What's your genome?
According to recent findings by researchers at the Max Delbrück Center and the European Molecular Biology Laboratory, just published, open access, in the journalNature Genetics, it all depends on which of your cells we look in.
You might think that the replication process, as our cells divide during growth and development, and to replace old, damaged and worn-out cells, would be perfect if designed by a perfect, omniscient designer, but apparently not. And as we age, the mistakes accumulate until we are a mosaic of different genomes, contributing to diseases caused by genetic abnormalities, including cancers.
On the other hand, this is exactly the sort of thing that a utilitarian, evolutionary process, where a suboptimal process will be retained if it gives more descendants that what went before, can be predicted to produce.
How the team discovered this is described in a news release from the Max Delbrück Center:
Blood stem cells from healthy people carry major chromosomal alterations, a study in “Nature Genetics” by researchers at the Max Delbrück Center and the European Molecular Biology Laboratory finds. The discovery suggests that we are all genetic mosaics, which may contribute to ageing-related diseases.
In a study led by Professor Jan Korbel, Senior Scientist and Head of Data Science at the European Molecular Biology Laboratory (EMBL), and Dr. Ashley Sanders, Group Leader at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB), researchers have found that approximately one in 40 human bone marrow cells carry massive chromosomal alterations – copy number variations and chromosomal rearrangements for example – without causing any apparent disease or abnormality. In addition, cell samples from people over the age of 60 tended to have higher numbers of cells with such genomic alterations, suggesting a previously unidentified mechanism that may contribute to ageing-related diseases. The study was published in the journal “Nature Genetics.”
The study highlights that we are all mosaics. Even so-called normal cells carry all sorts of genetic mutations. Ultimately, this means that there are more genetic differences between individual cells in our bodies than between different human beings.
Professor Jan O. Korbel, co-corresponding author.
Genome Biology Unit
European Molecular Biology Laboratory, Heidelberg, Germany
Detecting genomic details in single cells
Both Korbel and Sanders study how genetic structural variation – deletions, duplications, inversion and translocations of large sections of the human genome – contributes to the development of disease. In the cancer field, it is well known that genetic mutations can cause cells to grow out of control and lead to the formation of a tumor, explains Sanders. “We are applying similar concepts to understand how non-cancerous diseases develop,” she adds.
The discovery was enabled by a single-cell sequencing technology called Strand-seq, a unique DNA sequencing technique that can reveal subtle details of genomes in single cells that are too difficult to detect with other methods. Sanders is a pioneer in the development of the technology. As part of her doctoral research, she helped develop the Strand-seq protocol, which she later honed with colleagues while working as a post-doc in Korbel’s lab. Strand-seq enables researchers to detect structural variants in individual cells with better precision and resolution than any other sequencing technology allows, Sanders says. The technology has ushered in an entirely new understanding of genetic mutations and is now being widely used to characterize genomes and to help translate findings into clinical research.
Genetic mosaicism is commonWe are just recognizing that contrary to what we learned in textbooks, every cell in our body doesn't have the exact same DNA.
Dr. Ashley D. Sanders, co-corresponding author
Berlin Institute for Medical Systems Biology
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
The study represents the first time anyone has used Strand-seq technology to study mutations in the DNA of healthy people. The researchers included biological samples from a range of age groups – from newborn to 92-years-old – and found mutations in blood stems cells, which are located in the bone marrow, in 84 percent of the study participants, indicating that large genetic mutations are very common.
The study also found that in people over the age of 60, bone marrow cells carrying genetic alterations tended to be more abundant, with populations of specific genetic variants, or sub-clones, more common than others. The frequent presence of these so-called sub-clones suggests a possible connection to aging. But whether the mechanisms that keep sub-clones from proliferating in check break down as we age, or whether the expansion of sub-clones itself contributes to diseases of aging is not known, says Korbel.It’s just amazing how much heterogeneity there is in our genomes that has gone undetected so far. What this means in terms of how we define normal human aging and how this can impact the types of diseases we get is really an important question for the field.
Dr. Ashley D. Sanders
In the future, our single cell studies should give us clearer insights into how these mutations that previously went unnoticed affect our health and potentially contribute to how we age.
Professor Jan O. Korbel
AbstractThe only way this can be explained in terms of intelligent design by an omniscient designer is if the designer is malevolent and intended us to develop genetic-related diseases such as cancer, since, being omniscient, it would have known exactly what its design for the replication of the genome in every cell would result in. And replicating the genome in every cell in the body when only a fraction of it is needed in any specialised cell is itself an argument against intelligent design because it is wasteful, needlessly complex and requires a Heath-Robison style work around in the form of another layer of complexity, in epigenetics.
The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age, and discovered the heterogeneous mSV landscapes of hematopoietic stem and progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional somatic structural variants, including megabase-scale segmental aneuploidies. Capitalizing on comprehensive single-cell micrococcal nuclease digestion with sequencing reference data, we conducted high-resolution cell-typing for eight hematopoietic stem and progenitor cells. Clonally expanded mSVs disrupt normal cellular function by dysregulating diverse cellular pathways, and enriching for myeloid progenitors. Our findings underscore the contribution of mSVs to the cellular and molecular phenotypes associated with the aging hematopoietic system, and establish a foundation for deciphering the molecular links between mSVs, aging and disease susceptibility in normal tissues.
Main
Somatic subclonal (mosaic) mutations are present in nearly all tissues and accumulate with age1,2,3,4,5,6, yet their role in human health and disease is underexplored. Somatic structural variants, which comprise copy-number alterations (CNAs) and copy-neutral rearrangement classes, are the most common class of driver mutation in cancer7,8. Previous studies have associated mosaic CNAs in aged donors with unusual blood cell counts and susceptibility to age-associated diseases2,9,10,11,12, which underscores the potential for mSVs to alter molecular phenotypes in healthy individuals upon aging. However, the molecular processes behind these associations, which are anticipated to vary by cell type, are poorly understood.
Detecting mSVs poses an important technical challenge7,11, with bulk whole-genome sequencing (WGS) typically unable to differentiate cell types and identify mSVs present with a low variant allele frequency (VAF). Additionally, WGS of single-cell-derived clones is limited to mSVs that can be cultured long-term, potentially biasing against mSVs exhibiting large segmental aneuploidies7,13,14. Single-cell sequencing offers a solution in theory, yet most methods are suited only for detecting large CNAs, yielding an incomplete understanding of mSVs15.
Here we utilize Strand-seq, a haplotype-resolved single-cell sequencing technique14,16,17, to investigate the functional impact of mSVs. We focus on the blood compartment, where mosaic CNAs have been documented in aged donors2,11,18,19. Strand-seq allows resolving of diverse mSV classes, including de novo structural rearrangements, by analyzing their unique ‘diagnostic footprints’ utilizing the scTRIP framework14. Additionally, Strand-seq simultaneously yields nucleosome occupancy profiles from each single cell, generated via micrococcal nuclease (MNase) digestion16, which can be used to analyze the functional consequences of structual variants with the scNOVA framework20. In 1 of every 43 hematopoietic stem and progenitor cells (HSPCs), we detect de novo mSVs, which emerge regardless of age. We resolve the cell-type identity of mSV-bearing cells, revealing they are commonly enriched in myeloid progenitors and exhibit aberrant pathway activity previously associated with aging.
>Grimes, K., Jeong, H., Amoah, A. et al. Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01754-2
Copyright: © [year] The authors.
Published by [publisher]. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
For reasons which will forever remain suspect it seems, because none of them will ever admit to the underlying far right political agenda underpinning creationism, creationists reject the only explanation that doesn't make the god they purport to worship look like a sadistic malevolence, is the natural process of evolution, yet that is the only explanation which makes any sense of data such as this paper reveals.
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.
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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.
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Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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