Preimplantation Sequencing: a new era for PGD/PGS?

Embryology has been again in the focus of news with the birth of a child after genome sequencing from a biopsied embryo was born. The birth was announced at the ESHRE, London, July 2013 as last minute, unpublished achievement, and has become a major sensation, breaking news in TVs, front page reports in leading journals all over the world.

Although achievement was respectable, the reported priority was not entirely justified. Just in the previous abstract in the conference proceedings (that was available in printed form at the time of announcement; Li et al, Clinical application of massively parallel sequencing on chromosomal abnormalities detection of human blastocysts. Hum Reprod 2013, 28 (Suppl. 1): i26) BGI Shenzhen, China, in collaboration with CITIC Xiangya Hospital, Changsha, China has reported 7 babies after PGS with whole genome sequencing, and the number of births is growing exponentially. Maybe China is still far away for the Western world, but - getting closer...

BGI, a private non-profit institute has been established on 09. 09. 1999, at 9.09am (in China, nine is connected to "long time" or "forever") to contribute in the human genome project, as the only continental Asian institution. After several changes in the structure, 70 scientists, mostly the original founders have accepted the invitation of the rapidly growing southern city, Shenzhen, and transferred BGI into the building of a previous shoe factory in 2007. Now, 7 years later, BGI has 4.500 scientists (average age: 27 years) a worldwide network of sister institutions and partners, and has far the biggest sequencing capacity of the world, with 178 sequencing machines from Illumina, Life Tech, Roche and Complete Genomics, producing roughly 47% of sequencing data throughout the world. Recently, BGI has even bought its biggest competitor sequencing provider and sequencing machine producer Complete Genomics, USA. After many "first in the world" achievements published in Science and Nature, BGI is now running a plan to sequence one million humans, one million animals and one million plants to establish a database incomparable in size with anything previously known (or even expected) in the field of genomics.

During the past decade, the costs of decoding a full human genome decreased dramatically, from the initial (roughly) 3.000.000.000$ to 1,000$, so far. The next target, $100 may also be realistic in the foreseeable future. The key of this amazing advancement is a relatively new approach, Next Generation Sequencing (NGS), where millions to billions of DNA fragments (100 to 1,000 bp)are sequenced in parallel, with Massively Parallel Sequencing (MPS) and aligned to the reference sequence (resequencing) or assembled by many different sequence reads (de novo sequencing). However, such a dramatic reduction of costs is only realistic at large-scale application, with the latest high throughput (and very expensive) sequencing machines, and by analysing tens or hundreds of thousands samples and running the machines at their highest, 24x7 capacity. Also, the proper analysis of the results requires a highly professional bioinformatics team to produce custom application algorithms, developed according to the specific needs. Accordingly - unlike FISH, CGH, arrays, SNP and qPCR - single laboratories or local institutions are not capable to perform whole genome sequencing, not even low coverage sequencing decoding only a part (say 85 to 95%) of the genome. A far more reasonable organization model is to collect samples from individual laboratories, and perform the analysis in large institutions specialized for the purpose - just like BGI, or its European or American centers (BGI Europe, Copenhagen, or BGI Americas, Cambridge, Massachusetts).

Recently, BGI has launched an ambitious project providing PGD/PGS sample analysis service for clinics all over the world, by using the abovementioned next generation sequencing approach (Zhang C et al. A single cell level based method for copy number variation analysis by low coverage Massively Parallel Sequencing. PLOS One 2013, 8: e54236; Yin X, et al. Massively parallel sequencing for chromosomal abnormality testing in trophectoderm cells of human blastocysts. Biol Reprod 2013, 69: 1-6; Li J et al. Clinical application of massively parallel sequencing on chromosomal abnormalities detection of human blastocysts. Hum Reprod 2013, 28 (Suppl. 1): i26). Currently, PGD/PGS sample analysis for aneuploidies and monogenic disease are provided separately. However, in the near future, detection of chromosome abnormalities and monogenic disease will be performed at the same time, in a single test. The depth of analysis can be adjusted according to different requirements. It seems to be obvious that Preimplantation Sequencing is the future for PGD and PGS.

Moreover, as the success depends not only on sample analysis, but on the quality of work in the embryo laboratory (Ly KD et al. Preimplantation genetic screening: does it help or hinder IVF treatment and what is the role of the embryo? J Assist Reprod Genet 2011, 28: 833-49) BGI offers a complex package, teaching blastocyst culture, trophectodermal biopsy and sample processing in the lab, and OPS vitrification of selected embryos after biopsy for transfer in one of the subsequent cycles. Workshops at BGI, Shenzhen have been started in August, first for Chinese clinics, later for overseas embryologists. Additionally, there is an option to make on-site courses in laboratories all over the world.