Søren’s MSc project about Hi-C and spermatogenesis

Exploring the 3D Chromatin Landscape of the X Chromosome in Rhesus Macaques

Overview

The X chromosome plays a unique role in evolution and biology, exposed to distinct selective pressures due to its hemizygous nature. This study investigates the 3D chromatin architecture of the X chromosome in Macaca mulata (rhesus macaque), focusing on how evolutionary pressures and genetic drivers shape its structural and functional landscape.

Introduction: Evolution on the X Chromosome

The X chromosome is subject to unique evolutionary pressures due to its distinct inheritance patterns. Males, having only one X chromosome, are particularly vulnerable to deleterious mutations, as there is no homologous counterpart to buffer their effects. These pressures are further compounded by the X chromosome’s pivotal role in reproduction and brain function.

In humans, regions of reduced genetic diversity and incomplete lineage sorting (ILS) on the X chromosome have been associated with strong selective sweeps, such as extended common haplotypes (ECHs). Similarly, studies in baboons (Papio spp.) reveal regions of disproportionate ancestry on the X chromosome, suggesting sex-biased admixture and strong selective pressures. These findings highlight how structural and evolutionary dynamics uniquely shape the X chromosome, with implications for understanding genetic inheritance, speciation, and adaptation.

Key Objectives

• Uncover Safeguarding Mechanisms: Investigate biological mechanisms that maintain the integrity of the X chromosome, which is densely packed with essential genes related to reproduction and brain function.
  
• Reproducible Analysis: Employ a transparent, version-controlled computational framework for reproducibility and collaboration.

Methodology

• Hi-C Data Analysis:
  We compared two popular Hi-C analysis frameworks:
  • HiCExplorer
    
  • cooler/cooltools (Open2C)
    Open2C was selected for its flexibility and performance.
    
• A/B Compartment Analysis:
  • Used the ICE (Iterative Correction and Eigendecomposition) method to infer A/B chromatin compartments.
    
  • Analyzed data from macaque fibroblasts and four spermatogenesis stages to detect chromatin structural transitions.
    
• Genomic Intervals
  • Compared the compartments with regions under selection in both baboon and human using inhouse software, genominterv, available through conda at munch-group.

Findings

• Transition Zones:
  Identified 200 kbp transition zones between A/B compartments on the X chromosome in fibroblasts and round spermatids. These zones align with strong selective sweeps in humans (ECH-regions), but not with regions of negative selection in baboons (Papio spp.).
  
• Conserved Chromatin Features:
  Found that A/B compartment boundaries often overlap or are in close proximity to regions under selection in humans and baboons. This highlights conserved structural elements that may contribute to genome evolution by buffering non-advantageous alleles.

Significance

This study reveals insights into how chromatin architecture influences evolutionary pressures on the X chromosome. The conserved features we uncovered may play a pivotal role in safeguarding its integrity, furthering our understanding of genome evolution and adaptation.

Explore the Project

• Analysis Code: Access our version-controlled computational framework.
  
• Data Visualizations: Browse interactive plots and visualizations.
  
• Methods: Learn more about the tools and pipelines used.
  
• Results & Insights: Delve deeper into our findings.