Cascone, Ilaria (2025) Exploring genomic and epigenomic signatures of mastitis in Mediterranean Italian River Buffalo through Nanopore Sequencing. [Tesi di dottorato]

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Abstract

Mastitis represents one of the main challenges in dairy farming, with substantial economic and animal welfare implications. For these reasons, it has long been the focus of global research and remains a critical area of study in livestock. Integrative studies combining third-generation sequencing technologies, such as Nanopore, with functional analyses could offer valuable advances in understanding epigenetic mechanisms underlying health and productivity in livestock. The ability to monitor these alterations opens new perspectives for the early detection and diagnosis of mastitis. This project aims to expand genomic and epigenomic knowledge on mastitis in buffalo through three objectives: (1) assess the potential application of Nanopore sequencing for uncovering hidden genomic changes, through ultra-long reads spanning complex genomic regions (2) identify different epigenetic patterns between healthy and mastitic animals, and (3) detect selection signals in genomic regions involved in inflammatory and mastitis related processes. Blood samples from Mediterranean Italian River buffalo were analyzed using Nanopore sequencing. The generation of high quality reads allowed the identification of genomic rearrangements that remain unnoticed to conventional cytogenetic methods, representing a substantial advance in buffalo genomic resources. Two previously undetected chromosomal inversions, a 30-Mb inversion on BBU7 (relative to BTA6) and a 4-Mb inversion on BBU14 (relative to BTA13) were detected between homologous chromosomes of cattle and river buffalo. Distinct methylation patterns were observed between healthy and mastitic animals, revealing 22 differentially methylated cytosines (DMCs), 68% showing hypomethylation, and 32% showing hypermethylation in the control group. Eight differentially methylated genes (DMGs) were identified, involved in balancing immune responses, managing cellular stress, promoting tissue repair, and resolving inflammation during mastitis. Comparative analysis of ROH, iHs and XP-EHH was performed to explore selection signatures to identify population specific adaptive responses potentially associated with mastitis. A total of 24 genes were identified in the mastitic group and 28 genes in the healthy group. Functional enrichment analyses highlight the involvement of immune related pathways, metabolic processes, and cellular homeostasis mechanisms. This PhD thesis provides an integrated view of buffalo genome biology by combining genomic, epigenetic, and evolutionary perspectives through long-read sequencing technologies. The results expand current genomic knowledge of river buffalo, improve genomic resources for this species, and deepen understanding of the molecular mechanisms underlying mastitis.

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