2023年3月12日，我们邀请到的嘉宾是维康桑格研究所（Wellcome Sanger Institute）/剑桥大学的王依琛博士，她将分享：人类正常小肠中的体细胞突变。
本期内容介绍：
人类正常小肠中的体细胞突变。
Our body is a mosaic of genomes as somatic mutations accumulate in all cells since the very first cell division. These somatic mutations provide insights into ageing, development as well as the mutagenic processes that may contribute to cancer and disease development. Although cancer genomes have been extensively sequenced in the past decades, due to technological limitations, we are still in the process of understanding the diversity of somatic mutation patterns in normal cells. Recently, multiple technological advances have enabled detection of somatic mutations in many normal cell types, including blood, placenta, neurons, smooth muscle, cardiac muscle, epithelia of the liver, bronchus, endometrium, colorectum, skin, oesophagus, bladder, pancreas, prostate, ureter, thyroid, visceral fat, adrenal gland and testis. These studies have informed on the clonal structure of tissues, somatic mutation rates, mutational processes, and the presence of driver mutations conferring selection in normal cells of healthy individuals, and those with a range of diseases.
Here, as part of a wider human tissue survey, we whole genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals. Small intestine tumours constitute only ~4% of all gastrointestinal tumours, a markedly low incidence rate considering the length of the small intestine and the vigorously self-renewing nature of its epithelium. However, Somatic mutation rates of the small intestine similar to that of the large intestine, indicating that the low incidence rate of small bowel cancer is not due to lower mutation rates. Mutational signatures of APOBEC mutagenesis, SBSB2 and SBS13, were present in 17% normal small intestinal crypts, more frequent than most other normal tissues and ~28-fold more than normal large intestine. SBS2 and SBS13 are pervasive in many human cancer types and are thought to be caused by the cytosine deaminases APOBEC3A and APOBEC3B. However, their common presence in cancer contrasts with their scarcity in normal tissues that have been investigated so far, and there is incomplete understanding of the stimulus activating APOBEC mutagenesis, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. SBS2/13 mutation burdens varied between individuals and between crypts from the same individual. Crypts with SBS2/13 often had immediate crypt neighbours without SBS2/13, suggesting that the underlying cause of SBS2/13 is cell-intrinsic rather than a diffuse microenvironmental exposure. Phylogenetic reconstruction showed that APOBEC mutagenesis occurred throughout the human lifespan, including in young children, and was episodic with a small number of episodes occurring during the lineage from fertilised egg to adult small intestine cell. APOBEC1 mRNA levels were very high in small intestine epithelium, reflecting its physiological function of editing APOB mRNA, but low in large intestine epithelium and other cell types. In contrast, APOBEC3A and APOBEC3B mRNA levels were generally higher in large intestine. The results, therefore, indicate that APOBEC1 DNA editing is responsible for the high levels of SBS2/13 in small intestine. Thus, APOBEC1, together with APOBEC3A and APOBEC3B, contributes to DNA editing in human tissues and likely edits both RNA and DNA in normal small intestine epithelium.
● 直播时间 2023年3月12日 20:00-21:00
● 主办单位 人类遗传学交流网络
● 直播平台 深究科学
● 主讲嘉宾 维康桑格研究所（Wellcome Sanger Institute）/剑桥大学 王依琛
嘉宾介绍
王依琛同学就读于Wellcome Sanger Institute/剑桥大学，研究方向为基因组学，师从Professor Sir Mike Stratton和Dr. Peter Campbell。博士期间主要研究人类正常组织中的体细胞突变模式，以助于理解突变的产生机制以及寻找未知的癌症致病原因。相关工作发表在Nature，Nature Genetics上。