Cell lines from various organisms are used in biotechnology for the production of drugs, enzymes or chemicals. Besides bacteria (e.g. Escherichia coli) or yeast (e.g. Saccharomyces cerevisiae) cell lines from higher forms of life such as mice or humans are also used. One of the most important cell lines for the production of recombinant proteins was isolated from the ovaries of the Chinese hamster (Cricetulus griseus) in the USA over 50 years ago by Theodore T. Puck. Over the course of time various specialised cell lines were derived from this first Chinese Hamster Ovary (CHO) cell line. Thanks to their prolific growth in liquid cultures and high-yield protein production, CHO cell lines have become widely established in science and the pharmaceutical industry. A further advantage of the CHO cell is the fact that the proteins they produce (e.g. antibodies) closely resemble human proteins in their biological structure. Among all available mammalian cell lines, CHO cell lines are thus the most widely used production medium for pharmaceutical proteins.


Genetic manipulation is the key to optimising the production process and enhancing the product quality of the utilised cell lines. Decoding of the genome is essential to this task, as knowledge of the genome sequence allows the precise and controlled manipulation of the genetic information. As a result, international scientists have been keenly interested in the decoding of the Chinese hamster genome. In 2013 the genome of the Chinese hamster was first published in Nature Biotechnology by a research team from the USA and simultaneously by a second team comprising German and Austrian scientists, including Professor Dr. Alexander Goesmann from Justus Liebig University in Giessen [1, 2].


Since then there have been considerable advances in sequencing technology, and the performance of technical resources for analysis of the enormous amounts of data has been enhanced. On this account both teams have been cooperating for some time to consolidate all available data in an effort to further improve the quality of the genome sequence. Giessen was selected to once more conduct the bioinformatic analyses. Prof. Goesmann’s group has many years experience in the decoding and analysis of microbial genomes and they also assembled the first version of the hamster genome in 2013 for the German-Austrian team. Dr. Karina Brinkrolf, Oliver Rupp and Sven Griep from Justus Liebig University were also involved as researchers in this project.


The Chinese hamster genome has 11 chromosome pairs, which is roughly half as many as the human genome. However, it is almost as large, possessing as it does over 2.3 billion base pairs, which makes it 500 to 1,000 times larger than an average bacterial genome. For this project more than two billion short DNA sequences were generated by means of the Illumina Next-Generation-Sequencing method and in addition almost 15 million long DNA sequences were produced with the Single-Molecule-Real-Time-Sequencing (SMRT) method on Pacific Biosciences instruments. The Giessen bioinformatic team had to develop and test new techniques in order to process the raw data, which totalled more than one terabyte. The calculations for reconstructing the genome from the billions of sequence fragments took several months and an additional few months were needed to revise and summarise the results. An in-house high-performance computing cluster with over 1,000 CPU cores and dedicated servers with up to two terabytes main memory (RAM) were used. These hardware resources were co-financed by the German Network for Bioinformatic Infrastructure (de.NBI) whose objective is the coordination and provision of bioinformatics expertise and resources as a service to researchers nationwide, with a view to ensuring the efficient use of innovative bioinformatics technologies in all life science research sectors and enhancing Germany’s international competitiveness.


The result of this joint effort was the Chinese hamster genome which was recently published in Biotechnology & Bioengineering and is now comparable in quality to the existing genomes of model organisms such as mouse or rat. In comparison to the first two genome versions from the year 2013, the enhanced version contains a significantly lower number of genome fragments and consequently fewer gaps. This means in practice that more information on genes and their regulatory elements is available to scientists for their research, allowing the production of new recombinant proteins and the optimisation of existing production processes to be conducted even more systematically and with a considerably higher degree of control.

References:
[1] Brinkrolf K, Rupp O, Laux H, Kollin F, Ernst W, Linke B, Kofler R, Romand S, Hesse F, Budach WE, Galosy S, Müller D, Noll T, Wienberg J, Jostock T, Leonard M, Grillari J, Tauch A, Goesmann A, Helk B, Mott JE, Pühler A, Borth N. (2013) Chinese hamster genome sequenced from sorted chromosomes. Nat Biotechnol. doi: 10.1038/nbt.2645.
[2] Lewis NE, Liu X, Li Y, Nagarajan H, Yerganian G, O'Brien E, Bordbar A, Roth AM, Rosenbloom J, Bian C, Xie M, Chen W, Li N, Baycin-Hizal D, Latif H, Forster J, Betenbaugh MJ, Famili I, Xu X, Wang J, Palsson BO (2013) Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome. Nat Biotechnol. doi: 10.1038/nbt.2624.
[3] Rupp O, MacDonald ML, Li S, Dhiman H, Polson S, Griep S, Heffner K, Hernandez I, Brinkrolf K, Jadhav V, Samoudi M, Hao H, Kingham B, Goesmann A, Betenbaugh MJ, Lewis NE, Borth N, Lee KH (2018) A reference genome of the Chinese hamster based on a hybrid assembly strategy. Biotechnol Bioeng. doi: 10.1002/bit.26722.

Contact:
Prof. Dr. Alexander Goesmann
Systems Biology with focus on Genomics, Proteomics and Transcriptomics
Justus Liebig University Giessen
Heinrich-Buff-Ring 58
35392 Giessen
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Homepage: http://www.computational.bio