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James Priest couldn't understand it. He examined the DNA of a critically ill baby, looking for a genetic mutation that threatened to stop his heart. But the results appeared to be from two different babies.
"I was stunned," said Dr. Priest, a pediatric cardiologist at Stanford University.
The baby turned out to be carrying a mixture of genetically different cells, a condition known as mosaicism. Some of his cells carried the deadly mutation, others didn't. They could have belonged to a healthy child.
We're used to thinking that our cells share an identical set of genes, faithfully copied from when we were fertilized eggs. When we talk about our genome, all of the DNA in our cells, we use the singular.
However, over the decades it has become clear that the genome is not only different from person to person. It also differs from cell to cell. The condition is not unusual: we are all mosaics.
For some people, this could mean developing a serious condition, such as: B. heart disease. But mosaicism also means that healthy people are more different than scientists thought.
In medieval Europe, travelers traversing the forests would sometimes encounter a fearsome tree.
A growth that sprout from the trunk.it looked as if it belonged to a completely different plant🇧🇷 A dense bundle of branches formed, how you could turn it into a broom.
The Germans call it Hexenbesen: Hexenbesen. According to legend, witches used spells to summon broomsticks to fly across the night sky. The witches also used some as nests and left them for the hobgoblins to sleep in.
In the 19th century, plant breeders discovered that if they cut a witch's broom from one tree and grafted it onto another, the broom would grow and produce seeds. These seeds would also sprout on the witch's broomstick.
Today you can see examples of witches' brooms on common suburban lawns. Popular with landscape gardeners, the dwarf Alberta fir grows up to 10 feet tall. It is native to northern Canada, where in 1903 botanists discovered the first known dwarf clinging to a white spruce, a species that can grow ten stories tall.
rosa Grapefruitcame the same🇧🇷 A farmer from Florida noticed a strange branch on a grapefruit from Walters. These usually bear white fruit, but this branch was overloaded with pink-fleshed grapefruit. These seeds have since produced Pink Grapefruit.
Charles Darwin was fascinated by such curiosities. He marveled at reports of "bud sport," strange and uncharacteristic blooms on flowering plants. Darwin thought they had clues to the mysteries of heredity.
Plant and animal cells, he argued, must contain "particles" that determine their color, shape, and other properties. When they divide, the new cells must inherit these particles.
Something must mix this genetic material when the shoots appear, Darwin explained, like "the spark that ignites a mass of combustible matter".
It wasn't until the 20th century that it became clear that this combustible matter was DNA. Once a cell mutates, scientists have found that all of its descendants inherit that mutation.
The witch's broomstick and sporting buds became known as mosaics, named for the artworks made out of small tiles. Nature creates her mosaics from cells rather than mosaics in a rainbow of different genetic profiles.
Before DNA sequencing became commonplace, scientists struggled to identify genetic differences between human cells. Krebs provided the first clear evidence that humans, like plants, can become mosaics.
In the late 19th century, biologists studying cancer cells noticed that many of them had oddly shaped chromosomes. A German researcher, Theodor Boveri, speculated around the turn of the century that the gain of abnormal chromosomescould actually make a cell cancerous.
When Boveri presented his theory, he encountered fierce resistance. "The skepticism with which my ideas were received when I discussed them with the researchers who are acting as judges on the matter led me to abandon the project," he later said.
Boveri died in 1915, and it was almost five decades before scientists found out he was right.
David A. Hungerford and Peter Nowell discovered that people with a form of cancer called chronic myeloid leukemia were missing a significant portion of chromosome 22. It turned out that a mutation moved this part to chromosome 9. . 🇧🇷
It's hard to imagine that a tumor could have anything in common with a pink grapefruit. However, both are products of the same process: cell lines acquire new mutations not found elsewhere in the body.
Some skin diseasesIt turned out that this was also caused by mosaic🇧🇷 Certain genetic mutations cause one side of the body to go completely dark. Other mutations draw stripes on the skin.
The difference is in the time. If a cell acquires a mutation too early in development, it produces many daughter cells, which eventually spread throughout much of the body. Later mutations will have a more limited heritage.
A biography of the brain.
dr Walsh and his colleagues found evidence of mosaicism in some very unexpected places.
They studied a mysterious disorder called hemimegalencephaly, which causes one side of the brain to grow too large. the explorersTissue examined from patients who have undergone brain surgeryto treat seizures caused by hemimegalencephaly.
Some of the patients' brain cells, but not all cells, shared the same mutated genes. It's possible that these mutated neurons in the brain multiply faster than others, causing one side to enlarge.
Preliminary studies suggest that mosaicismunderlying many other diseases🇧🇷 Last year, Christopher Walsh, a geneticist at Harvard University, and his colleagues published evidence that mosaic mutationscan increase the risk of autism.
But scientists are also discovering that mosaicism does not automatically mean illness. In fact, it's the norm.
When a fertilized egg cell, called a zygote, begins dividing in the womb, many of the first cells in its offspring have the wrong number of chromosomes. Some are accidentally duplicated and some are lost.
Most of these imbalanced cells slowly divide or die off completely, while normal cells multiply much faster. But a surprising number of embryos survive with some variation in their chromosomes.
Markus Grompe, a biologist at Oregon Health & Science University, and his colleagues analyzed liver cells from children and adults without liver disease. Between a quarter and a half of the cellswere aneuploid, usually missing one copy of a chromosome.
In addition to altered chromosomes, human embryos also receive minor mutations in the genome. DNA fragments can be copied or deleted. Individual genetic letters can be misrepresented.
It was not possible to study these molecular changes in detail until DNA sequencing technology was sufficiently mature.
In 2017, researchers at the Wellcome Trust Sanger Institute in England looked at 241 women and sequenced batches of white blood cells from each. every womanabout 160 new mutations acquired, each present in a significant fraction of their cells.
The scientists theorized that women acquired these mutations as embryos, giving rise to two or three new mutations each time a cell divides. As these new mutations appeared, the embryonic cells passed them on to their offspring, a tessellated legacy.
Walsh and his colleagues discovered intricate mosaics in the brains of healthy people. In one study, they removed neurons from the brain of a 17-year-old boy who died in a car accident. They sequenced the DNA of each neuron and compared it to DNA from the boy's liver, heart and lung cells.
The researchers found that each neuron had hundreds of mutations not found in other organs. But many of the mutations were shared by only a few of the other neurons.
dr It occurred to Walsh that he could use mutations to reconstruct cell lines to learn how they came about. The researchers used the patterns to trace a kind of genealogy, first linking each neuron to its close relatives and then to its more distant relatives.
When they were done, the scientists found that the cells belonged to five main lineages. All cells of each lineage inherited the same unique mosaic signature.
Even stranger, the scientists found cells in the boy's heart with the same signature as mutations found in some neurons in the brain. Other lineages included cells from other organs.
Based on these results, the researchersCreate a biography of the child's brain.
When there was only one embryonic ball in the womb, five cell lines emerged, each with different mutations. Cells from these lineages migrated in different directions and eventually helped form various organs, including the brain.
The cells that made up the brain became neurons, but not all belonged to the same family. Different lines merged. Essentially, the child's brain was made up of millions of mosaic groups, each made up of tiny cellular relatives.
It's hard to say what these mosaic neurons mean for our lives, what it means for each of us when a witch's broomstick grows out of our skull. "We don't yet know if they affect our abilities or challenges," said Dr. Walsh.
What we do know is that mosaicism introduces randomness into our brain development. The mutations that occur randomly form different patterns in different people. "The same zygote would never develop exactly the same twice," said Dr. Walsh.
a heart in pieces
As ubiquitous as mosaicism is, it remains easy to ignore and surprisingly difficult to document.
Astrea Li, the girl whom Dr. Priest, who was being evaluated at Stanford, suffered cardiac arrest the day she was born. His doctors placed a defibrillator in his heart to get it back to normal rhythm.
Doctor Priest sequenced Astrea's genome to look for the cause of her illness. He concluded that it had a mutation in one copy of a gene called SCN5A. This mutation may have caused him problems because it encodes a protein that helps trigger his heartbeat.
But as dr. When Priest ran another test, she couldn't find the mutation.
To unravel this mystery, he teamed up with Steven Quake, a Stanford biologist who pioneered methods for sequencing the genomes of individual cells. dr Priest extracted 36 white blood cells from the boy's blood, and scientists sequenced the entire genome of each cell.
In 33 of the cells, both copies of a gene called SCN5A were normal. But in the other three cells, the researchers found a mutation in one of the copies of the gene. Astrea had mosaic blood.
Their saliva and urine also contained mosaic cells, some of which carried the mutation. These finds indicated that Astrea had become a mosaic very early in its evolution.
Skin cells in saliva, bladder cells in urine, and blood cells were from a different cell layer of two-week-old embryos.
Astrea's SCN5A mutation must have come from a cell that existed before this stage. Later, their daughter cells ended up in these three layers and eventually in tissues scattered throughout the body.
They might as well have landed in your heart. And there, theoretically, the mutation could have caused Astrea's problems.
while dr Priest reconstructed the origins of Astrea's mosaic while she was recovering from surgery to implant her defibrillator. Her parents, Edison Li and Sici Tsoi, took her home. And for a few months it seemed like he was over the hill.
One day, however, his defibrillator detected an irregular heartbeat and delivered a shock, along with a wireless message to Astrea's doctors.
Back at the hospital, doctors discovered a new problem: her heart had grown dangerously. Researchers have linked mutations in the SCN5A gene to the condition.
His heart soon stopped. His doctors installed a mechanical pump, and a donor heart was soon available.
Astrea underwent a transplant and recovered well enough to go home. He had a normal childhood, doing pirouettes with his sister and obsessively listening to the Frozen soundtrack.
The transplant didn't just breathe new life into Astrea. there was dr Sacerdote also the very rare opportunity to see a mosaic heart up close.
The transplant surgeons cut out some pieces of Astrea's heart muscle. dr Priest and his colleagues extracted the SCN5A gene from cells taken from different parts of his heart.
On the right side of my heart, he and his colleaguesfound that more than 5 percent of the cells had mutated genes🇧🇷 On the left side, almost 12% did.
To study the effect of this mosaic, Dr. Priest and his colleagues created a computer simulation of Astrea's heart. They programmed it with grains of mutated cells and crashed it.
The simulated heart was beating erratically, like Astrea's.
The experience made Dr. Sacerdote wondering how many more humans might be at risk from a hidden mix of mutations.
Unless he ends up with another patient like Astrea, we may never know.
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