Genome sequencing of the unborn

By Razib Khan | June 6, 2012 1:12 pm

Noninvasive Whole-Genome Sequencing of a Human Fetus:

Analysis of cell-free fetal DNA in maternal plasma holds promise for the development of noninvasive prenatal genetic diagnostics. Previous studies have been restricted to detection of fetal trisomies, to specific paternally inherited mutations, or to genotyping common polymorphisms using material obtained invasively, for example, through chorionic villus sampling. Here, we combine genome sequencing of two parents, genome-wide maternal haplotyping, and deep sequencing of maternal plasma DNA to noninvasively determine the genome sequence of a human fetus at 18.5 weeks of gestation. Inheritance was predicted at 2.8 × 106 parental heterozygous sites with 98.1% accuracy. Furthermore, 39 of 44 de novo point mutations in the fetal genome were detected, albeit with limited specificity. Subsampling these data and analyzing a second family trio by the same approach indicate that parental haplotype blocks of ~300 kilo–base pairs combined with shallow sequencing of maternal plasma DNA is sufficient to substantially determine the inherited complement of a fetal genome. However, ultradeep sequencing of maternal plasma DNA is necessary for the practical detection of fetal de novo mutations genome-wide. Although technical and analytical challenges remain, we anticipate that noninvasive analysis of inherited variation and de novo mutations in fetal genomes will facilitate prenatal diagnosis of both recessive and dominant Mendelian disorders.

Here’s the last paragraph:

The ability to noninvasively sequence a fetal genome to high accuracy and completeness will undoubtedly have profound implications for the future of prenatal genetic diagnostics. Although individually rare, when considered collectively, the ~3500 Mendelian disorders with a known molecular basis (19) contribute substantially to morbidity and mortality (20). Currently, routine obstetric practice includes offering a spectrum of screening and diagnostic options to all women. Prenatal screening options have imperfect sensitivity and focus mainly on a small number of specific disorders, including trisomies, major congenital anomalies, and specific Mendelian disorders. Diagnostic tests, generally performed through invasive procedures, such as chorionic villus sampling and amniocentesis, also focus on specific disorders and confer risk of pregnancy loss that may inversely correlate with access to high-quality care. Noninvasive, comprehensive diagnosis of Mendelian disorders early in pregnancy would provide much more information to expectant parents, with the greater accessibility inherent to a noninvasive test and without tangible risk of pregnancy loss. The less tangible implication of incorporating this level of information into prenatal decision-making raises many ethical questions that must be considered carefully within the scientific community and on a societal level. A final point is that as in other areas of clinical genetics, our capacity to generate data is outstripping our ability to interpret it in ways that are useful to physicians and patients. That is, although the noninvasive prediction of a fetal genome may be technically feasible, its interpretation—even for known Mendelian disorders—will remain a major challenge.

CATEGORIZED UNDER: Personal Genomics
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  • Dm

    In fact one could argue that even for the known de novo mutations or rare heritable Mendelian disorders, the interpretation might leave room for doubt about direct causality and/or penetrance. They just aren’t studied well enough, both on statistical and biochemical level. As to the uncharacterized variation, it’s bad enough for adult’s genome riddles, but it becomes a whole new level of uncertainty when parents have to ponder their possible dangers and/or advantages.

    I could see a world where every intelligent human being is prodded to take up a career in either genetic counseling, or genetic misinterpretation litigation.

  • duende

    Although prenatal care of some sort can be normalized (almost all American babies are born in hospitals) the sort of “pregnancy projects” that affluent or well-educated go through to give their babies the best starts in life is something that will be almost impossible to impart to pregnant women who eat fast food every day, smoke etc. In the future babies born to poor or underclass women will be disadvantaged from the day they are conceived. And the future is now,

  • ackbark

    I just had my adoptive father’s dna done at 23andMe and one of the more striking things was that they said he has a lower than average risk of alcoholism.

    Well, he’s been drunk since 1935. I’m not making that up. But he is the kind of person, until he became elderly, would rarely actually look like he was drunk.

    I’m just mentioning that because it seems to me, at our present state of knowledge, tests like that could easily go way wrong.

  • Razib Khan

    more striking things was that they said he has a lower than average risk of alcoholism.

    useless without a specific value/odds. though i think the long term of utility of this sort of thing isn’t going to be in the small odds shifts you see in genotyping analyses.

  • dave

    I hate to think of the scary, the mad scientist in the lab creating the “perfect human”, just watched a good doc on savants, these geniuses it seems are predisposed to under developed, or over developed genes, focused attention like this could be very scary, just what the heck are we really looking for? When it’s been found that sometimes we need these variants being that they’re all interconnected and serve other purposes………

  • AG

    This might be marginal relavant. But for you information.
    Original research
    Additional findings and correlation

    Looks like Rushton scores another point.

    [re: rushton, make sure you have this sort of behavior in your prior distribution (not the first time he’s been caught in this sort of shit). -razib]


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About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at


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