Unraveling the Mystery: Why Every Human is a Tapestry of Genetic Flaws

Your journey began when the egg met the sperm, merging the DNA from your biological progenitors. Your initial cell started replicating its newly combined genome and dividing to create a body.

And almost at once, genetic errors began to accumulate.

“The process of gathering errors throughout your genome persists for your entire life,” explains Phil H. Jones, a cancer researcher at the Wellcome Sanger Institute in Hinxton, England.

Researchers have long been aware that DNA replication systems make the occasional mistake—that’s often how cancers initiate—but only recently has technology advanced enough to catalog every genetic error. This has shown that we are infused with inaccuracies. Every individual is a vast mosaic of cells, mostly similar, but with variations from one cell or cell cluster to another.

Cellular genomes may differ by a single genetic letter at one position and by a larger missing chromosome segment at another. By mid-life, an average body cell likely contains approximately a thousand genetic errors, according to Michael Lodato, a molecular biologist at the University of Massachusetts Chan Medical School in Worcester.

These alterations—whether in blood, skin, or brain—accumulate even though the cell’s DNA-replicating machinery is remarkably precise, and despite the cells having strong repair capabilities. Given that the adult body contains around 30 trillion cells, with roughly 4 million of these dividing every second, even infrequent errors compound over time. (Mistakes are significantly fewer in cells that lead to egg and sperm; the body appears to allocate more energy and resources to prevent mutations in reproductive tissues to ensure pristine DNA is transmitted to future generations.)

“The remarkable thing is, we all continue functioning quite well,” Jones comments.

Researchers are still in the nascent stages of exploring the origins and effects of these mutations. The National Institutes of Health is committing $140 million to map them, in addition to millions previously invested by the National Institute of Mental Health to examine mutations in the brain. While many alterations are likely harmless, certain ones may have repercussions for cancers and neurological disorders. Fundamentally, some scientists theorize that a lifetime’s worth of random genomic errors could be a key factor underlying much of the aging process.

“We’ve understood this for less than a decade, and it feels like the discovery of a new continent,” states Jones. “We haven’t even begun to grasp what all of this signifies.”

Suspicious from the beginning

Since the revelation of DNA’s structure in the 1950s, scientists have theorized that genetic errors and other mutations accumulating in non-reproductive, or somatic, tissues could elucidate disease and aging.

By the 1970s, it was recognized that growth-advancing mutations within a small fraction of cells were responsible for the emergence of cancers.

“The presumption was that this event’s frequency was exceedingly low,” remarks Jan Vijg, a geneticist at the Albert Einstein College of Medicine in New York.

However, identifying and examining these mutations proved to be immensely challenging. Conventional DNA sequencing could only process substantial quantities of genetic material, retrieved from large clusters of cells, to expose only the most prevalent sequences. Rare mutations eluded detection. This began to shift around 2008, according to stem cell biologist Siddhartha Jaiswal from Stanford University in California. Modern techniques are so precise that mutations present in a minuscule fraction of cells—even just a single cell—can be discerned.

In the early 2010s, Jaiswal was curious to understand how mutations might build up in individuals’ blood cells ahead of blood cancers’ onset. Analyzing blood samples from over 17,000 individuals, he and his colleagues confirmed their hypothesis: Cancer-associated mutations were scarce in those under 40 but increased in prevalence with age, constituting about 10 percent or more of blood cells post the 70th year.

Additionally, the team observed that the mutated cells were frequently genetically identical to one another: They formed clones. Jaiswal speculates that one of the thousands of blood cell-producing stem cells absorbs mutations that enhance its growth and division capacity. Over the years, it starts to dominate over the normally functioning stem cells, producing a large cluster of genetically similar cells.

Unsurprisingly, these rapidly dividing mutated blood cell clones were correlated with an increased risk for blood cancers. However, they were also linked to higher risks of heart disease, stroke, and mortality from any cause, possibly due to their inflammation-promoting nature. Interestingly, they were also associated with approximately one-third lower risk of Alzheimer’s dementia. Jaiswal, co-author of a paper discussing the health consequences

of hematopoietic cell clones in the 2023 Annual Review of Medicine, hypothesizes that certain clones could be more effective at infiltrating brain matter or eliminating harmful proteins.

While Jaiswal and his team were investigating the blood clones they documented in 2014, scientists at the Wellcome Sanger Institute initiated research into bodily mutations in various tissues, beginning with the skin of the eyelid. As individuals age, some experience sagging eyelids and opt for surgical removal of a portion of skin to remedy the issue. The researchers obtained these samples from four participants and excised circles measuring one or two millimeters for genetic analysis. “It was full of discoveries,” remarks Inigo Martincorena, a geneticist affiliated with Wellcome Sanger. Although the patients did not have skin cancer, their skin was infested with thousands of clones, with one-fifth to one-third of the eyelid skin cells harboring mutations linked to cancer.

The revelation that numerous skin cells in individuals without skin cancer harbored mutations created quite a stir. “I was astonished,” states James DeGregori, a cancer biologist from the University of Colorado Anschutz Medical Campus in Aurora, who was not part of the research.

The Wellcome Sanger team subsequently identified clusters of identical, mutated cells in a range of other tissues, including the esophagus, bladder, and colon. For instance, they analyzed colonic crypts, which are indentations in the intestinal lining; there are approximately ten million of these per individual, each home to around 2,000 cells, all descending from a limited number of stem cells confined to the crypt. In a study encompassing more than 2,000 crypts from 42 individuals, the researchers discovered hundreds of genetic variations within crypts from people in their 50s.

inhibit the proliferation of adjacent cells, enabling mutant cells to dominate a crypt more swiftly. While this alone is not necessarily sufficient to induce colorectal cancer, on rare occasions, cells may gather additional cancer-causing mutations, spill over crypt boundaries, and lead to malignancies.

“Wherever researchers have sought these somatic mutations—across every organ—they are discovered,” observes Jones. He has come to regard the body as an evolutionary battleground. As cells accrue mutations, they may become more (or less) adept at growing and dividing. Over time, some cells that reproduce more effectively can surpass others and create substantial clones.

“Yet,” notes DeGregori, “we don’t become lumpy.” Our tissues must possess mechanisms to prevent clones from evolving into cancer, he proposes. Indeed, uncontrolled mutant clones in mice have been observed to return to normal growth, as Jones and a co-author highlight in the 2023 Annual Review of Cancer Biology.

Jones and his associates identified a form of protection in the human esophagus. By middle age, many esophageal clones—often constituting the majority of esophageal tissue—possess mutations disrupting a gene known as NOTCH1. This does not hinder the esophagus’s ability to transport food, but cancers seem to require NOTCH1 for growth. Malignant mutations may accumulate in esophageal cells, but if NOTCH1 is missing, these cells appear less likely to form tumors.

In essence, not all bodily mutations are detrimental or neutral; some may even be advantageous. Fortunately for us, these beneficial mutations often prevail.

Diving into the brain

Our DNA-replicating machinery has a myriad of opportunities to make mistakes in the cells of the esophagus, colon, and blood since they frequently divide. However, neurons in the brain cease to divide before or shortly after birth, so scientists initially believed they would remain genetically immaculate, affirms Christopher Walsh, a neurogeneticist at Boston Children’s Hospital.

Nonetheless, there were indications that mutations accumulating over a lifetime could trigger issues in the brain. In 2004, researchers reported on a patient suffering from Alzheimer’s disease due to a mutation existing in only a subset of brain cells. This mutation was novel—it was not inherited from either parent.

In 2012, Walsh’s team reported on an examination of brain tissue removed during surgery intended to correct excessive brain growth causing seizures. Out of eight samples, three contained mutations impacting a gene that regulates brain size, but these mutations were not consistently found in the blood, suggesting they developed in only certain areas of the body.

There are several ways brain cells might acquire mutations, explains Lodato. A mutation could arise early in development, prior to the brain’s completion and the cessation of cell division. Alternatively, within an adult brain cell, DNA could sustain damage and fail to be repaired adequately.

By 2012, interest in non-inherited brain mutations was growing. Thomas Insel, then director of the National Institute of Mental Health, posited that these kinds of mutations could underlie numerous psychiatric conditions. Non-inherited mutations in the brain may help elucidate a long-standing enigma in neurological disorders: why identical twins frequently do not share psychiatric diagnoses (for instance, if one twin develops schizophrenia, the other has only about a 50 percent chance of developing it).

Mosaicism provides “a very persuasive explanation,” remarks neuroscientist Mike McConnell, the scientific director for the Lennox-Gastaut Syndrome Foundation in San Diego, a nonprofit organization dedicated to supporting families and research into a severe form of epilepsy.

Beginning in the early 2010s, McConnell, Walsh, Lodato, and others started documenting mutations, both significant and minor, scattered throughout the brains of deceased individuals. They cataloged deletions and duplications of singular genes, multiple genes, or entire chromosomes; they identified entire chromosome segments relocated to new loci in the genome. Eventually, Walsh, Lodato, and their collaborators discovered a thousand or more single-nucleotide mutations in the genetic code within all nerve cells of individuals around the age of 50. That last revelation “felt entirely implausible to us,” recalls Walsh. “We questioned our own findings.”

Confronted with such astonishing results, the researchers delved deeper. They examined 159 neurons from 15 individuals who had passed between 4 months and 82 years of age. They reported that the frequency of mutations rose with age, signifying that errors accumulated over time, similar to other body areas. “The brain is a mosaic, in an intimate and profound way,” states Lodato.

To further investigate that mosaicism, the National Institute of Mental Health supported a sequence of projects from 2015 to 2019 examining brain tissue mosaicism in samples, primarily obtained post-mortem and stored in tissue banks, from over 1,000 neurotypical individuals.or experienced conditions such as Tourette syndrome and autism spectrum disorder.

Single-nucleotide variations were predominantly observed, states McConnell, who co-directed the initiative. Investigators gathered over 400 terabytes of DNA sequences and supplementary information, and developed analytical instruments, forming a robust framework for the subsequent phase of brain mosaicism investigations. Through this research and others, scientists have associated brain mosaicism with neurological disorders, including autism, epilepsy, and schizophrenia.

At Lodato’s laboratory, graduate researchers Cesar Bautista Sotelo and Sushmita Nayak are currently exploring how accumulated mutations may trigger amyotrophic lateral sclerosis, a debilitating disease also referred to as Lou Gehrig’s disease. Geneticists can detect an identified mutation in roughly 10 percent of non-hereditary instances. However, the fresh data on mosaicism imply that significantly more individuals may harbor mutations in ALS genes within their brains or spinal columns, even if absent in the rest of their anatomy.

This is significant, as researchers are developing treatments aimed at some of the 40-plus genes that, upon mutation, lead to ALS. In 2023, the Food and Drug Administration sanctioned the first such intervention, targeting a commonly mutated ALS gene. For patients to qualify for these therapies, they must identify their mutations.

Consequently, Nayak asserts, “we strongly promote a shift in the current methodology of diagnosing ALS.” Rather than solely analyzing DNA from a blood sample, other tissues such as saliva, hair, or skin could also be evaluated, in case an ALS mutation developed during the formation of cells that didn’t yield blood but did form other bodily tissues.

Insights on Aging

Currently, the health ramifications of our body’s mosaicism remain largely unclear to demand any immediate action, particularly in scenarios like the blood clones where no relevant therapies are available. “We don’t really encourage people to stress about this,” claims Jaiswal. “At this moment, there’s no logical basis to test individuals who are healthy.”

Nevertheless, numerous scientists interpret the findings as support for a well-established theory: that a lifetime of mutations ultimately culminates in the inevitable condition we recognize as aging.

Martincorena and his team evaluated a facet of that theory in a 2022 research. If the accumulation of mutations contributes to aging, they hypothesized, then short-lived creatures like mice ought to amass mutations quickly, whereas longer-lived species such as humans should gather mutations more slowly, potentially due to superior repair mechanisms.

To examine this hypothesis, the researchers undertook a five-year expedition analyzing colon crypt samples from eight individuals, together with a diverse group of animals: 19 laboratory mice and rats; 15 domesticated animals like cats, dogs, cattle, and rabbits; and 14 more exotic beings that included tigers, lemurs, a harbor porpoise, and four naked mole rats, which are renowned for their remarkable lifespan of over 30 years. As expected, the species with longer lifespans demonstrated a slower rate of mutation accumulation.

“This does not prove that somatic mutations directly cause aging, but it is consistent with the hypothesis that they may at least partially contribute,” notes Martincorena. Two elements are involved: Accumulating mutations lead to a decreased lifespan, which in turn makes mutation defense less vital, prompting short-lived species to invest less in DNA repair.

The notion that mutations could play a role in aging is intriguing, as it implies that eliminating them could be a genetic source of youth. “If, tomorrow, I discover a method to prevent these mutations from accumulating, I believe I would become a billionaire,” remarks Bautista Sotelo. Presently, at least one biotechnology startup, Matter Bio in New York City, has secured funding with the goal of restoring the human genome. (Whether such an initiative could ever be implemented across broad groups of cells remains uncertain: “I don’t believe you can entirely eradicate the mutations,” says DeGregori.)

The narrative of bodily mutations is far from complete. “Based on the revelations we are currently making, this journey has merely begun,” remarks Martincorena. “I anticipate numerous surprises in the coming years.”

Knowable Magazine is an independent journalistic initiative from Annual Reviews.