RBCs during invasion [21,20], and between var gene products on infected RBCs and various human receptors, enabling sequestration [22]. However, their function in DBLMSP and DBLMSP2 remains largely unknown [23].

The evolutionary history of P. falciparum surface antigens, including DBLMSP and DBLMSP2, has been difficult to study until now because of reference bias: Reads spanning highly diverged nonreference alleles fail to align to a reference genome, making them hard to reconstruct. To address this, we previously developed gramtools, a software for mapping reads and genotyping using a genome graph incorporating multiple references simultaneously [24,25]. In this study, we developed a new pipeline combining local assembly to reconstruct DBLMSP and DBLMSP2 alleles together with gramtools for comprehensive genotyping. Applying it to Illumina population sequencing data, we assembled the first comprehensive set of alleles for these genes, across >3,500 global P. falciparum samples. Studying these in detail, we found that although DBLMSP and DBLMSP2 have diverged substantially, 1 specific region (the DBL domain) contains sequences shared across both genes. We found clear evidence this was driven by gene conversion of DBL sequence between the 2 genes, thus creating highly diverse gene lineages despite the recent gorilla-to-human transmission bottleneck. Interestingly, we also found evidence that DBLMSP2 may have evolved a constrained function specifically in humans.

For the remainder of this paper, we refer to DBLMSP and DBLMSP2 collectively as DBLMSP1/2.

So, what are creationists to make of this evidence that if there was any intelligence involved in this redesign of the parasite that causes malaria so it could evade medical science's anti-malarial drugs, it used an evolutionary process to make it happen? And where does this leave Michael J Behe's embarrassing claim (for creationists) and false dichotomy fallacy, that anti-malarial resistance in P. falciparum could not have evolved so was 'intelligently'[sic] designed, as his 'proof' that a designer god really exists and is making chemistry and/or physics do things they couldn't do on their own?


The Malevolent Designer: Why Nature's God is Not Good

This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.

Illustrated by Catherine Webber-Hounslow.

Available in Hardcover, Paperback or ebook for Kindle


The Unintelligent Designer: Refuting The Intelligent Design Hoax

ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.

Available in Hardcover, Paperback or ebook for Kindle


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1 comment :

  1. Creationists and Fundamentalists claim the creator is intelligent but much of this intelligence is devoted to making its creation suffer and die. It's a perverted, demented, malevolent kind of intelligence. It's an evil kind of intelligence. Why can't they see that? This is especially obvious with malaria and its resistance to antibiotics. When it comes to torturing and killing its creation the creator is a genius, an evil genius. This isn't something to be proud of, rather its something to be ashamed of. When it comes to inflicting cruelty and misery the creator is intelligent. But when it comes to kindness, caring, mercifulness, the creator is a failure and gets a failing grade. It's more than embarrassing for creationists. Creationism ought to be called Cretinism. The more we learn about Nature the more we see the cruelties, defects, flaws in it.


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