Crowder Christopher D, Denny Richard L, Barbour Alan G
Departments of Medicine and Microbiology & Molecular Genetics University of California Irvine, Irvine, California.
Division of Mathematical and Computer Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
Yale J Biol Med. 2017 Jun 23;90(2):195-218. eCollection 2017 Jun.
Relapsing fever agents like undergo multiphasic antigenic variation that is attributable to spontaneous DNA non-reciprocal transpositions at a particular locus in the genome. This genetic switch results in a new protein being expressed on the cell surface, allowing cells with that phenotype to escape prevailing immunity. But the switch occurs in only one of several genomes in these spirochetes, and a newly-switched gene is effectively "recessive" until homozygosity is achieved. The longer that descendants of the switched cell expressed both old and new proteins, the longer this lineage risks neutralization by antibody to the old protein. We investigated the implications for antigenic variation of the phenotypic lag that polyploidy would confer on cells. We first experimentally determined the average genome copy number in daughter cells after division during mouse infection with strain HS1. We then applied discrete deterministic and stochastic simulations to predict outcomes when genomes were equably segregated either linearly, i.e. according to their position in one-dimensional arrays, or randomly partitioned, as for a sphere. Linear segregation replication provided for a lag in achievement of homozygosity that was significantly shorter than could be achieved under the random segregation condition. For cells with 16 genomes, this would be a 4-generation lag. A model incorporating the immune response and evolved matrices of switch rates indicated a greater fitness for polyploid over monoploid bacteria in terms of duration of infection.
像 这样的回归热病原体经历多相抗原变异，这归因于基因组中特定位点的自发DNA非相互转座。这种基因开关导致一种新的蛋白质在细胞表面表达，使具有该表型的细胞能够逃避现有的免疫反应。但这种开关只发生在这些螺旋体的几个基因组中的一个，并且新转换的基因在达到纯合性之前实际上是“隐性的”。转换细胞的后代同时表达旧蛋白和新蛋白的时间越长，该谱系被针对旧蛋白的抗体中和的风险就越大。我们研究了多倍体赋予细胞的表型滞后对抗原变异的影响。我们首先通过实验确定了HS1菌株感染小鼠期间分裂后子细胞中的平均基因组拷贝数。然后，我们应用离散确定性和随机模拟来预测基因组以线性方式（即根据它们在一维阵列中的位置）均匀分离或随机分配（如对于球体）时的结果。线性分离复制导致达到纯合性的滞后明显短于随机分离条件下所能达到的滞后。对于具有16个基因组的细胞，这将是4代的滞后。一个结合免疫反应和转换率进化矩阵的模型表明，就感染持续时间而言，多倍体细菌比单倍体细菌具有更高的适应性。
