Why Is Every Human Being Riddled With Genetic Errors?
And almost immediately, genetic mistakes started to accrue.
“That process of accumulating errors across your genome goes on throughout life,” says Phil H. Jones, a cancer biologist at the Wellcome Sanger Institute in Hinxton, England.
Scientists have long known that DNA-copying systems make the occasional blunder—that’s how cancers often start—but only in recent years has technology been sensitive enough to catalog every genetic booboo. And it’s revealed we’re riddled with errors. Every human being is a vast mosaic of cells that are mostly identical, but different here or there, from one cell or group of cells to the next.
Cellular genomes might differ by a single genetic letter in one spot, by a larger lost chromosome chunk in another. By middle age, each body cell probably has about a thousand genetic typos, estimates Michael Lodato, a molecular biologist at the University of Massachusetts Chan Medical School in Worcester.
These mutations—whether in blood, skin or brain—rack up even though the cell’s DNA-copying machinery is exceptionally accurate, and even though cells possess excellent repair mechanisms. Since the adult body contains around 30 trillion cells, with some 4 million of them dividing every second, even rare mistakes build up over time. (Errors are far fewer in cells that give rise to eggs and sperm; the body appears to expend more effort and energy in keeping mutations out of reproductive tissues so that pristine DNA is passed to future generations.)
“We’ve known about this for less than a decade, and it’s like discovering a new continent,” says Jones. “We haven’t even scratched the surface of what this all means.”
Suspicious from the start
Scientists had suspected since the discovery of DNA’s structure in the 1950s that genetic misspellings and other mutations accruing in non-reproductive, or somatic, tissues could help explain disease and aging.By the 1970s, researchers knew that growth-promoting mutations in a fraction of cells were the genesis of cancers.
“The assumption was that the frequency of this event was very, very low,” says Jan Vijg, a geneticist at the Albert Einstein College of Medicine in New York.
But it was extremely difficult to detect and study these mutations. Standard DNA sequencing could only analyze large quantities of genetic material, extracted from vast groups of cells, to reveal only the most common sequences. Rare mutations flew under the radar. That started to change around 2008 or so, says stem cell biologist Siddhartha Jaiswal of Stanford University in California. New techniques are so sensitive that mutations present in a tiny fraction of cells—even a single cell—can be uncovered.
In the early 2010s, Jaiswal was interested in how mutations might accumulate in people’s blood cells before they develop blood cancers. From the blood of more than 17,000 people, he and colleagues found what they’d predicted: Cancer-linked mutations were rare in people under 40, but they occurred in higher amounts with age, making up about 10 percent or more of blood cells after the 70th birthday.
But the team also saw that the cells with mutations were often genetically identical to one another: They were clones. The cause, Jaiswal figures, is that one of the body’s thousands of blood cell-making stem cells picks up mutations that make it a little bit better at growing and dividing. Over decades, it begins to win out over normally growing stem cells, generating a large group of genetically matched cells.
Not surprisingly, these efficiently dividing mutated blood cell clones were linked to risk for blood cancer. But they were also associated with increased risk for heart disease, stroke and death by any cause, perhaps because they promote inflammation. And unexpectedly, they were associated with about a one-third lower risk of Alzheimer’s dementia. Jaiswal, co-author of an article on the health impacts of blood cell clones in the 2023 Annual Review of Medicine, speculates that some clones might be better at populating brain tissue or clearing away toxic proteins.
As Jaiswal and colleagues were pursuing the blood clones they reported in 2014, researchers at the Wellcome Sanger Institute commenced investigations of body mutations in other tissues, starting with eyelid skin. With age, some people get droopy eyelids and have a bit of skin surgically removed to fix it. The researchers acquired these bits from four individuals and cut out circles one or two millimeters across for genetic sequencing. “It was full of surprises,” says Inigo Martincorena, a geneticist at Wellcome Sanger. Though the patients did not have skin cancer, their skin was riddled with thousands of clones, and one-fifth to one-third of the eyelid skin cells contained cancer-linked mutations.
The findings, that so many skin cells in people without skin cancer had mutations, made a splash. “I was blown away,” says James DeGregori, a cancer biologist at the University of Colorado Anschutz Medical Campus in Aurora, who was not involved in the study.
Wellcome Sanger researchers went on to identify clusters of identical, mutated cells in a variety of other tissues, including the esophagus, bladder and colon. For example, they examined colonic crypts, indentations in the intestinal wall; there are some ten million of these per person, each inhabited by about 2,000 cells, all arising from a handful of stem cells confined to that crypt. In a study of more than 2,000 crypts from 42 people, the researchers found hundreds of genetic variations in crypts from people in their 50s.
About 1 percent of otherwise normal crypts in that age group contained cancer-linked mutations, some of which can suppress proliferation of nearby cells, allowing mutant cells to take over a crypt faster. This alone is not necessarily sufficient to create colorectal cancer, but on rare occasions, cells can acquire additional cancer-causing mutations, overflow crypt boundaries and cause malignancies.
“Everywhere people have looked for these somatic mutations, in every organ, we find them,” says Jones. He’s come to see the body as a kind of evolutionary battleground. As cells accumulate mutations, they can become more (or less) able to grow and divide. With time, some cells that reproduce more readily can overtake others and create large clones.
“And yet,” notes DeGregori, “we don’t turn lumpy.” Our tissues must have ways to stop clones from becoming cancer, he suggests. Indeed, overgrowing mutant clones in mice have been seen to revert to normal growth, as Jones and a co-author describe in the 2023 Annual Review of Cancer Biology.
Jones and colleagues found one example of protection in the human esophagus. By middle age, many esophagus clones—often making up the bulk of esophagus tissue—have mutations disrupting a gene called NOTCH1. This doesn’t affect the ability of the esophagus to move food along, but cancers seem to need NOTCH1 to grow. Bad mutations may accumulate in esophageal cells, but if NOTCH1 is absent, they appear less likely to become tumors.
In other words, some of the bodily mutations aren’t bad or neutral, but even beneficial. And, lucky for us, these good mutations prevail a lot of the time.
Getting inside the brain
Our DNA-copying machinery has plenty of opportunity to make errors in cells of the esophagus, colon and blood because they divide constantly. But neurons in the brain stop dividing before or soon after birth, so scientists originally assumed they would remain genetically pristine, says Christopher Walsh, a neurogeneticist at Boston Children’s Hospital.Yet there were hints that mutations accruing through life could cause problems in the brain. Back in 2004, researchers reported on a patient who had Alzheimer’s disease due to a mutation present in only some brain cells. The mutation was new—it had not been inherited from either parent.
And in 2012, Walsh’s group reported an analysis of brain tissue that had been removed during surgery to correct brain overgrowth that was causing seizures. Three out of eight samples had mutations affecting a gene that regulates brain size, but these mutations were not consistently present in the blood, suggesting they arose in only part of the body.
There are a couple of ways that brain cells could pick up mutations, says Lodato. A mutation could occur early in development, before the brain was completed and its cells had stopped dividing. Or, in a mature brain cell, DNA could be damaged and not repaired properly.
By 2012, interest in non-inherited brain mutations was heating up. Thomas Insel, director of the National Institute of Mental Health at the time, proposed that these kinds of mutations might underlie many psychiatric conditions. Non-inherited mutations in the brain could explain a longstanding puzzle in neurological diseases: why identical twins often don’t share psychiatric diagnoses (for example, if one twin develops schizophrenia, the other has only about a 50 percent chance of getting it).
gene mutation, genomic sequencing, rare disorders, single nucleotide polymorphism, epigenetic alterations, copy number variations, chromosomal abnormalities, mitochondrial disorders, autosomal inheritance, recessive traits, precision medicine, CRISPR technology, genetic counseling, exome analysis, hereditary syndromes, phenotypic variability, non-coding DNA mutations, gene therapy breakthroughs, transcriptomics
#Genetics #RareDiseases #GeneMutation #GenomicSequencing #PrecisionMedicine #CRISPR #GeneTherapy #GeneticCounseling #HereditarySyndromes #ChromosomalAbnormalities #Epigenetics #ExomeAnalysis #PhenotypicVariability #MolecularDiagnostics #RareSyndromes #InheritedDisorders #MitochondrialDiseases #CNVs #Transcriptomics #GeneticHealth
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