Evolutionary Innovations in Mammalian Germline Regulatory Biology

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Lesch, Bluma

Abstract

2025Evolution of developmental gene regulation underlies the emergence of many species-specific traits, encompassing divergence in regulatory machinery that controls gene expression and changes in the resulting RNA profiles. Mammalian spermatogenesis is a deeply conserved developmental program that is essential for fitness. Paradoxically, spermatogenic development also allows rapid divergence in gene expression and is a source of evolutionary novelty and gene birth. Using a high-resolution dataset comprising bulk and single-cell data from juvenile and adult testes of opossum (Monodelphis domestica), a model marsupial, I define the developmental timing of the spermatogenic ‘first wave’ in opossum and delineate conserved and divergent gene expression programs across the placental-marsupial split by comparison to equivalent data from mouse (Mus musculus), a model placental mammal. I substantiate and extend these findings using genome-wide chromatin and multi-species transcriptome data from four additional amniote species to identify hundreds of genes with evidence of rapid fixation of expression. I identify three classes of genes with different evolutionary trajectories: a deeply conserved central gene regulatory program governing spermatogenic progression; a class of genes exhibiting dynamic expression across placental mammals; and genes with evidence for directional selection in the placental mammal ancestor and constraint within the placental mammalian lineage, representing placental innovations in germline gene expression that may elucidate genetic contributions to germ cell biology and infertility. Further, I ask what mechanisms underly this expression divergence by studying TRAF6, a gene that gained a bivalent chromatin state and transcriptional repression specifically in the mouse germline. Using ChIP-qPCR and GFP reporter expression in mouse whole testis and embryonic stem cells, I identify a correlation between bivalent chromatin state, gene repression, and loss of CTCF binding. I discover that while changing the Traf6 chromatin state in mouse male germ cells has no effect on fertility, it leads to changes in somatic function in the adult immune system.

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