Nature Bai Fan/Huang Yanyi team and collaborators reveal somatic mutations in normal human tissues

Cells in various normal tissues in the human body are inevitably accumulating mutations

August 25, 2021, Peking University Biomedical Frontier Innovation Center (BIOPIC), Beijing Future Gene Diagnosis Advanced Innovation Center (ICG) Bai Fan Group, Huang Yanyi Group, Tsinghua University School of Life Science Wang Jianbin Group and Chinese Medicine The research team of Lin Dongxin and Wu Chen from the Cancer Hospital of the Academy of Sciences and Peking Union Medical College jointly published a research paper entitled A body map of somatic mutagenesis in morphologically normal human tissues in the academic journal Nature

Different from the situation that cancer cells in tumor tissues usually originate from the expansion of a single clone (monoclonal), somatic cells in normal tissues usually accumulate gene mutations independently and develop in the form of polyclonal parallel evolution, so the accumulation of mutations in the same gene They often only appear in a small number of cells, making it difficult for traditional genome sequencing technologies based on a large number of cells to detect these somatic mutations in normal tissues

The research team first achieved a technological breakthrough and developed a low-initiated (600-cell) deep whole genome/exome sequencing technology, making it possible to capture a small number of somatic mutations in normal tissues

The study obtained samples of nine organs from five body donors over 85 years of age who were diagnosed as normal by histopathology, including bronchus, esophagus, cardia, stomach, duodenum, liver, pancreas, colon and rectum.

Figure 1: 9 kinds of normal tissue somatic mutation and copy number variation map

By correcting the sensitivity of mutation detection and considering the clonal structure of different organs, the researchers compared the accumulation of mutations in different organs and tissues from the same individual and found that normal liver tissue has the highest somatic mutation load among the 9 tissues and organs, even It is higher than many epithelial cell tissues, and the mutation load in pancreatic parenchymal cells is the lowest

However, unlike the case of somatic mutations, gene copy number alteration (copy number alteration), especially the large-scale genome copy number alteration, rarely occurs in various normal tissues, and the occurrence of copy number alteration has a certain organ preference

Next, the researchers analyzed the potential driving reasons for the accumulation of a large number of somatic mutations in different normal tissues by analyzing the single-base-substitution mutational signature

Among them, the endogenous mutation characteristics SBS1 and SBS5 related to age and aging process widely appear in all tissues, which indicates that the mutation process related to aging is an important reason for the accumulation of somatic mutations in normal human tissues

In addition, two mutation characteristics related to exogenous mutagenic factors, SBS4 (related to smoking) and SBS22 (related to the mutagen aristolochic acid) mainly appeared in liver tissues, which revealed that exogenous environmental factors are normal for the human body.

Figure 2: Analysis of somatic mutation characteristics of normal tissues

Through further mining of the data, the researchers analyzed cancer-related "driver gene" mutations accumulated in various normal tissues, and found a total of 32 mutated "driver genes", including NOTCH1, TP53, ARID1A and ERBB2 and other widely recognized genes related to tumorigenesis

(1) NOTCH1 is the driver gene with the most mutations in normal tissues involved in the research, and its mutations are widely seen in a variety of tissues; (2) TP53 is the gene with the most cancer-related hotspot mutations in normal tissues; ( 3) The accumulation of "driver gene" mutations has obvious heterogeneity between organs and between individuals, and has certain organ preference

Figure 3: The accumulation of driver gene mutations in various normal tissues

Finally, the researchers analyzed the expansion and evolution of somatic mutant clones in various normal tissues of the same individual

(1) The mutant clones in the esophagus and cardia tissues have relatively large expansion but the somatic mutation load is relatively low; (2) The mutant clones in the colon and rectum tissues have relatively small expansion but the somatic mutation load is relatively high; (3) Partially Liver tissue samples have both a higher somatic mutation load and a larger mutant clone expansion

　　Furthermore, by combining the location information of spatial sampling and the clustering of mutant clone cell ratios, the researchers constructed a spatial expansion map of mutant clones with sub-millimeter resolution (Figure 4), and found that mutant clones may expand to nearly millimeters in normal esophagus.

Figure 4: Somatic mutant clone expansion and evolution

　　Peking University Biomedical Frontier Innovation Center (BIOPIC) postdoctoral fellow Li Ruoyan (currently working at Wellcome Sanger Institute in Cambridge, UK), PhD student Di Lin, PhD student Li Jie, School of Life Sciences, Tsinghua University, and Dr.

　　Link to the paper: https://