Quantifying the roles of drift and selection in spermatogonial stem cell dynamics

ConnorShrader

University of Utah

"Quantifying the roles of drift and selection in spermatogonial stem cell dynamics"

Stem cells maintain and repair our tissues, but not all stem cells are identical. As organisms age, distinct stem cell 'clones' can begin to dominate the cell population. While this behavior has been observed across multiple species and organs, the mechanisms and consequences of stem cell clonality are still poorly understood. We have developed a novel experimental approach using a CRISPR-Cas9 system to uniquely “barcode” spermatogonial stem cell clones in the testes of male zebrafish. Once these fish reach sexual maturity, we sample sperm each month to determine the contribution of each stem cell clone to the sperm pool over time. The observed clonal dynamics may be driven by factors such as genetic drift, selection, or sampling error. We hypothesize that a small number of clones are under positive selection, resulting in their eventual dominance in the sperm pool. To bridge the gap between theory and data, we have developed stochastic models of stem cell dynamics in the testis. These models are formulated as hidden Markov models that describe rules for the division and differentiation of stem cells within the testis. We first evaluate our ability to estimate model parameters on simulated data. Then, we apply our model to the experimental data to quantify evidence for genetic drift and selection. Our models provide insight into how individual stem cell behavior can lead to population-level clonality.
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