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Clonal behavior of germ cells during male sex differentiation

  • Author(s): Nguyen, Daniel
  • Advisor(s): Conti, Marco
  • et al.
Abstract

Natural selection is the process by which variation within a population is assessed and resolved, leading to success of certain individual winners over losers. Though this principle is well studied at an organismal level, cellular populations are also subject to selection as they navigate through developmental transitions. Germline development in the fetal period is complex and diverse, necessitating that germ cells complete numerous cell state transitions to appropriately prepare for gametogenesis in the adult. The events of fetal germ cell development can therefore function as selective barriers that assess developmental competency in a germ cell population. Here, we examine how fetal events in male germ cell development contribute to the variation in a germ cell population. We utilize clonal labeling and various analyses at a cellular resolution to determine the heritable basis for winner germ cells that successfully complete development versus losers that fail to do so.

We identify apoptosis as a major selective process that nonrandomly eliminates germ cells. We show that apoptosis is due to cell-intrinsic properties rather than extrinsic causes. Clonal labeling reveals that specific clonal populations are removed by apoptosis. We further analyze by apoptotic germ cells within an entire population by single-cell RNA sequencing to identify characteristics associated with developmental losers. We find that fidelity to the male sex differentiation program is a highly heterogeneous attribute discerning winner germ cells from those eliminated by apoptosis. When we extend our assessment of germ cell heterogeneity over developmental time, we identify an early differentiating population that is resilient to apoptosis and more capable of suppressing transposons.

These results indicate that variation in germ cells is revealed during male differentiation to lead to highly divergent outcomes. This variation is clonal in nature and therefore heritable. The consequence of developmental selection acting on this germ cell heterogeneity is predicted to benefit germ cell function. In this sense, fetal development improves germ cell quality by serving as a natural selection process.

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