DNA Double Take - NY Times
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Nathan McCorkle
Mar 25, 2014, 6:06:44 PM3/25/14
to diybio
http://www.nytimes.com/2013/09/17/science/dna-double-take.html?_r=0
From biology class to "C.S.I.," we are told again and again that our
genome is at the heart of our identity. Read the sequences in the
chromosomes of a single cell, and learn everything about a person's
genetic information -- or, as 23andme, a prominent genetic testing
company, says on its Web site, "The more you know about your DNA, the
more you know about yourself."
"There have been whispers in the matrix about this for years, even
decades, but only in a very hypothetical sense," said Alexander Urban,
a geneticist at Stanford University. Even three years ago, suggesting
that there was widespread genetic variation in a single body would
have been met with skepticism, he said. "You would have just run
against the wall."
But a series of recent papers by Dr. Urban and others has demonstrated
that those whispers were not just hypothetical. The variation in the
genomes found in a single person is too large to be ignored. "We now
know it's there," Dr. Urban said. "Now we're mapping this new
continent."
Dr. James R. Lupski, a leading expert on the human genome at Baylor
College of Medicine, wrote in a recent review in the journal Science
that the existence of multiple genomes in an individual could have a
tremendous impact on the practice of medicine. "It's changed the way I
think," he said in an interview.
Scientists are finding links from multiple genomes to certain rare
diseases, and now they're beginning to investigate genetic variations
to shed light on more common disorders.
Science's changing view is also raising questions about how forensic
scientists should use DNA evidence to identify people. It's also
posing challenges for genetic counselors, who can't assume that the
genetic information from one cell can tell them about the DNA
throughout a person's body.
Human Blueprint
When an egg and sperm combine their DNA, the genome they produce
contains all the necessary information for building a new human. As
the egg divides to form an embryo, it produces new copies of that
original genome.
For decades, geneticists have explored how an embryo can use the
instructions in a single genome to develop muscles, nerves and the
many other parts of the human body. They also use sequencing to
understand genetic variations that can raise the risk of certain
diseases. Genetic counselors can look at the results of genetic
screenings to help patients and their families cope with these
diseases -- altering their diet, for example, if they lack a gene for a
crucial enzyme.
The cost of sequencing an entire genome has fallen so drastically in
the past 20 years -- now a few thousand dollars, down from an estimated
$3 billion for the public-private partnership that sequenced the first
human genome -- that doctors are beginning to sequence the entire
genomes of some patients. (Sequencing can be done in as little as 50
hours.) And they're identifying links between mutations and diseases
that have never been seen before.
Yet all these powerful tests are based on the assumption that, inside
our body, a genome is a genome is a genome. Scientists believed that
they could look at the genome from cells taken in a cheek swab and be
able to learn about the genomes of cells in the brain or the liver or
anywhere else in the body.
In the mid-1900s, scientists began to get clues that this was not
always true. In 1953, for example, a British woman donated a pint of
blood. It turned out that some of her blood was Type O and some was
Type A. The scientists who studied her concluded that she had acquired
some of her blood from her twin brother in the womb, including his
genomes in his blood cells.
Chimerism, as such conditions came to be known, seemed for many years
to be a rarity. But "it can be commoner than we realized," said Dr.
Linda Randolph, a pediatrician at Children's Hospital in Los Angeles
who is an author of a review of chimerism published in The American
Journal of Medical Genetics in July.
Twins can end up with a mixed supply of blood when they get nutrients
in the womb through the same set of blood vessels. In other cases, two
fertilized eggs may fuse together. These so-called embryonic chimeras
may go through life blissfully unaware of their origins.
One woman discovered she was a chimera as late as age 52. In need of a
kidney transplant, she was tested so that she might find a match. The
results indicated that she was not the mother of two of her three
biological children. It turned out that she had originated from two
genomes. One genome gave rise to her blood and some of her eggs; other
eggs carried a separate genome.
Women can also gain genomes from their children. After a baby is born,
it may leave some fetal cells behind in its mother's body, where they
can travel to different organs and be absorbed into those tissues.
"It's pretty likely that any woman who has been pregnant is a
chimera," Dr. Randolph said.
Everywhere You Look
As scientists begin to search for chimeras systematically -- rather
than waiting for them to turn up in puzzling medical tests -- they're
finding them in a remarkably high fraction of people. In 2012,
Canadian scientists performed autopsies on the brains of 59 women.
They found neurons with Y chromosomes in 63 percent of them. The
neurons likely developed from cells originating in their sons.
In The International Journal of Cancer in August, Eugen Dhimolea of
the Dana-Farber Cancer Institute in Boston and colleagues reported
that male cells can also infiltrate breast tissue. When they looked
for Y chromosomes in samples of breast tissue, they found it in 56
percent of the women they investigated.
A century ago, geneticists discovered one way in which people might
acquire new genomes. They were studying "mosaic animals," rare
creatures with oddly-colored patches of fur. The animals didn't
inherit the genes for these patches from their parents. Instead, while
embryos, they acquired a mutation in a skin cell that divided to
produce a colored patch.
Mosaicism, as this condition came to be known, was difficult to study
in humans before the age of DNA sequencing. Scientists could only
discover instances in which the mutations and the effects were big.
In 1960, researchers found that a form of leukemia is a result of
mosaicism. A blood cell spontaneously mutates as it divides, moving a
big chunk of one chromosome to another.
Later studies added support to the idea that cancer is a result of
mutations in specific cells. But scientists had little idea of how
common cases of mosaicism were beyond cancer.
"We didn't have the technology to systematically think about them,"
said Dr. Christopher Walsh, a geneticist at Children's Hospital in
Boston who recently published a review on mosaicism and disease in
Science. "Now we're in the midst of a revolution."
Benign Differences
The latest findings make it clear that mosaicism is quite common --
even in healthy cells.
Dr. Urban and his colleagues, for example, investigated mutations in
cells called fibroblasts, which are found in connective tissue. They
searched in particular for cases in which a segment of DNA was
accidentally duplicated or deleted. As they reported last year,30
percent of the fibroblasts carried at least one such mutation.
Michael Snyder of Stanford University and his colleagues searched for
mosaicism by performing autopsies on six people who had died of causes
other than cancer. In five of the six people they autopsied, the
scientists reported last October, they found cells in different organs
with stretches of DNA that had accidentally been duplicated or
deleted.
Now that scientists are beginning to appreciate how common chimerism
and mosaicism are, they're investigating the effects of these
conditions on our health. "That's still open really, because these are
still early days," Dr. Urban said.
Nevertheless, said Dr. Walsh, "it's safe to say that a large
proportion of those mutations will be benign." Recent studies on
chimeras suggest that these extra genomes can even be beneficial.
Chimeric cells from fetuses appear to seek out damaged tissue and help
heal it, for example.
But scientists are also starting to find cases in which mutations in
specific cells help give rise to diseases other than cancer. Dr.
Walsh, for example, studies a childhood disorder of the brain called
hemimegalencephaly, in which one side of the brain grows larger than
the other, leading to devastating seizures.
"The kids have no chance for a normal life without desperate surgery
to take out half of their brain," he said.
Dr. Walsh has studied the genomes of neurons removed during those
surgeries. He and his colleagues discovered that some neurons in the
overgrown hemisphere have mutations to one gene. Two other teams of
scientists have identified mutations on other genes, all of which help
to control the growth of neurons. "We can get our hands on the
mechanism of the disease," said Dr. Walsh.
Other researchers are now investigating whether mosaicism is a factor
in more common diseases, like schizophrenia. "This will play itself
out over the next 5 or 10 years," said Dr. Urban, who with his
colleagues is studying it.
Moving Cautiously
Medical researchers aren't the only scientists interested in our
multitudes of personal genomes. So are forensic scientists. When they
attempt to identify criminals or murder victims by matching DNA, they
want to avoid being misled by the variety of genomes inside a single
person.
Last year, for example, forensic scientists at the Washington State
Patrol Crime Laboratory Division described how a saliva sample and a
sperm sample from the same suspect in a sexual assault case didn't
match.
Bone marrow transplants can also confound forensic scientists.
Researchers at Innsbruck Medical University in Austria took cheek
swabs from 77 people who had received transplants up to nine years
earlier. In 74 percent of the samples, they found a mix of genomes --
both their own and those from the marrow donors, the scientists
reported this year. The transplanted stem cells hadn't just replaced
blood cells, but had also become cells lining the cheek.
While the risk of confusion is real, it is manageable, experts said.
"This should not be much of a concern for forensics," said Manfred
Kayser, a professor of Forensic Molecular Biology at Erasmus
University in Rotterdam. In the cases where mosaicism or chimerism
causes confusion, forensic scientists can clear it up by other means.
In the Austrian study, for example, the scientists found no marrow
donor genomes in the hair of the recipients.
For genetic counselors helping clients make sense of DNA tests, our
many genomes pose more serious challenges. A DNA test that uses blood
cells may miss disease-causing mutations in the cells of other organs.
"We can't tell you what else is going on," said Nancy B. Spinner, a
geneticist at the University of Pennsylvania, who published a review
about the implications of mosaicism for genetic counseling in the May
issue of Nature Reviews Genetics.
That may change as scientists develop more powerful ways to
investigate our different genomes and learn more about their links to
diseases. "It's not tomorrow that you're going to walk into your
doctor's office and they're going to think this way," said Dr. Lupski.
"It's going to take time."
--
-Nathan
From biology class to "C.S.I.," we are told again and again that our
genome is at the heart of our identity. Read the sequences in the
chromosomes of a single cell, and learn everything about a person's
genetic information -- or, as 23andme, a prominent genetic testing
company, says on its Web site, "The more you know about your DNA, the
more you know about yourself."
"There have been whispers in the matrix about this for years, even
decades, but only in a very hypothetical sense," said Alexander Urban,
a geneticist at Stanford University. Even three years ago, suggesting
that there was widespread genetic variation in a single body would
have been met with skepticism, he said. "You would have just run
against the wall."
But a series of recent papers by Dr. Urban and others has demonstrated
that those whispers were not just hypothetical. The variation in the
genomes found in a single person is too large to be ignored. "We now
know it's there," Dr. Urban said. "Now we're mapping this new
continent."
Dr. James R. Lupski, a leading expert on the human genome at Baylor
College of Medicine, wrote in a recent review in the journal Science
that the existence of multiple genomes in an individual could have a
tremendous impact on the practice of medicine. "It's changed the way I
think," he said in an interview.
Scientists are finding links from multiple genomes to certain rare
diseases, and now they're beginning to investigate genetic variations
to shed light on more common disorders.
Science's changing view is also raising questions about how forensic
scientists should use DNA evidence to identify people. It's also
posing challenges for genetic counselors, who can't assume that the
genetic information from one cell can tell them about the DNA
throughout a person's body.
Human Blueprint
When an egg and sperm combine their DNA, the genome they produce
contains all the necessary information for building a new human. As
the egg divides to form an embryo, it produces new copies of that
original genome.
For decades, geneticists have explored how an embryo can use the
instructions in a single genome to develop muscles, nerves and the
many other parts of the human body. They also use sequencing to
understand genetic variations that can raise the risk of certain
diseases. Genetic counselors can look at the results of genetic
screenings to help patients and their families cope with these
diseases -- altering their diet, for example, if they lack a gene for a
crucial enzyme.
The cost of sequencing an entire genome has fallen so drastically in
the past 20 years -- now a few thousand dollars, down from an estimated
$3 billion for the public-private partnership that sequenced the first
human genome -- that doctors are beginning to sequence the entire
genomes of some patients. (Sequencing can be done in as little as 50
hours.) And they're identifying links between mutations and diseases
that have never been seen before.
Yet all these powerful tests are based on the assumption that, inside
our body, a genome is a genome is a genome. Scientists believed that
they could look at the genome from cells taken in a cheek swab and be
able to learn about the genomes of cells in the brain or the liver or
anywhere else in the body.
In the mid-1900s, scientists began to get clues that this was not
always true. In 1953, for example, a British woman donated a pint of
blood. It turned out that some of her blood was Type O and some was
Type A. The scientists who studied her concluded that she had acquired
some of her blood from her twin brother in the womb, including his
genomes in his blood cells.
Chimerism, as such conditions came to be known, seemed for many years
to be a rarity. But "it can be commoner than we realized," said Dr.
Linda Randolph, a pediatrician at Children's Hospital in Los Angeles
who is an author of a review of chimerism published in The American
Journal of Medical Genetics in July.
Twins can end up with a mixed supply of blood when they get nutrients
in the womb through the same set of blood vessels. In other cases, two
fertilized eggs may fuse together. These so-called embryonic chimeras
may go through life blissfully unaware of their origins.
One woman discovered she was a chimera as late as age 52. In need of a
kidney transplant, she was tested so that she might find a match. The
results indicated that she was not the mother of two of her three
biological children. It turned out that she had originated from two
genomes. One genome gave rise to her blood and some of her eggs; other
eggs carried a separate genome.
Women can also gain genomes from their children. After a baby is born,
it may leave some fetal cells behind in its mother's body, where they
can travel to different organs and be absorbed into those tissues.
"It's pretty likely that any woman who has been pregnant is a
chimera," Dr. Randolph said.
Everywhere You Look
As scientists begin to search for chimeras systematically -- rather
than waiting for them to turn up in puzzling medical tests -- they're
finding them in a remarkably high fraction of people. In 2012,
Canadian scientists performed autopsies on the brains of 59 women.
They found neurons with Y chromosomes in 63 percent of them. The
neurons likely developed from cells originating in their sons.
In The International Journal of Cancer in August, Eugen Dhimolea of
the Dana-Farber Cancer Institute in Boston and colleagues reported
that male cells can also infiltrate breast tissue. When they looked
for Y chromosomes in samples of breast tissue, they found it in 56
percent of the women they investigated.
A century ago, geneticists discovered one way in which people might
acquire new genomes. They were studying "mosaic animals," rare
creatures with oddly-colored patches of fur. The animals didn't
inherit the genes for these patches from their parents. Instead, while
embryos, they acquired a mutation in a skin cell that divided to
produce a colored patch.
Mosaicism, as this condition came to be known, was difficult to study
in humans before the age of DNA sequencing. Scientists could only
discover instances in which the mutations and the effects were big.
In 1960, researchers found that a form of leukemia is a result of
mosaicism. A blood cell spontaneously mutates as it divides, moving a
big chunk of one chromosome to another.
Later studies added support to the idea that cancer is a result of
mutations in specific cells. But scientists had little idea of how
common cases of mosaicism were beyond cancer.
"We didn't have the technology to systematically think about them,"
said Dr. Christopher Walsh, a geneticist at Children's Hospital in
Boston who recently published a review on mosaicism and disease in
Science. "Now we're in the midst of a revolution."
Benign Differences
The latest findings make it clear that mosaicism is quite common --
even in healthy cells.
Dr. Urban and his colleagues, for example, investigated mutations in
cells called fibroblasts, which are found in connective tissue. They
searched in particular for cases in which a segment of DNA was
accidentally duplicated or deleted. As they reported last year,30
percent of the fibroblasts carried at least one such mutation.
Michael Snyder of Stanford University and his colleagues searched for
mosaicism by performing autopsies on six people who had died of causes
other than cancer. In five of the six people they autopsied, the
scientists reported last October, they found cells in different organs
with stretches of DNA that had accidentally been duplicated or
deleted.
Now that scientists are beginning to appreciate how common chimerism
and mosaicism are, they're investigating the effects of these
conditions on our health. "That's still open really, because these are
still early days," Dr. Urban said.
Nevertheless, said Dr. Walsh, "it's safe to say that a large
proportion of those mutations will be benign." Recent studies on
chimeras suggest that these extra genomes can even be beneficial.
Chimeric cells from fetuses appear to seek out damaged tissue and help
heal it, for example.
But scientists are also starting to find cases in which mutations in
specific cells help give rise to diseases other than cancer. Dr.
Walsh, for example, studies a childhood disorder of the brain called
hemimegalencephaly, in which one side of the brain grows larger than
the other, leading to devastating seizures.
"The kids have no chance for a normal life without desperate surgery
to take out half of their brain," he said.
Dr. Walsh has studied the genomes of neurons removed during those
surgeries. He and his colleagues discovered that some neurons in the
overgrown hemisphere have mutations to one gene. Two other teams of
scientists have identified mutations on other genes, all of which help
to control the growth of neurons. "We can get our hands on the
mechanism of the disease," said Dr. Walsh.
Other researchers are now investigating whether mosaicism is a factor
in more common diseases, like schizophrenia. "This will play itself
out over the next 5 or 10 years," said Dr. Urban, who with his
colleagues is studying it.
Moving Cautiously
Medical researchers aren't the only scientists interested in our
multitudes of personal genomes. So are forensic scientists. When they
attempt to identify criminals or murder victims by matching DNA, they
want to avoid being misled by the variety of genomes inside a single
person.
Last year, for example, forensic scientists at the Washington State
Patrol Crime Laboratory Division described how a saliva sample and a
sperm sample from the same suspect in a sexual assault case didn't
match.
Bone marrow transplants can also confound forensic scientists.
Researchers at Innsbruck Medical University in Austria took cheek
swabs from 77 people who had received transplants up to nine years
earlier. In 74 percent of the samples, they found a mix of genomes --
both their own and those from the marrow donors, the scientists
reported this year. The transplanted stem cells hadn't just replaced
blood cells, but had also become cells lining the cheek.
While the risk of confusion is real, it is manageable, experts said.
"This should not be much of a concern for forensics," said Manfred
Kayser, a professor of Forensic Molecular Biology at Erasmus
University in Rotterdam. In the cases where mosaicism or chimerism
causes confusion, forensic scientists can clear it up by other means.
In the Austrian study, for example, the scientists found no marrow
donor genomes in the hair of the recipients.
For genetic counselors helping clients make sense of DNA tests, our
many genomes pose more serious challenges. A DNA test that uses blood
cells may miss disease-causing mutations in the cells of other organs.
"We can't tell you what else is going on," said Nancy B. Spinner, a
geneticist at the University of Pennsylvania, who published a review
about the implications of mosaicism for genetic counseling in the May
issue of Nature Reviews Genetics.
That may change as scientists develop more powerful ways to
investigate our different genomes and learn more about their links to
diseases. "It's not tomorrow that you're going to walk into your
doctor's office and they're going to think this way," said Dr. Lupski.
"It's going to take time."
--
-Nathan
![Mega [Andreas Stuermer]'s profile photo](http://lh3.googleusercontent.com/a-/ALV-UjUNVm1hB8tAcAAFPeCKG7sAAOMXtiGvFTd7NEBaHFgxRcdy1Lnb=s40-c)
Mega [Andreas Stuermer]
Mar 25, 2014, 6:26:36 PM3/25/14
to diy...@googlegroups.com
>Women can also gain genomes from their children. After a baby is born,
it may leave some fetal cells behind in its mother's body, where they
can travel to different organs and be absorbed into those tissues.
Someone mentioned not to play around with one's own stem cells because exactly this could happen :D
it may leave some fetal cells behind in its mother's body, where they
can travel to different organs and be absorbed into those tissues.
On the other hand, in that case it still are not yor cells, but your childs. That may make the difference why it rather does not evolve into cancer? The ommune system may rather fight your childs cells than yours. On the other hand, how can they even survive then?
Meredith L. Patterson
Mar 25, 2014, 6:39:28 PM3/25/14
to DIYBio Mailing List
I'd definitely like to know more about the immune mechanisms involved here. (Up to and including recs for good immunology texts, both innate and adaptive, particularly with respect to cytokine signalling.)
Cheers,
--mlp
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Mathieu H
Mar 26, 2014, 12:18:15 AM3/26/14
to diy...@googlegroups.com
Excellent post.
Thank you!
Thank you!
Cathal Garvey
Mar 26, 2014, 4:45:28 AM3/26/14
to diy...@googlegroups.com
Actually, the immunological mechanisms of embryos and cancer are very
alike; cancer makes use of pregnancy-associated immune-modulating
systems very regularly.
In my undergrad years I studied a dull protein called "Murine Pregnancy
Associated Glycoprotein 22". That whole class of glycoproteins are
involved in immune signalling to mothers, saying "please don't kill me,
I'm your offspring".
There's also a global change in immunity in mothers, though that is both
fetal and innate to the mothers' hormone, as I understand it. This
pushes the balance of immune response away from the "adaptive"
(self/nonself) immune response and towards the "innate" response
(complement, macrophages, interferons, etc.), to prevent immune assault
upon the placenta. The side-effect is that pregnant women are far more
susceptible to disease and infection from french cheese! :)
Although I'm not well-read on the longer-term mechanisms, I suspect
there's a pathway or two that mediate negotiations with
antigen-presenting cells, so that they bring baby (or cancer) antigens
to immature T-Cells and induce anergy in any that might attack the baby.
--
T: @onetruecathal, @IndieBBDNA
P: +3538763663185
W: http://indiebiotech.com
alike; cancer makes use of pregnancy-associated immune-modulating
systems very regularly.
In my undergrad years I studied a dull protein called "Murine Pregnancy
Associated Glycoprotein 22". That whole class of glycoproteins are
involved in immune signalling to mothers, saying "please don't kill me,
I'm your offspring".
There's also a global change in immunity in mothers, though that is both
fetal and innate to the mothers' hormone, as I understand it. This
pushes the balance of immune response away from the "adaptive"
(self/nonself) immune response and towards the "innate" response
(complement, macrophages, interferons, etc.), to prevent immune assault
upon the placenta. The side-effect is that pregnant women are far more
susceptible to disease and infection from french cheese! :)
Although I'm not well-read on the longer-term mechanisms, I suspect
there's a pathway or two that mediate negotiations with
antigen-presenting cells, so that they bring baby (or cancer) antigens
to immature T-Cells and induce anergy in any that might attack the baby.
T: @onetruecathal, @IndieBBDNA
P: +3538763663185
W: http://indiebiotech.com
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