A new method \cite{Ludwig_2019} traces the cellular relationship and hierarchies (the
“pedigrees”) of human cells within the body by reading the DNA
sequences of hundreds to thousands of mitochondria extracted from single
cells.
Various genetic labeling techniques have been developed for lineage
tracing in other model organisms. However, the above techniques are not
applicable in intact humans. Cell lineage tracing is the most direct way
to understand the development of complex cell types and their
relationships in an organism, and an important method to trace abnormal
cells over time to monitor developmental mosaicism, as demonstrated in C. elegans . In mammals, cell lineage tracing is particularly
important for tracing cancer cells and their migration because cancers
present special difficulties due to fast-paced proliferation and
sequential genetic mutations. Lineage tracing can also determine if
transplantation is successful and transplanted cells or tissues are on
the correct site.
The researchers showed that single-cell RNA sequencing (RNA-seq) and
transposase accessible chromatin sequencing (ATAC-seq) methods could be
used in combination to trace the inheritance of mitochondrial mutations,
chromosomal states, and gene expressions at the same time, in multiple
human cell colonies obtained from cultured cells, multiple human
tissues, tumor cells, and transplanted cells. ATAC-seq detects the
regions of chromosomes that are not wrapped into nucleosomes by histone
proteins, thus defining cellular or chromosomal states. Using this
method, they identified large numbers of mitochondrial DNA mutations and
heteroplasmy (the presence of different types of mitochondrial genomes)
that were associated with specific cell populations, tissues, or
individuals. These experiments led to an important conclusion that
mitochondrial mutations were inherited in the cellular colonies with
extensive divisions stably and without being affected by cellular or
chromosomal state, and the high mutation rate in mitochondrial DNA
allows cellular sub-colonies to be traced with high resolution.
Thus, the single-cell sequencing of mitochondrial DNA mutations provides
a method that is much more accurate, stable, and affordable than a
single-cell genome sequencing method to study clonal architecture in
human health and diseases.
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