arXiv subjects

Hanrong Chen

Publications and source records attributed to Hanrong Chen.

3 recordsLinked to original sources

arXiv2021

Heterologous autoimmunity and prokaryotic immune defense

Some prokaryotes possess CRISPR-Cas systems that provide adaptive immunity to viruses guided by DNA segments called spacers acquired from invading phage. However, the patchy incidence and limited memory breadth of CRISPR-Cas systems suggest that their fitness benefits are offset by costs. Here, we propose that cross-reactive CRISPR targeting can lead to heterologous autoimmunity, whereby foreign spacers guide self-targeting in a spacer-length dependent fashion. Balancing antiviral defense against autoimmunity predicts a scaling relation between spacer length and CRISPR repertoire size. We find evidence for this scaling through comparative analysis of sequenced prokaryotic genomes, and show that this association also holds at the level of CRISPR types. In contrast, the scaling is absent in strains with nonfunctional CRISPR loci. Finally, we demonstrate that stochastic spacer loss can explain variations around the scaling relation, even between strains of the same species. Our results suggest that heterologous autoimmunity is a selective factor shaping the evolution of CRISPR-Cas systems.

q-bio.PE↗

arXiv2018

How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes

T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies. Past theoretical work cast thymic selection as an extreme value problem, and characterized the statistical enrichment or depletion of amino acids in the post-selection TCR repertoire, showing how T cells are selected to be able to specifically recognize peptides derived from diverse pathogens, yet have limited self-reactivity. Here, we investigate how the degree of enrichment is modified by nonuniform contacts that a TCR makes with peptide-MHC. Specifically, we were motivated by recent experiments showing that amino acids at certain positions of a TCR sequence have large effects on thymic selection outcomes, and crystal structure data that reveal a nonuniform contact profile between a TCR and its peptide-MHC ligand. Using a representative TCR contact profile as an illustration, we show via simulations that the degree of enrichment now varies by position according to the contact profile, and, importantly, it depends on the implementation of nonuniform contacts during thymic selection. We explain these nontrivial results analytically. Our study has implications for understanding the selection forces that shape the functionality of the post-selection TCR repertoire.

q-bio.PE↗

arXiv2011

Propagating left/right asymmetry in the zebrafish embryo: one-dimensional model

During embryonic development in vertebrates, left-right (L/R) asymmetry is reliably generated by a conserved mechanism: a L/R asymmetric signal is transmitted from the embryonic node to other parts of the embryo by the L/R asymmetric expression and diffusion of the TGF-$β$ related proteins Nodal and Lefty via propagating gene expression fronts in the lateral plate mesoderm (LPM) and midline. In zebrafish embryos, Nodal and Lefty expression can only occur along 3 narrow stripes that express the co-receptor \emph{one-eyed pinhead} (oep): Nodal along stripes in the left and right LPM, and Lefty along the midline. In wild-type embryos, Nodal is only expressed in the left LPM but not the right, because of inhibition by Lefty from the midline; however, bilateral Nodal expression occurs in loss-of-handedness mutants. A two-dimensional model of the zebrafish embryo predicts this loss of L/R asymmetry in oep mutants \cite{henley-xu-burdine}. In this paper, we simplify this two-dimensional picture to a one-dimensional model of Nodal and Lefty front propagation along the oep-expressing stripes. We represent Nodal and Lefty production by step functions that turn on when a linear function of Nodal and Lefty densities crosses a threshold. We do a parameter exploration of front propagation behavior, and find the existence of \emph{pinned} intervals, along which the linear function underlying production is pinned to the threshold. Finally, we find parameter regimes for which spatially uniform oscillating solutions are possible.

q-bio.TO↗