KAIST ​유전체 돌연변이 모자이시즘 연구실

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Somatic mosaicism, a fundamental challenge for understanding tissue homeostasis and aging

 

Please read our papers! (Youk et al., Exp Mol Med 2021; Park et al., Nature 2021; Nam et al., Nature 2023) 

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Genome-wide sequencing, such as whole-genome sequencing, are now widely used for disease gene discovery studies, and many novel causal pathogenic genes (and mutations) are found from sporadic genomic diseases (Koboldt et al., Cell 2013). However, the success rates for ‘pin-pointing’ causal mutations or mechanisms were estimated to be 30% or less even for clinically indisputable genomic diseases (Fresard et al., Cold Spring Harb Mol Case Stud 2018). Indeed, there is a substantial level of ‘missing heritability’ where current genome-wide techniques hardly reach. 

 

The human body consists of 40 trillion somatic cells developing from a single common ancestral cell, the fertilized egg. Through a series of mitotic cell divisions from embryo stage, accompanied by the doubling of genomes in each cell generation, a complex multicellular system is finally organized. It is generally assumed that the genetic constitution of a fully developed adult is uniform among cells and virtually identical to the initial embryonic state. To a large extent, this is an assumption of convenience, because until recently it has been impossible to sensitively measure ‘somatic mosaicism’, the genetic heterogeneity among somatic cells and tissues within an individual. Nonetheless, the concept of accumulating genomic changes was first proposed more than 60 years ago (Szilard, PNAS 1959), and largely discussed as an important factor in the aging process as well as the tumorigenesis (Zhang et al., Annu Rev. Genet. 2018). However, ordinary bulk-tissue-sequencing is not feasible to sensitively detect somatic mutations and resultant mosaicism in normal tissues, because the vast majority of mutations are confined in a very small fraction of cells, which are undetectable by typical <100x sequencing depth (Dou et al., Trends Genet. 2018) 

 

Multiple lines of evidence now suggest that mutation during mitosis is a common event in human bodies, with a substantially high mutation rate, 0.1-10 base substitutions per cell division (Martincorena et al., Science 2015). Given that ~10^16 mitoses are required to generate an adult human individual, and homeostatic cell divisions are necessary in many tissues, it is likely that cells within our body harbor countless numbers of genomic changes that could cause human diseases (Campbell et al., Trends Genet. 2015). For the order among clones across the individual lifespan, compressing the appearance of genomic heterogeneity would be essential, which is based on two main cellular processes: (1) DNA repair of damaged genomes and (2) replacement of injured cells with cells from healthy clones. If these processes are not properly working in human tissues, pathogenic clones will rapidly emerge in human tissues, leading to break tissue homeostasis.

 

Indeed, a wide range of human diseases including tumors and immune-related and neurodevelopmental diseases have been occasionally found to be dominantly caused by somatic mutations and pathogenic clonal expansion. However, comprehensive landscapes of somatic mosaicism among tissue types in the human lifetime have largely remained unexplored. As a result, we do not have a fundamental understanding of the rate and processes of somatic mutation in the different lineages of normal cells, the levels of clonal competition and emergence of clonal expansions through the aging process, and the tangible contributions of these processes to human diseases.

 

Uncovering the landscape of spatiotemporal clonal dynamics in human tissues

 

My lab intends (I) to accurately uncover the landscape of somatic mosaicism and subsequent clonal competition in human, animal and plant tissues, (II) to reveal underlying molecular mechanisms for the acquisition of diverse spectrums of somatic mutations, (III) to precisely measure the functional consequences of somatic mosaicisms, and finally (IV) to develop strategies for preventing and controlling genomic mutagenesis. To overcome the technical limitations of current single-genome technologies, we synergistically integrate four cutting-edge techniques: (1) CloneWGS, which explores genome-wide mutations from clonally expanded cells (usually organoids) in vitro; (2) LCM-WGS, which explores genome-wide mutations from naturally expanded clonal patches in human tissues; (3) Duplex DNA sequencing, which explores whole single-genomes from physically isolated cells; and (4) long-read sequencing for phasing a variant with its nearby heterozygote polymorphisms. Each technology has its own pros and cons, but collectively, they complement each other and are sufficiently powerful to reveal the clonal architectures of normal and diseased human tissues. Our efforts will provide the panorama of mutational acquisition and subsequent clonal evolution both in normal and pathogenic tissues. Our study will make a huge paradigm shift in understanding genetic cause and molecular pathogenesis of diseases in the level of cellular heterogeneity. By doing so, the proposed study could inform therapeutic avenues to prevent and mitigate senescence and tissue degeneration developing from mutant clones.

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