Researchers developed a noninvasive method to detect fetal aneuploidy using shotgun sequencing of cell-free DNA from maternal blood. By sequencing cell-free DNA from 18 pregnant women and a male donor, they obtained an average of 5 million sequence tags per sample, enabling the detection of chromosomal abnormalities. This approach is polymorphism-independent and can identify trisomies 21, 18, and 13 in pregnancies as early as the 14th week of gestation. The method allows for the characterization of cell-free plasma DNA, revealing that it is enriched for nucleosome-bound sequences. The study demonstrated that fetal DNA constitutes less than 10% of total DNA in maternal plasma, but the method can detect aneuploidy even at low fetal DNA fractions. The results showed that the sequence tag density of chromosomes 13, 18, and 21 was significantly higher in pregnancies with trisomies, indicating the presence of aneuploidy. The study also found that fetal DNA fraction correlates with gestational age, and that the size distribution of cell-free plasma DNA is consistent with apoptotic origins. The findings suggest that shotgun sequencing can be used for noninvasive prenatal diagnosis of fetal aneuploidy, offering a universal, polymorphism-independent test. The method has potential applications in various fields, including perinatology, oncology, and transplantation, by providing insights into the biology of pregnancy and disease. The study highlights the importance of further research to improve the reliability and accuracy of noninvasive prenatal diagnosis.Researchers developed a noninvasive method to detect fetal aneuploidy using shotgun sequencing of cell-free DNA from maternal blood. By sequencing cell-free DNA from 18 pregnant women and a male donor, they obtained an average of 5 million sequence tags per sample, enabling the detection of chromosomal abnormalities. This approach is polymorphism-independent and can identify trisomies 21, 18, and 13 in pregnancies as early as the 14th week of gestation. The method allows for the characterization of cell-free plasma DNA, revealing that it is enriched for nucleosome-bound sequences. The study demonstrated that fetal DNA constitutes less than 10% of total DNA in maternal plasma, but the method can detect aneuploidy even at low fetal DNA fractions. The results showed that the sequence tag density of chromosomes 13, 18, and 21 was significantly higher in pregnancies with trisomies, indicating the presence of aneuploidy. The study also found that fetal DNA fraction correlates with gestational age, and that the size distribution of cell-free plasma DNA is consistent with apoptotic origins. The findings suggest that shotgun sequencing can be used for noninvasive prenatal diagnosis of fetal aneuploidy, offering a universal, polymorphism-independent test. The method has potential applications in various fields, including perinatology, oncology, and transplantation, by providing insights into the biology of pregnancy and disease. The study highlights the importance of further research to improve the reliability and accuracy of noninvasive prenatal diagnosis.