Second generation noninvasive fetal genome analysis reveals de novo mutations, single-base parental inheritance, and preferred DNA ends
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ABSTRACT:
PROVIDER: EGAS00001001882 | EGA |
REPOSITORIES: EGA
Publications
[Acute puerperal kidney failure. A new syndrome?].
Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke 19711001 30
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Project description:Plasma DNA obtained from a pregnant woman was sequenced to a depth of 270× haploid genome coverage. Comparing the maternal plasma DNA sequencing data with the parental genomic DNA data and using a series of bioinformatics filters, fetal de novo mutations were detected at a sensitivity of 85% and a positive predictive value of 74%. These results represent a 169-fold improvement in the positive predictive value over previous attempts. Improvements in the interpretation of the sequence information of every base position in the genome allowed us to interrogate the maternal inheritance of the fetus for 618,271 of 656,676 (94.2%) heterozygous SNPs within the maternal genome. The fetal genotype at each of these sites was deduced individually, unlike previously, where the inheritance was determined for a collection of sites within a haplotype. These results represent a 90-fold enhancement in the resolution in determining the fetus's maternal inheritance. Selected genomic locations were more likely to be found at the ends of plasma DNA molecules. We found that a subset of such preferred ends exhibited selectivity for fetal- or maternal-derived DNA in maternal plasma. The ratio of the number of maternal plasma DNA molecules with fetal preferred ends to those with maternal preferred ends showed a correlation with the fetal DNA fraction. Finally, this second generation approach for noninvasive fetal whole-genome analysis was validated in a pregnancy diagnosed with cardiofaciocutaneous syndrome with maternal plasma DNA sequenced to 195× coverage. The causative de novo BRAF mutation was successfully detected through the maternal plasma DNA analysis.
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Project description:In many organisms, meiotic crossover recombination is suppressed near the extreme ends of chromosomes. Here we show that multiple, often chromosome-specific, suppressive mechanisms with differing ranges combine to achieve the consistently low enrichment of recombination-promoting axis proteins and downregulation of DNA double-strand breaks (DSBs) within 20 kb of telomeres in Saccharomyces cerevisiae. Suppression of axis proteins is associated with cis-encoded signals, including reduced coding density and the subtelomeric Y’ elements, which are present at many chromosome ends, but also requires chromatin modifiers, including the histone methyltransferase Dot1 and the Sir silencing complex. We show that Dot1 suppresses Sir complex activity at least in part independently of its canonical target, H3K79, to downmodulate axis protein deposition near chromosome ends. In parallel, the Sir complex, but not Dot1, suppresses the induction of DSBs by limiting the openness of promoters, the preferred sites of meiotic DSB formation. The separable downmodulation of axis protein deposition and DSB induction likely contributes to the robust reduction of meiotic recombination effectors near chromosome ends.
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