Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2014 Jan;46(1):82-7. doi: 10.1038/ng.2848. Epub 2013 Dec 8.
Advances in sequencing technologies have enabled the identification of mutations acquired by bacterial pathogens during infection. However, it remains unclear whether adaptive mutations fix in the population or lead to pathogen diversification within the patient. Here we study the genotypic diversity of Burkholderia dolosa within individuals with cystic fibrosis by resequencing individual colonies and whole populations from single sputum samples. We find extensive intrasample diversity, suggesting that mutations rarely fix in a patient's pathogen population--instead, diversifying lineages coexist for many years. Under strong selection, multiple adaptive mutations arise, but none of these sweep to fixation, generating lasting allele diversity that provides a recorded signature of past selection. Genes involved in outer-membrane components, iron scavenging and antibiotic resistance all showed this signature of within-patient selection. These results offer a general and rapid approach for identifying the selective pressures acting on a pathogen in individual patients based on single clinical samples.
测序技术的进步使得能够鉴定细菌病原体在感染过程中获得的突变。然而，目前尚不清楚适应性突变是否在人群中固定，还是导致患者体内病原体的多样化。在这里，我们通过对单个痰液样本中的单个菌落和整个群体进行重测序，来研究囊性纤维化患者体内鲍曼不动杆菌的基因型多样性。我们发现了广泛的样本内多样性，这表明突变很少在患者的病原体群体中固定——相反，多样化的谱系共存多年。在强烈选择下，会出现多个适应性突变，但没有一个突变会固定下来，从而产生持久的等位基因多样性，为过去的选择提供了记录特征。涉及外膜成分、铁摄取和抗生素耐药性的基因都表现出这种患者内选择的特征。这些结果提供了一种基于单个临床样本识别个体患者中病原体所受选择压力的通用且快速的方法。
