> "Foetal DNA makes up about 10% of a pregnant woman's blood plasma." <- I'd be quite surprised to learn that DNA makes up 10% of anyone's plasma, so I think they're saying that 10% of the DNA isolated from plasma is found to be fetal.
> "The latest research isolated foetal genetic signatures in the floating DNA, then compared its characteristics against the genetic maps of the mother and father. That way, scientists were able to construct a genome-wide genetic map of the foetus, which they could then scan for variations and mutations."
Update: OK, I was a bit confused by the DNA extraction process. From what I can tell, they only took DNA from the parents once, at ~12 weeks gestation. They then GWASsed them and found sites where the fetus would be an obligate heterozygote because the mother was homozygous for one allele while the father was homozygous for another. (So if mom is AA and dad is GG, the fetus must be AG, assuming no point mutation occurs there.)
But if the blood is only drawn once, 10% of the maternal DNA will be fetal DNA, so how are they confidently calling sites as homozygous in the mother? I suppose this makes sense if Birdseed is robust to 5% error in the data, and if so this is quite clever. (5% because 10% of the DNA is fetal, and at the obligate het sites half of that 10% will be maternal so only 5% total will be of paternal origin.)
Now, their method is for high-depth whole-genome sequencing, which is still very expensive, but there's no reason they couldn't use targeted sequencing with this approach (they address this in the discussion). That would allow for a potentially inexpensive test for inherited genetic disorders without invading the fetal privileged space (which is what we currently do, and which is high-risk).
The hard part is figuring out the maternally inherited foetal DNA, because it's already present in the mother's bloodstream. For features which are present in the mother but not the father, it's fairly easy with the data they have. For vice versa, it's probably not going to be possible for some time.
Agreed, mostly, at least from first principles. The enrichment will be very modest. On average for any given chromosome, 45% of DNA in the mother's blood should be maternal DNA from one chromosomal copy or the other. This gets us to 90%.
The remaining 10% is split between one paternal copy and one maternal copy.
This means that--if we ignore other differences such as fragment length--you're potentially trying to label the chromosomal copy that comprises 50% of DNA as the one inherited by the fetus, versus the one comprising 45% of DNA as the one not inherited by the fetus. That's a very small enrichment.
Now, because of the length differences that they identified, they may be able to vastly enrich for fetal DNA (or precipitate out maternal DNA), obviating this problem.
> without invading the fetal privileged space (which is what we currently do, and which is high-risk). [emphasis mine]
The standard process is amniocentesis, and according to wikipedia, that has a miscarriage rate "as low as 1 in 1600", plus an unspecified risk of infection. While that's almost certainly higher than the risk due to drawing the mother's blood, I wouldn't call it a "high-risk" procedure.
Would you feel the same way if the risk of death from a diagnostic test for cancer was 1/1600? The answer probably hinges upon the type of cancer, the treatment available, etc, but clearly this is not something you'd use for a population screening tool.
Up until ~4 years ago, the risk of miscarriage from amniocentesis was thought to be 1/200, but if the 1/1600 number is true, that's good. Nevertheless, it's not something that you're going to want to be doing to every pregnant woman. On the other hand, we draw plenty of blood from pregnant women, so we can essentially get this without additional risk to the fetus, except the risk of elective termination.
Another route to chimerism is through the cells that routinely pass from a mother to fetus and remain there for life.
Dr. Ann Reed, chairwoman of rheumatology research at the Mayo Clinic, who uses sensitive DNA tests to look for chimerism, finds that about 50 to 70 percent of healthy people are chimeras. The more scientists look for chimerism, the more they find it. It seemed not to exist in the past, she said, because no one was explicitly looking for small amounts of foreign cells in people's bodies.
Further, experiments in mice show that stem cells from a fetus can take up residence in the mother's body, possibly indefinitely and granting benefits:
Taken all together, these results suggests a woman might have persistent chimeric cells from any or all of the following, if including all remote possibilities:
• her own mother
• a 'vanished twin'
• a grandmother or earlier matrilineal ancestor (if those cells persisted in the mother and then also transfered to the fetus)
• older siblings (if those cells persisted in the common mother and then also transferred to the later fetus)
• her own children
• and of course, any donors from which the woman receives blood or tissue during a medical procedure
There is a pregnancy condition called PUPPP -- itchy hives. I don't have a reference to the study on hand, but it is known that most women who suffer from PUPPP give birth to boys, and that male DNA is present in the hives. One theory about it goes that male DNA is a skin irritant.
Bad science journalist draws conclusions not stated in the research reported upon. It's clear to me that scanning for DNA fragments cannot tell you anything about chromosome abnormalities, so I doubt the researchers said any such thing.
Thus, this research is completely useless to anyone who would choose to screen for the most common birth defects (not just sort of useless -- if you are doing CVS or amnio, you have a cleaner source of DNA).
This technique seems only really useful for people who want to screen for specific recessive diseases like tay-sachs or sickle cell, and don't want to do a more invasive test.
> It's clear to me that scanning for DNA fragments cannot tell you anything about chromosome abnormalities, so I doubt the researchers said any such thing.
It's not at all clear to me; why would you think this?
To take trisomy 21 as an example (Down's syndrome cause), this means the fetus has three copies of chromosome 21. After a CVS or amnio, the lab will look at the cells under the microscope and look for two copies of each chromosome. If they find three instead, that's a chromosome abnormality. If you break open the cells and end up with DNA fragments floating around, it's possible to sequence the DNA but there's not any information that can tell you whether a cell had an extra copy of a chromosome. It's like asking whether the apples to make a cup of juice were all packed in the same box or multiple boxes.
Apparently this same researcher does have a down syndrome test, but it is based on measuring RNA ratios and does not seem to rely on sequencing the fetus's DNA at all.
Glad I asked! I was thinking about chromosomal rearrangements, which would be detectable using this method, but I agree with your point about nondisjunction.
How does DNA get into the bloodstream? It shouldnt be getting out of the nucleus let alone the cell membrane and beyond that there's that whole placenta thing.
> "The latest research isolated foetal genetic signatures in the floating DNA, then compared its characteristics against the genetic maps of the mother and father. That way, scientists were able to construct a genome-wide genetic map of the foetus, which they could then scan for variations and mutations."
Now I'm interested to read more. The article can be found behind the following paywall: http://stm.sciencemag.org/content/2/61/61ra91.abstract .
Update: OK, I was a bit confused by the DNA extraction process. From what I can tell, they only took DNA from the parents once, at ~12 weeks gestation. They then GWASsed them and found sites where the fetus would be an obligate heterozygote because the mother was homozygous for one allele while the father was homozygous for another. (So if mom is AA and dad is GG, the fetus must be AG, assuming no point mutation occurs there.)
But if the blood is only drawn once, 10% of the maternal DNA will be fetal DNA, so how are they confidently calling sites as homozygous in the mother? I suppose this makes sense if Birdseed is robust to 5% error in the data, and if so this is quite clever. (5% because 10% of the DNA is fetal, and at the obligate het sites half of that 10% will be maternal so only 5% total will be of paternal origin.)
Now, their method is for high-depth whole-genome sequencing, which is still very expensive, but there's no reason they couldn't use targeted sequencing with this approach (they address this in the discussion). That would allow for a potentially inexpensive test for inherited genetic disorders without invading the fetal privileged space (which is what we currently do, and which is high-risk).