How do mutations of mitochondrial DNA affect your health? A new embryonic stem (ES) cell–based platform may allow better investigations

Good news!

"Highlights

• Salk scientists have created a platform to study mitochondrial DNA mutations that lead or contribute to human disease
• They generated a library of 155 mitochondrial DNA mutant cells, nearly the human level of mitochondrial DNA mutant diversity
• The platform and library will accelerate innovation in the mitochondrial disease therapeutic space

...

“Mitochondrial DNA accumulates mutations at a high rate, and more than 260 inherited disease-causing mtDNA mutations have been identified in humans,” ..."

From the significance and abstract:

"Significance

Mitochondrial DNA (mtDNA) accumulates mutations at a high rate, and more than 260 pathogenic germline mtDNA mutations have been identified in humans, producing diverse and often tissue-specific disorders.

In addition, numerous population-specific mtDNA variants have arisen through evolution and may influence adaptation and disease susceptibility.

However, the lack of animal models representing this diversity has limited mechanistic insight and therapeutic development.

Our scalable embryonic stem (ES) cell–based platform enables efficient generation of mouse models carrying functional mtDNA mutations across a broad spectrum of physiological effects. This resource will facilitate systematic investigation of mtDNA variation in health, disease, and evolution, and accelerate efforts to develop treatments for mitochondrial disorders.

Abstract

Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease.

However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation.

Here, we develop a scalable embryonic stem (ES) cell–based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection.

Optimized ES cell–embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission.

Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation.

These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development."

How does mitochondrial DNA affect your health? - Salk Institute for Biological Studies "Salk Institute researchers establish new platform for studying mitochondrial DNA in human physiology, adaptation, disease mechanisms, and therapeutic development"

A scalable embryonic stem cell–based platform for efficient generation of mitochondrial DNA mutant mice (no public access)

Hidden mutations in immune cells linked to autoimmune disease

Good news! This could be a breakthrough!

"New research suggests that autoimmune diseases may be driven by DNA mutations in immune cells that remove the natural brakes on the immune system. It reveals a previously hidden role for somatic mutations — DNA changes acquired throughout life — in diseases beyond cancer.

Researchers ... used a series of cutting-edge techniques to identify previously unseen changes in DNA that may contribute to thyroid autoimmunity, where the immune system attacks the thyroid gland. ...

The researchers used several advanced DNA analysis techniques.
Firstly, they used a method called NanoSeq, which they recently developed and allows detection of rare mutations invisible to traditional DNA sequencing methods, to look for genetic changes that may drive the disease. They found that many B cells had developed inactivating mutations in key genes that normally control the immune system.

Next, using additional methods that look at the DNA of individual cells and microscopic areas of tissue, the researchers found that many B cells in each patient carried several mutations in key genes.

Two critical immune-checkpoint genes, TNFRSF14 and CD274 (or PDL1), were often lost independently in multiple clones of mutated B cells in each patient. Some of these clones had even acquired as many as six driver mutations over many years, silently building up changes in DNA before symptoms appeared, a highly unexpected observation outside of cancer.

Importantly, artificial inactivation of these genes, in experimental studies or during cancer immunotherapy, is known to cause thyroid autoimmunity. The researchers have now found frequent mutations in these genes occurring in autoimmune patients. ..."

From the abstract:

"Our immune system contains multiple checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis posits that somatic mutations in immune-regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints1–3, but testing this has been challenging due to technical limitations.

Here, we use whole-exome and targeted NanoSeq, an accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed many B cell clones convergently acquiring loss-of-function mutations in the key immune checkpoint genes TNFRSF14 (HVEM) and CD274 (PD-L1), as well as less frequent mutations in other immune genes.

In highly inflamed biopsies, we detected tens to hundreds of independent immune checkpoint mutant clones. Laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing, and antibody synthesis localised these mutations to B cells, confirmed some to be self-reactive, and identified clones carrying multiple hits.

We found widespread TNFRSF14 biallelic loss, and clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small fraction of cells (typically <1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations.

Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution, providing new insights into the molecular basis of autoimmune disease."

Hidden mutations in immune cells linked to autoimmune disease "Mutations in immune cells may be the missing piece in the autoimmune disease puzzle."

Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity (no public access)

Sperm donor with a cancer-causing mutation fathered nearly 200 children, some of the children have already died

Serious stuff! Food for thought! Apparently, this particular genetic mutation was known since 2023!

Were the would be parents informed about how many children were fathered by the same donor? Would this information be provided if a would be parent asks about it?

How good is the screening of donor semen and donor health?

Had I learnt that the same donor has already fathered dozens or even more than 100 children, I would have had some second thoughts as a would be parent.

"In an alarming case that researchers say should spark regulatory changes, a sperm donor who unknowingly carried a cancer-causing genetic mutation has fathered at least 197 children across Europe. According to an investigation published earlier this week by a group of 14 European news organizations, some children have already died.

The donor is reportedly healthy, but before he was born, some of his cells mutated, damaging a gene known as TP53. This gene encodes what’s known as a tumor suppressor protein, which regulates how quickly cells grow and divide. People missing a functional version of that gene are at risk of Li-Fraumeni syndrome, an inherited disorder that greatly increases the risk of developing cancer, particularly during childhood. ...

The new investigation builds on work by cancer geneticist Edwige Kasper, who learned in 2023 of a sperm donor with a “variant of unknown significance” in TP53. ... At the annual meeting of the European Society of Human Genetics this past May, Kasper announced that the donor had fathered at least 67 children, some of whom had already developed leukemia and non-Hodgkin’s lymphoma. ..."

ScienceAdviser

Discovering GRIN2A: A Single Gene's Role in Childhood Mental Illness

Amazing stuff! This suggests that perhaps more genetics research is necessary for mental disorders!

"In a breakthrough study, scientists have discovered that a variant in one gene, GRIN2A, can directly cause mental illness – something previously believed to be the result of several mutations working together. What's more, these conditions often present in childhood instead of more commonly during adulthood. ..."

"Until now, researchers assumed that schizophrenia, anxiety disorders or depression arise from an interplay of many different factors, including genetic ones. An international study led by the Institute of Human Genetics at the University of Leipzig Medical Center has now demonstrated for the first time that changes in a single gene can in fact cause a mental illness. ..."

From the abstract:

"Rare genetic factors have been shown to substantially contribute to mental illness, but so far, no precision treatments for mental disorders have been described. It was recently identified that rare variants in GRIN2A encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) confer a substantial risk for schizophrenia.

To determine the prevalence of mental disorders among individuals with GRIN2A-related disorders, we enquired the presence of psychiatric symptoms in 235 individuals with pathogenic variants in GRIN2A who had previously enrolled in our global GRIN registry.

We identified null variants in GRIN2A (GRIN2Anull) to be significantly associated with a broad spectrum of mental disorders including schizophrenia compared to a longitudinal population cohort (FinRegistry) as well as missense variants (GRIN2Amissense).

In our cohort, GRIN2Anull-related mental disorders manifest in early childhood or adolescence, which is substantially earlier than the average adult onset in the general population. In 68% of co-incident epilepsy and mental disorder, mental disorders start after epilepsy offset and the age of epilepsy offset correlated with mental disorder onset.

GRIN2Anull-related phenotypes appear to occasionally even manifest as isolated mental disorder, i.e. as schizophrenia or mood disorder without further GRIN2A-specific symptoms, such as intellectual disability and/or epilepsy.

As L-serine is known to mediate co-agonistic effects on the NMDAR, we applied it to four individuals with GRIN2Anull-related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype.

GRIN2Anull appears to be the first monogenic cause of early-onset and even isolated mental disorders, such as early-onset schizophrenia.

Genetic testing should be considered in the diagnostic work-up of affected individuals to improve diagnosis and potentially offer personalized treatment as increasing brain concentrations of NMDAR co-agonists appears to be a promising precision treatment approach successfully targeting deficient glutamatergic signaling in individuals with mental disorders, i.e. due to GRIN2Anull."

Discovering GRIN2A: A Single Gene's Role in Childhood Mental Illness

Changes in a single gene can cause mental illness (original news release)

GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy (open access)

Fig. 1: Cumulative incidence of mental disorders and Hazard Ratios for index carriers of pathogenic GRIN2A variants carriers.

Hidden evolution of genetic mutations in sperm raises disease risk for children as men age

It was known for several decades that sperm deteriorates with age, but this study provides more details and how it develops over time. Probably, older men should have their sperm checked if they intend to become fathers.

"Harmful genetic changes in sperm become substantially more common as men age because some are actively favoured during sperm production, new research has revealed. 

In a landmark study ... researchers ... have comprehensively mapped how harmful DNA changes in sperm cells can increase across the genome as men age.  ...

In a new study, researchers used NanoSeq, an ultra-accurate DNA sequencing method to analyse sperm from 81 healthy men, aged between 24 and 75 years, with unprecedented precision. The sperm samples were collected as part of the TwinsUK cohort, the UK’s largest adult twin registry, providing a unique opportunity to study genetic variation across a diverse and well-characterised population.

The results show that around 2 per cent of sperm from men in their early 30s carried disease-causing mutations, but this rises to 3–5 per cent of sperm from middle-aged (43 to 58 years) and older men (59 to 74 years). Whilst men may be more likely to father children at a younger age, the researchers found that in those aged 70, 4.5 per cent of sperm carry disease-causing mutations. ...

This risk is driven not just by the steady build-up of random changes in DNA, but by a subtle form of natural selection acting on the sperm-producing cells in the testes, giving some mutations a competitive edge during sperm production. 

The researchers identified 40 genes where certain changes in DNA are favoured during sperm production, including many linked to childhood diseases, severe neurodevelopmental disorders and inherited cancer risk. While 13 genes  have already been associated with this process, the new findings show it is far more widespread than previously understood, affecting a broad range of genes important for cell growth and development. ..."

From the abstract:

"Mutations that occur in the cell lineages of sperm or eggs can be transmitted to offspring. In humans, positive selection of driver mutations during spermatogenesis can increase the birth prevalence of certain developmental disorders. Until recently, characterizing the extent of this selection in sperm has been limited by the error rates of sequencing technologies.

Here we used the duplex sequencing method NanoSeq to sequence 81 bulk sperm samples from individuals aged 24–75 years. 

Our findings revealed a linear accumulation of 1.67 (95% confidence interval of 1.41–1.92) mutations per year per haploid genome driven by two mutational signatures associated with human ageing.

Deep targeted and exome NanoSeq5 of sperm samples identified more than 35,000 germline coding mutations.

We detected 40 genes (31 newly identified) under significant positive selection in the male germline that have activating or loss-of-function mechanisms and are involved in diverse cellular pathways.

Most of the positively selected genes are associated with developmental or cancer predisposition disorders in children, whereas four of the genes exhibited increased frequencies of protein-truncating variants in healthy populations.

We show that positive selection during spermatogenesis drives a 2–3-fold increased risk of known disease-causing mutations, which results in 3–5% of sperm from middle-aged to older individuals with a pathogenic mutation across the exome.

These findings shed light on germline selection dynamics and highlight a broader increased disease risk for children born to fathers of advanced age than previously appreciated."

Hidden evolution in sperm raises disease risk for children as men age "Researchers reveal how certain harmful DNA variations become more common in sperm as men age, raising genetic disease risk for offspring."

Sperm sequencing reveals extensive positive selection in the male germline (open access)

Fig. 1: Mutational burden and signature analysis in sperm and matched blood.

Change trackers: New consortium to catalog DNA somatic mutations across the human lifetime of 150 individuals

Good news!

"... In a new project, a team of researchers from multiple institutions including Yale will catalog these changes, known as somatic mutations, more than two decades since scientists first logged snapshots of 3 billion DNA base pairs that make up the human DNA. The project will focus specifically on mutations across 19 tissue sites in 150 individuals without disease. ...

The project, called the Somatic Mosaicism across Human Tissues (SMaHT) Network, and which will include more than 300 researchers ..."

From the abstract:

"From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants.

Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions.

This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases."

Change trackers: New consortium to catalog DNA mutations across human lifetime | Yale News "In a multi-institution project, scientists will track genetic mutations occurring across the lifetime of 150 healthy individuals with the aim of understanding how they affect development, aging, and disease."

The Somatic Mosaicism across Human Tissues Network (open access)

Fig. 1: Somatic mutations, causes and patterns.

The terrible Legacy of Nuclear Testing by the former Soviet Union in Kazakhstan

Communist regimes don't treat humans very kindly!

"From 1949 to 1989, the Soviet Union detonated 456 nuclear weapons at the Semipalatinsk Test Site in Kazakhstan, exposing 1.5 million people to radioactive fallout.

Generations of people in the region now suffer high rates of cancer, fertility problems, heart disease, and genetic birth defects.

Researchers have found the radiation nearly doubled inherited gene mutation risks.

Ongoing Struggle: Despite persistent health issues, neither Russia or Kazakhstan has offered long-term, large-scale aid. ..."

Global Health NOW: Argentina’s Health System Overhaul; The Legacy of Nuclear Testing in Kazakhstan; and Novel Mental Health Care in an L.A. Jail

Atomic bombs destroyed their lives – now they want Russia to pay "Amid calls to restart nuclear testing, families are still suffering from mutations passed down through the generations"

The Atomic Lake in eastern Kazakhstan was formed by a nuclear bomb 10 times as powerful as the one that destroyed Hiroshima

Just one example of many. Abilmansur Erzhanov, 7, was born unable to hear as a result of his grandmother and mother being exposed to radiation

How quickly do humans mutate? Four generations help answer the question

Recommendable!

Continuous, programmable mutagenesis of single genomic loci of the living mammalian genome (HACE)

Amazing stuff! This could be a game changer!

"... researchers have created a tool that allows them to rapidly create mutations only in particular genes of interest without disturbing the rest of the genome. Described in Science, their tool, called Helicase-Assisted Continuous Editing (HACE), can be deployed to predetermined regions of the genome in intact, living cells. ...

“By allowing targeted mutagenesis in specific parts of the genome, this tool opens the door to creating enzymes and treatments that were previously out of reach.” ...

Unlike current methods for mutagenesis, which involve inserting extra copies of genes or broadly mutating many different genes at once, HACE offers the advantage of being directed to locations — like going to a specific address, rather than a neighborhood. The team’s novel bioengineering involves combining a helicase, which is an enzyme that naturally “unzips” DNA, with a gene-editing enzyme. They then use the gene-editing technology CRISPR-Cas9 to guide the protein pair to the gene they want to mutate. As the helicase unzips the DNA, it introduces mutations into only that gene sequence. ...

To demonstrate the tool’s power in the lab, the scientists used it to identify drug resistance mutations in a gene called MEK1, which cancer treatments often target but frequently fail because the diseased cells mutate resistance mechanisms. Using HACE, the team sequenced only those mutated genes and pinpointed several unique changes associated with resistance to cancer drugs like trametinib and selumetinib, offering insights into how mutations affect drug performance.

They also examined how mutations in SF3B1, a gene involved in a biomolecular process called RNA splicing, affects RNA assembly. Mutations in this gene are common in blood cancers, but it’s been unclear which mutations cause the splicing defects; with HACE, the team could easily identify those changes. ..."

From the editor's summary and abstract:

"The ability to mutate regions of the human genome can help us understand the effects of individual genetic variants on gene function. Chen et al. present a new tool for long-range mutagenesis that can be targeted to any genomic locus. Helicase-assisted continuous editing (HACE) uses a nickase–Cas9–single-guide RNA (sgRNA) to recruit a helicase-deaminase fusion enzyme, which then travels more than 1000 base pairs, incurring mutations across the region. The authors multiplexed HACE with sgRNAs to diversify coding and noncoding sequences, thereby identifying single mutations that confer drug resistance, perturb RNA splicing, or modulate expression of an inducible immune gene. HACE provides a powerful tool for the mutagenesis of endogenous loci and has the potential to explore new sequence space through directed evolution in mammalian cells. ...

"Structured Abstract

INTRODUCTION

A fundamental challenge of genomics is to chart the impact of the three billion bases in the human genome on protein function and gene regulation. Thus, a critical goal is to develop strategies for mutagenizing genomic sequences systematically and at high throughput. In particular, targeted mutagenesis of single genomic loci could emulate the natural evolution process to reveal sequence-structure relationships, gain- and loss-of-function phenotypes, and cooperative mutations. However, no method exists that can perform continuous mutagenesis at targeted regions in the endogenous genomes of mammalian cells.

RATIONALE

We sought to develop a tool to perform targeted mutagenesis on the endogenous mammalian genome. Looking to nature, we observed that helicases are highly processive enzymes that can traverse large genomic regions. Some helicases, including those involved in DNA damage repair, can load and start unwinding DNA at single-stranded DNA regions in the genome. We reasoned that such helicases could be used for long-range targeted mutagenesis when fused to a deaminase enzyme. The fusion construct and its interval of hypermutation could then be programmably targeted, through single-guide RNAs (sgRNAs), to specific genomic regions using a Cas9 nickase. The directional and long-range DNA-unwinding event by the recruited helicase will then generate random mutations in the region.

RESULTS

We designed a platform called helicase-assisted continuous editing (HACE), which combines long-range editing of entire loci with the sequence programmability inherent to CRISPR gene editing tools. HACE uses CRISPR-Cas9 to direct the loading of a helicase-deaminase fusion for targeted hypermutation of the downstream genomic sequence. HACE achieved locus-specific deamination across >1000 nucleotides with mutations continuously accumulating over time. We further evaluated HACE prototypes incorporating diverse helicases, Cas9 variants, and deaminases, showing that they have tunable edit rates and ranges. We also showed that HACE can be multiplexed to target multiple genomic regions with a minimal number of guide RNAs. We then applied HACE in coding and noncoding genomic contexts to functionally dissect endogenous mutations conferring drug resistance, changes in enzymatic activity, and altered cis-regulatory element function. In the coding space, we identified variants that lead to mitogen-activated protein kinase kinase 1 (MEK1)–inhibitor drug resistance and also identified variants in SF3B1, a splicing factor, that lead to alternative 3′ splice-site usage. Turning to regulatory regions, we defined functional artificial variants in the enhancer regions of CD69 and pinpointed specific bases and motifs that mediate the impact of RUNX transcription factors on CD69 regulation. HACE solves two limitations faced by conventional base editing screens: the requirement of an NGG protospacer adjacent motif in the sgRNA recognition sequence and the occurrence of bystander mutations that can create artificial linkages and confound screening results. The long editing range of HACE can also uncover combinatorial effects and interactions between multiple distant mutations across a locus.

CONCLUSION

HACE makes possible the continuous, long-range, programmable diversification of endogenous mammalian genomes. We envision that HACE will substantially expand the functional genomics toolbox and enable the building of systematic sequence-function maps of both coding and noncoding genomes. Furthermore, HACE can be developed into a directed evolution system in the endogenous genome, enabling the selection of sequences for desired functions in mammalian biology."

Finding a way to harness evolution— Harvard Gazette "New tool allows researchers to study gene mutation directly within living human cells"

Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes (no public access)

Development of a system to perform long-range targeted continuous mutagenesis of endogenous genomes.

New nanoparticles can perform gene editing in the lungs

Good news! After liver and muscles, the lungs are next!

"Engineers ... have designed a new type of nanoparticle that can be administered to the lungs, where it can deliver messenger RNA encoding useful proteins.

With further development, these particles could offer an inhalable treatment for cystic fibrosis and other diseases of the lung, the researchers say. ...

In a study of mice, Anderson and his colleagues used the particles to deliver mRNA encoding the machinery needed for CRISPR/Cas9 gene editing. That could open the door to designing therapeutic nanoparticles that can snip out and replace disease-causing genes. ...
Messenger RNA holds great potential as a therapeutic for treating a variety of diseases caused by faulty genes. One obstacle to its deployment thus far has been difficulty in delivering it to the right part of the body, without off-target effects. ..."

"The ability to create in vivo genomic medicines for tissues other than the liver has been impeded by difficulties in delivery. Using a high-throughput platform, we developed lipid nanoparticles that can effectively deliver mRNA and CRISPR–Cas9 gene editing tools to the lungs through intratracheal administration, expanding the potential clinical uses of gene editing and mRNA-based technologies."

From the abstract:

"The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR–Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases."

New nanoparticles can perform gene editing in the lungs | MIT News | Massachusetts Institute of Technology Using these RNA-delivery particles, researchers hope to develop new treatments for cystic fibrosis and other lung diseases.

Lipid nanoparticle-enabled gene editing in the lung via inhalation

Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing (no public access)

Alzheimer’s-defying brain offers clues to treatment, prevention

Good news! Exciting research! A very unusual case!

"... As researchers at Massachusetts General Hospital and other centers first described in 2019, the woman, from Medellin, Colombia, was a member of an extended family with a mutation in a gene labeled PSEN1. The PSEN1 E280A mutation is autosomal dominant, meaning that only a single copy of the gene is required to cause disease. Carriers of the mutation typically exhibit symptoms of Alzheimer’s in their 40s or 50s, and die from the disease soon after, but this woman did not begin to show signs of Alzheimer’s until her early 70s. She died in 2020 from metastatic melanoma at the age of 77.

The key difference in the Colombian woman’s ability to fend off the disease for three decades appeared to be that in addition to having the PSEN1 E280A mutation, she was also a carrier of both copies of a mutation known as APOE3 Christchurch. ...

The APOE family of genes control production of apolipoproteins, which transport lipids (fats) in blood and other bodily fluids. The APOE2 variant is known to be protective against Alzheimer’s dementia, while the APOE4 variant is linked to an increased risk for the disease.

APOE3, the most common variant, is not typically associated with either reduced or increased risk for Alzheimer’s. ...
the woman did, in fact, have pathologic features of Alzheimer’s disease in her brain, but not in regions of the brain where the hallmarks of Alzheimer’s are typically found. ...
“This patient gave us a window into many competing forces — abnormal protein accumulation, inflammation, lipid metabolism, homeostatic mechanisms — that either promote or protect against disease progression, and begin to explain why some brain regions were spared while others were not,” ...
In this case, the tau pathology largely spared the frontal cortex, which is important for judgment and other “executive” functions, and the hippocampus, which is important for memory and learning. Instead, the tau pathology involved the occipital cortex, the area of the brain at the back of the head that controls visual perception. ...
“This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer’s: let’s observe, learn, and imitate nature,” ..."

From the abstract:

"We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies."

Alzheimer’s-defying brain offers clues to treatment, prevention – Harvard Gazette Genetic mutation found that could shed light on mechanism for disease resistance, lead to new therapies

Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (open access)

Corals Upend Longstanding Idea About Genetic Inheritance in animals

Amazing stuff! More variety for sessile animals!

"... The finding points to a new source of genetic variation in coral that may hasten the rate at which these organisms evolve and adapt. ..."

From the abstract:

"Since 1892, it has been widely assumed that somatic mutations are evolutionarily irrelevant in animals because they cannot be inherited by offspring. However, some nonbilaterians segregate the soma and germline late in development or never, leaving the evolutionary fate of their somatic mutations unknown. By investigating uni- and biparental reproduction in the coral Acropora palmata (Cnidaria, Anthozoa), we found that uniparental, meiotic offspring harbored 50% of the 268 somatic mutations present in their parent. Thus, somatic mutations accumulated in adult coral animals, entered the germline, and were passed on to swimming larvae that grew into healthy juvenile corals. In this way, somatic mutations can increase allelic diversity and facilitate adaptation across habitats and generations in animals."

Corals Upend Longstanding Idea About Genetic Inheritance | The Scientist Magazine® Most animals can’t pass on mutations that arise spontaneously throughout their lives—but Elkhorn corals can.

Inheritance of somatic mutations by animal offspring (open access)

Fig. 1. Detection and mapping of somatic mutations across a parent coral colony and five nearest neighbor colonies (ramets) from the same coral genet

Are genetic mutations random in humans? Probably not!

Here are two studies showing that mutations of the human and other organism genome are not random!

"... For the past century, an assumption central to Charles Darwin's evolutionary theory is that mutations are random and accidental and that natural selection favors such accidents. In an article published in the scientific peer-reviewed journal Genome Research, researchers have found the first evidence of non-random mutations in human genes. ...
Using a new and innovative method, the researchers ... have managed to prove that the rate of generation of the human hemoglobin S (HbS) mutation which protects one from malaria is higher in people from Africa in contrast to people from Europe. In other words, the mutation is not random but rather exists preferentially within the population of Africa where it is more needed."

"The work, published in Nature on January 12, finds that there’s a discrepancy in the rates of mutations among genes in model plant Arabidopsis thaliana. Specifically, genes playing a crucial role in survival and reproduction mutate far less often than those that are less important. ... On top of that, genes considered essential had a 37 percent lower mutation rate than those in which modifications would be less likely to prove disastrous. ...
[researchers] found evidence of specific epigenetic characteristics such as cytosine methylation that prevent mutations from occurring in those regions, not unlike protective barriers. These structures and the variability in mutation rates within a single organism’s genome ... suggest that “evolution created mechanisms that changed how evolution works.” ...
So the study’s authors calculated mutation bias among silent mutations, which don’t result in functional changes and still encode the same amino acid sequence as before when new proteins are synthesized. The effect, the paper shows, is still present among silent mutations as well as non-coding gene regions called introns, suggesting that the different mutation rates “is best explained by a genuine mutation difference” and not selection"

Are genetic mutations random in humans? Israeli study says no - The Jerusalem Post

De novo mutation rates at the single-mutation resolution in a human HBB gene-region associated with adaptation and genetic disease (open access)

Essential Genes Protected from Mutations (Long, comprehenisve article) Epigenetic structures appear to reduce the rate of changes in genes essential for survival and reproduction, a study finds, challenging the notion that mutations are evenly distributed throughout the genome prior to selection.

Mutation bias reflects natural selection in Arabidopsis thaliana (open access)

No excess mutations in the children of Chernobyl survivors, new study finds

For over 30 years, environmentalists, alarmists and the like have warned the public with their apocalyptic exaggerations about the Chernobyl nuclear accident!

"... Working with colleagues at the Broad Institute, Chanock’s team sequenced the genomes of 105 parents and 130 children born between 1987 and 2002. Numbers of DNMs [de novo mutations] were no greater than those seen in the general population—even at the highest radiation doses, the researchers report today in Science. ..."

"Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated whether children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation post-accident were born with more germline de novo mutations (DNMs). Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs versus previous studies. ..."

No excess mutations in the children of Chernobyl survivors, new study finds | Science | AAAS

Here is the link to the underlying research article:

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident (open access)

The Genes We Lost Along the Way

Very recommendable! Amazing stuff!

Did you know we once had a gene that produces the precursor of vitamin C?

"... The non-functional gulonolactone oxidase pseudogene (GULOP) was mapped to human chromosome 8p21 that corresponds to an evolutionarily conserved segment on either porcine chromosome 4 (SSC4) or 14 (SSC14). GULO produces the precursor to ascorbic acid, which spontaneously converts to the vitamin ("vitamin C"). ..." (Source)

Innovative tool offers hope for children with rapid-aging disease progeria

Good news! This may well be another great breakthrough for genetic base editors like CRISPR! This new gene editing method may also be applicable to other genetic diseases! However, it may take a while to safely transfer this new treatment from mice to humans!

"... a team of scientists from the Broad Institute of MIT and Harvard ..., the National Institutes of Health, and Vanderbilt University Medical Center to achieve an almost unbelievable leap for the CRISPR gene-editing tool known as base editing, moving the technology a critical step closer to being a treatment for progeria, a deadly premature aging disease. Several hundred children worldwide live with the malady. In most cases, just one small error involving one of the four main bases, or building blocks, of DNA — a thymine (T) in place of a cytosine (C) at one position in just one copy of the lamin A gene in a cell nucleus — causes the body to produce a toxic protein known as progerin. ... used an adenine base-editing treatment in mice to successfully convert an impressive percentage of those errant Ts back to Cs in DNA, RNA, and protein, leading to a dramatic improvement in tissue health (including the heart) and lifespan — mice lived about 2½ times longer with just a single treatment and reached the start of what would be old age in normal, healthy mice. ... Because their effort proved so successful, the work not only offers a path to treat progeria, it provides a blueprint for testing novel gene-editing treatments for other genetic diseases like sickle cell anemia and muscular dystrophy. ...
“To our knowledge, this work resulted in the strongest rescue of the symptoms of progeria by multiple measures,” he continued. “Five years ago, we were still finishing the development of the very first base editor. If you had told me then that within five years, a single dose of a base editor could address progeria in an animal at the DNA, RNA, protein, vascular pathology, and lifespan levels, I would have said, ‘There’s no way.’ ...
Since about half of all known disease-causing mutations are single-letter errors (like progeria), other scientists could use this study as a guide to hone base editors to cure more genetic disorders in humans. ...
While the team observed no significant off-target edits, some of the longest-living mice developed liver tumors, a known complication when using adeno-associated viruses (AAVs) to deliver genes into mice that are allowed to live into old age. ..."

"Hutchinson–Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years ...Lentiviral delivery of the ABE [Adenine base editor] to fibroblasts from children with HGPS resulted in 87–91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. ..."

Innovative tool offers hope for children with rapid-aging disease Progeria study finds base-editing therapy more than doubles the lifespan of mice

Here is the underlying research article:

In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice (behind paywall)

Israeli Scientists Identify Genetic Mutation in mice Associated With Autism

Good news! "The research indicates that these findings could be instrumental in developing drugs to directly change the neural processes in the cerebellum and offer hope for effective medications for the main symptoms of autism in the future."

"Recent years have provided substantial research displaying the effect of genetic mutations on the development of autism and other neurodevelopmental disorders.  Based on those studies, researchers have focused attention on the commonalities behind those mutations and how they impact on the functioning of the brain. ...
Upon further investigation, the research team also observed that the genetic mutation affected the proliferation of cells in the brain and inhibited the production of new neurons. ..."

"Several genes implicated in autism spectrum disorder (ASD) are chromatin regulators, including POGZ. ...
We demonstrate that Pogz deficient mice show microcephaly, growth impairment, increased sociability, learning and motor deficits, mimicking several of the human symptoms. ..."

Israeli Scientists Identify Genetic Mutation Associated With Autism

Hebrew University identifies genetic mutation associated with autism, offering hope for effective therapeutics

Here is the underlying research paper:

Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice (open access, published November 2020)

The research team:

The coronavirus is mutating — does it matter?

Springer Nature speculates in a long News Feature about possible mutations of the SARS-Cov-2 virus and its dangers! Lot's of conjecture and fearmongering!
However, these mutations seem to be very small and limited (e.g. single nucleotide) and not very frequent given its "29,903-letter RNA code". No reason for alarmism!

In fact, this article discusses at extraordinary length only one single nucleotide mutation (i.e. D614G). This one is apparently harmless.

"Compared with HIV, SARS-CoV-2 is changing much more slowly as it spreads. ... Analysing hospitalization data from Sheffield, UK, the team found no evidence that viruses carrying the mutation [D614G] made people any sicker. ... Despite the virus’s sluggish mutation rate, researchers have catalogued more than 12,000 mutations in SARS-CoV-2 genomes. But scientists can spot mutations faster than they can make sense of them. Many mutations will have no consequence for the virus’s ability to spread or cause disease, because they do not alter the shape of a protein, whereas those mutations that do change proteins are more likely to harm the virus than improve it ..."
How many of those hastily cataloged mutations are artifacts? Yes, keep that in mind that many of these mutations are harmful to the virus!

The coronavirus is mutating — does it matter? Different SARS-CoV-2 strains haven’t yet had a major impact on the course of the pandemic, but they might in future.

A woman’s genetic mutation may hold the key to stopping Alzheimer’s

Good news! Very recommendable! Fascinating research!

Thanks to a family in Medellin, Colombia we know now much more about Alzheimer's. "The Colombian family, 5,000 members strong, includes an estimated 1,000 or so people who carry the Paisa mutation in the presenilin 1 gene. "

"Perhaps this unusually resilient woman in Colombia shows a way to halt the disease, or at least slow it down."

"This pileup [of amyloid] is already visible in brain scans of people in their 20s who carry the mutation. By their mid-40s, many of these people have trouble remembering; they typically develop full-blown dementia by age 50.

Inheriting just one copy of the mutation is enough to lead to excess amyloid, and ultimately dementia."

A woman’s genetic mutation may hold the key to stopping Alzheimer’s | Science News: A single mutation in a woman who evaded Alzheimer’s may point to new ways to treat the disease.

Ready For DNA Base Editors

Posted: 10/28/2017

Trigger

Just read these articles (1 & 2) about a new adenine base editor. Many of us, who are now familiar with the CRISPR Cas 9, will appreciate these latest advances in genetics.

Enormous Implications

“Being able to make this type of conversion [to flip base pairs] is particularly important because approximately half of the 32,000 disease-associated point mutations already identified by researchers are a change from a G•C base pair to a A•T base pair.

…

Liu said that particular change is unusually common in part because about 300 times a day in every human cell, a spontaneous chemical reaction converts a cytosine (C) base into uracil (U), which behaves like thymine (T). While there are natural cellular repair mechanisms to fix that spontaneous change, the machinery is not perfect and occasionally fails to make the repair. The result can be the mutation of the G•C base pair to an A•U or A•T base pair, which can lead to certain genetic diseases. …

A major addition to genome-editing technologies, the adenine base editor joins other base-editing systems recently developed in Liu’s lab, such as BE3 and its improved variant, BE4. Using these base editors, researchers can now correct all the so-called “transition” mutations — C to T, T to C, A to G, or G to A — that together account for almost two-thirds of all disease-causing point mutations, including many that cause serious illnesses that currently have no treatment.” (emphasis added)