21ENGBIO Engineering Human Artificial Chromosomes (HACs) to Encode Genome Complexity

许多癌症的一个标志是一个人的基因组中存在突变，例如，23对染色体中的一些失去或获得了遗传物质。前列腺癌是英国和欧洲最常诊断的癌症，每年导致近110，000例男性死亡（IARC，2020）。高达20%的前列腺癌病例由于8号染色体右臂的突变而呈现基因组不稳定的标志，这与生存率低有关。我们认为，额外的基因可能会导致前列腺癌，然而，目前还没有模型来定义这些关系及其在人类细胞培养中的后果。合成基因组学是一个生物工程领域，它使用基因工程和新方法来解决当前方法在创建人工DNA到整个基因组大小方面的局限性。合成基因组学能够生成和编辑整个人类人工染色体。通过合成相似长度的人类染色体的一部分，但改变合成单位内基因的顺序和数量，可以研究基因数量，位置和翻译的影响。该项目的成功将导致细胞生物学以及研究人类疾病的模型的制作和使用发生重大变化。这将包括癌症研究的新模型（用于本申请的范例）。

A hallmark of many cancers is the presence of mutations in a person's genome, for example, where some of the 23 pairs of chromosomes have either lost or gained genetic material. Prostate cancer is the most commonly diagnosed cancer in the UK and Europe, and responsible for close to 110,000 male deaths annually (IARC, 2020). Up to 20% of prostate cancer cases present hallmarks of genomic instability due to mutations in the right arm of chromosome 8, which is associated with poor survival. We believe that extra genes may be driving prostate cancer, however, there are currently no models to define these relationships and their consequences in human cells culture. Synthetic Genomics is a bio-engineering field that uses genetic engineering and novel approaches to tackle the limitations of current methods in creating artificial DNA up to whole genome size. Synthetic Genomics enables the generation and editing of entire Human Artificial Chromosomes. By synthesising a similar length of a part of a human chromosome, but vary the order and number of the genes within the synthesized unit, the effect of gene number, location and translation can be studied. Success in this project would lead to a step-change for cell biology and the making and use of models to study human disease. This would include new models for cancer research (the exemplar used for this application).