Abstract
The depth of a cell of a multicellular organism is the number of cell divisions it underwent since the zygote, and knowing this basic cell property would help address fundamental problems in several areas of biology. At present, the depths of the vast majority of human and mouse cell types are unknown. Here, we show a method for estimating the depth of a cell by analyzing somatic mutations in its microsatellites, and provide to our knowledge for the first time reliable depth estimates for several cells types in mice. According to our estimates, the average depth of oocytes is 29, consistent with previous estimates. The average depth of B cells ranges from 34 to 79, linearly related to the mouse age, suggesting a rate of one cell division per day. In contrast, various types of adult stem cells underwent on average fewer cell divisions, supporting the notion that adult stem cells are relatively quiescent. Our method for depth estimation opens a window for revealing tissue turnover rates in animals, including humans, which has important implications for our knowledge of the body under physiological and pathological conditions.
Highlights
Direct observation of cell divisions, which was used to reconstruct the cell lineage of the 959 somatic cells of Caenorhabditis elegans [1] implicitly yielded the depths of these cells
Correlation Between Genetic Distance and Cell Depth Our work develops the notion of genetic molecular clocks into a quantitative method for depth estimation of single cells of any type
Its DNA is replicated with almost perfect fidelity, yet somatic mutations occur in every cell division [9]
Summary
Direct observation of cell divisions, which was used to reconstruct the cell lineage of the 959 somatic cells of Caenorhabditis elegans [1] implicitly yielded the depths of these cells. Direct observations cannot be done for humans and mice since they are opaque and have a tremendous number of cells [2]. Calculations based on cell numbers, proliferation kinetics and various theoretical assumptions have been used to estimate the depths of human [3] and mouse [4] oocytes (approximately 25 cell divisions in both), and of human sperm (approximately 30 divisions at age 15 with additional 23 divisions per year thereafter [3]). The evolutionary-biology concept of a molecular clock [5] – a relatively constant rate of molecular evolution – has been suggested for estimation of cell depths using either epigenetic [6] or genetic [7] mechanisms. The depths of the vast majority of human and mouse cells are unknown, and no systematic method for their estimation has been proposed so far
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