Phylogenetic analysis of developmental and postnatal mouse cell lineages

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98109, USA.
Evolution & Development (Impact Factor: 2.72). 01/2010; 12(1):84-94. DOI: 10.1111/j.1525-142X.2009.00393.x
Source: PubMed


Fate maps depict how cells relate together through past lineage relationships, and are useful tools for studying developmental and somatic processes. However, with existing technologies, it has not been possible to generate detailed fate maps of complex organisms such as the mouse. We and others have therefore proposed a novel approach, "phylogenetic fate mapping," where patterns of somatic mutation carried by the individual cells of an animal are used to retrospectively deduce lineage relationships through phylogenetic inference. Here, we have cataloged genomic polymorphisms at 324 mutation-prone polyguanine tracts for nearly 300 cells isolated from a single mouse, and have explored the cells' lineage relationships both phylogenetically and through a network-based approach. We present a model of mouse embryogenesis, where an early period of substantial cell mixing is followed by more coherent growth of clones later. We find that cells from certain tissues have greater numbers of close relatives in other specific tissues than expected from chance, suggesting that those populations arise from a similar pool of ancestral lineages. Finally, we have investigated the dynamics of cell turnover (the frequency of cell loss and replacement) in postnatal tissues. This work offers a longitudinal study of developmental lineages, from conception to adulthood, and provides insight into basic questions of mouse embryology as well as the somatic processes that occur after birth.

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    • "We compared the composition of pairs of tissues in a Spearman correlation matrix for the 17 Tg/-$WT and seven Tg/Tg$WT chimaeras (Online Resource 6; Supplementary Table S3) but not for the small group of three WT$WT chimaeras. As expected from previous correlation analyses with chimaeras (Falconer et al. 1981) and reconstruction of cell lineage trees from somatic mutations (Wasserstrom et al. 2008; Salipante et al. 2010; Behjati et al. 2014), almost all the correlation coefficients were positive. Nearly all the correlations were statistically significant for the Tg/-$WT chimaeras and many were significant for the Tg/Tg$WT chimaeras. "
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    ABSTRACT: Recent reports of a new generation of ubiquitous transgenic chimaera markers prompted us to consider the criteria used to evaluate new chimaera markers and develop more objective assessment methods. To investigate this experimentally we used several series of fetal and adult chimaeras, carrying an older, multi-copy transgenic marker. We used two additional independent markers and objective, quantitative criteria for cell selection and cell mixing to investigate quantitative and spatial aspects of developmental neutrality. We also suggest how the quantitative analysis we used could be simplified for future use with other markers. As a result, we recommend a five-step procedure for investigators to evaluate new chimaera markers based partly on criteria proposed previously but with a greater emphasis on examining the developmental neutrality of prospective new markers. These five steps comprise (1) review of published information, (2) evaluation of marker detection, (3) genetic crosses to check for effects on viability and growth, (4) comparisons of chimaeras with and without the marker and (5) analysis of chimaeras with both cell populations labelled. Finally, we review a number of different chimaera markers and evaluate them using the extended set of criteria. These comparisons indicate that, although the new generation of ubiquitous fluorescent markers are the best of those currently available and fulfil most of the criteria required of a chimaera marker, further work is required to determine whether they are developmentally neutral. Electronic supplementary material The online version of this article (doi:10.1007/s11248-015-9883-7) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2015 · Transgenic Research
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    • "Figure 1a shows how many different mutant alleles are identified for each marker across all of the approximately 100 cells genotyped for each mouse. Combining data from all cells harvested, each mouse exhibits an average of 0.5 mutant alleles/polyG locus/cell, which is more than one hundred-fold greater than we previously observed (0.003 mutations/locus/cell) using mice with intact DNA repair machinery [14]. Figure 1b shows the number of polyG marker mutations detected per cell for each mouse (from among all approximately 110 markers). "
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    ABSTRACT: Background The C. elegans cell fate map, in which the lineage of its approximately 1000 cells is visibly charted beginning from the zygote, represents a developmental biology milestone. Nematode development is invariant from one specimen to the next, whereas in mammals, aspects of development are probabilistic, and development exhibits variation between even genetically identical individuals. Consequently, a single defined cell fate map applicable to all individuals cannot exist. Results To determine the extent to which patterns of cell lineage are conserved between different mice, we have employed the recently developed method of “phylogenetic fate mapping” to compare cell fate maps in siblings. In this approach, somatic mutations arising in individual cells are used to retrospectively deduce lineage relationships through phylogenetic and—as newly investigated here—related analytical approaches based on genetic distance. We have cataloged genomic mutations at an average of 110 mutation-prone polyguanine (polyG) tracts for about 100 cells clonally isolated from various corresponding tissues of each of two littermates of a hypermutable mouse strain. Conclusions We find that during mouse development, muscle and fat arise from a mixed progenitor cell pool in the germ layer, but, contrastingly, vascular endothelium in brain derives from a smaller source of progenitor cells. Additionally, formation of tissue primordia is marked by establishment of left and right lateral compartments, with restricted cell migration between divisions. We quantitatively demonstrate that development represents a combination of stochastic and deterministic events, offering insight into how chance influences normal development and may give rise to birth defects.
    Full-text · Article · Jan 2013 · BMC Genomics
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    • "We applied a method of cell lineage tree reconstruction developed in our laboratory [31], [32], [33], [34], [35]. This method, which was also applied by others [36], [37], [38], [39], is based on the fact that somatic mutations that accumulate during normal cell division endow each cell of the body with a unique genomic signature [32]. The cellular genomic signature used in the current study is derived from a set of microsatellite (MS) loci in mismatch-repair (MMR) deficient mice (Mlh1−/−). "
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    ABSTRACT: Myofiber cultures give rise to myogenic as well as to non-myogenic cells. Whether these myofiber-associated non-myogenic cells develop from resident stem cells that possess mesenchymal plasticity or from other stem cells such as mesenchymal stem cells (MSCs) remain unsolved. To address this question, we applied a method for reconstructing cell lineage trees from somatic mutations to MSCs and myogenic and non-myogenic cells from individual myofibers that were cultured at clonal density. Our analyses show that (i) in addition to myogenic progenitors, myofibers also harbor non-myogenic progenitors of a distinct, yet close, lineage; (ii) myofiber-associated non-myogenic and myogenic cells share the same muscle-bound primordial stem cells of a lineage distinct from bone marrow MSCs; (iii) these muscle-bound primordial stem-cells first part to individual muscles and then differentiate into myogenic and non-myogenic stem cells.
    Full-text · Article · Oct 2011 · PLoS ONE
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