Kumar Akash, Ryan Allison, Kitzman Jacob O, Wemmer Nina, Snyder Matthew W, Sigurjonsson Styrmir, Lee Choli, Banjevic Milena, Zarutskie Paul W, Lewis Alexandra P, Shendure Jay, Rabinowitz Matthew
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195 USA.
Natera Inc, San Carlos, CA 94070 USA.
Genome Med. 2015 Apr 8;7(1):35. doi: 10.1186/s13073-015-0160-4. eCollection 2015.
Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD).
We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha-thalassemia.
Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent.
Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.
植入前基因诊断（PGD）能够在胚胎植入前对其进行遗传疾病分析。大多数PGD检测在检测的变异范围或大家庭成员的可获得性方面受到限制。虽然单细胞测序的最新进展显示出前景，但它们仍然受到DNA扩增偏差以及新鲜胚胎移植所需的快速周转时间（<36小时）的限制。在这里，我们描述并验证了一种用于推断胚胎遗传全基因组序列以进行植入前基因诊断（PGD）的方法。
我们将单倍型解析的亲代基因组测序与快速胚胎基因分型相结合，以预测一对有传播α地中海贫血风险的夫妇中第5天人类胚胎的全基因组序列。
在大约300万个父系和/或母系杂合位点预测了遗传，准确率超过99%。此外，我们成功地进行了相位分析并预测了每个亲本HBA1/HBA2缺失的传递。
我们的结果表明，植入前全基因组预测可能有助于对胚胎中已知遗传基础的疾病进行全面诊断。
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