Innovation and Development

Accomplishment of Draft Genome Sequencing of Wheat A Genome

Bread wheat (Triticum aestivum), one of the most widely cultivated and consumed food crops in the world, is a hexaploid containing A, B and D genomes. Due to its complex polyploidy nature and large genome size (17 Gb), the genetic and functional analysis of bread wheat is extremely challenging. The A genome, originally from the diploid wild einkorn wheat Triticum urartu with a genome size about 5 Gb, is the basic genome of bread wheat and other polyploidy wheats, and plays a central role in wheat evolution, domestication and genetic improvement. The wheat genome research team (Profs Ling Hongqing, Zhang Aimin, Wang Daowen and Li Zhensheng) of the State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, CAS, collaborated with BGI-Shenzhen, China, and Prof. Jan Dvorak and Dr. Mingcheng Liu, University of California, Davis, USA, determined the draft genome sequencing of Triticum urartu (accession G1812) using a whole-genome shotgun strategy on the Illumina HiSequation (2000) platform. The scientists assembled the genome sequence, and predicted 34,879 protein-coding gene models in the T. urartu genome. They found that the large genome size of the wheat A genome was due to enlarged intergenic space with repetitive elements, such as Gypsy and Copia retrotransposons, during the evolution. Compared to the genomes of rice, maize, sorghum and Byachypodium distachyon, 3,425 T. urartu-specific genes, 24 new micro RNAs and more abundant disease resistance genes (R genes) were identified in T. urartu genome. Together, these data suggest that T. urartu may have distinctive responses to biotic and abiotic stresses and developmental processes, which may enable wheat to adapt to more diverse environments. Additionally, some agronomically important genes, such as TuGASR7 involved in control of grain length and weight, and a large number of SSR, ISBP and SNP molecular markers were identified, which should facilitate further functional genomics and molecular breeding studies of wheat and related species. In essence, the draft genome sequence of T. urartu provides a diploid reference for the analysis of polyploidy wheat genomes, and is a valuable resource for the genetic improvement of wheat to meet the future challenges of global food security and sustainable agriculture. The research results were published in the magazine Nature titled “Draft genome of the wheat A-genome progenitor Triticum urartu” on April 4, 2013.

New Anti-leukaemia Drug Being Identified

Chronic myelogenous leukaemia (CML) has a high mortality rate of 20%-30%, two years after a confirmed diagnosis. Gleevec therapy alone can alleviate the condition in many patients suffering from CML.? However, because of extensive usage of Gleevec, it is becoming less effective. The clinical drug resistance mediated by the T315I mutation of Bcr-Abl remains a significant medical problem and at this time there are no drugs targeting the T315I point mutation on the market. As a result, it is urgent to develop novel drugs for the treatment of this type of drug-resistant leukaemia. GIBH project team led by Dr. Ding Ke has successfully designed and synthesized aryl alkynes and triazole benzamidetwo series of Bcr-abl small inhibitors with strong intellectual property using the principles of rational and computer-aided drug design. Among them, the compound GZD824 show good drugability and development prospects, which has been applied patent-pending (201010216603.7, PCT/CN2011/00935). The biological activity studies have shown that: 1) GZD824 inhibited Bcr-Abl and Bcr-Abl T315I with IC50 values of 0.34 nM and 0.68 nM, respectively, and also effectively against E255K and E255V mutations in the P-loop. 2) GZD824 inhibited K562, Ku812 and drug resistant strains Ba/F3 T315I with IC50 values of 0.2-10nM. 3) GZD824 has a good anti-tumor activity in vivo, For example, in K562 and Ku812 xenograft animal model, the oral dose 1-2mg/kg/day can eliminate the tumor; in mutations of Bcr-AblT315I animal models, oral administration of 20mg/kg/day dose can completely eliminate the tumor, and significantly prolong survival time. 4) GZD824 has good oral bioactivity (48.7%), half-life (T1 / 2 = 8-10 hours) and steady-state plasma concentration. In summary, GZD824 was discoveried as a new class of anti-leukaemia drug candidate by GIBH, which has been ongoing preclinical evaluation. The results on the development of GZD824 are published in Journal of Medicinal Chemistry [J. med.Chem 2013, 56 (3), 879-894; J. med. Chem. 2012, 55 (22), 10033-10046].