Disease susceptibility and phenotypic adaptations as seen through the lens of comparative functional genomics

A central challenge in biology is understanding the genetic basis of phenotypic diversity and disease susceptibility. In mammals, trait evolution and disease mechanisms are largely driven by changes in gene expression and their regulation. These changes often result from sequence variations within the genome, which can affect gene function and regulatory elements, ultimately influencing the phenotype. This thesis investigates how evolutionary changes in genomic background and selection events at the expression and regulation levels impact cancer susceptibility and phenotypic adaptation. Through the use of two distinct model rodent clades: mice species and African mole-rats, this research offers insights into the molecular drivers of evolution and disease susceptibility across different evolutionary timescales. In the first part of the thesis, I present a project I worked on as part of the Liver Cancer Evolution (LCE) consortium. To gain insight into the influence of the genetic background on mutagenesis and cancer susceptibility, the LCE consortium used a model of chemically induced liver carcinogenesis across four mouse species. Here, I leverage whole-genome sequencing and RNA-seq experiments of hundreds of liver tumours to comprehensively characterise mitochondrial genomes (mtDNA) across four mouse species with distinct cancer susceptibility and progression. I devised a novel heteroplasmy detection approach that accounts for the circular nature of the mitochondrial genome and efficiently filters out false-positive heteroplasmies caused by nuclear mitochondrial read misalignment. I performed heteroplasmy detection on 573 tumour genomes in four evolutionary divergent mouse species. Despite their recent divergence, I found that the mouse species investigated had different mtDNA mutation burdens and per-gene mutation rates. However, the forces shaping their mutational signatures were similar: most mutations were the product of replication-coupled DNA damage and there was a neutral selective pressure for missense and loss of function mutations. In addition, I investigated mitochondrial content and expression levels in tumour versus normal samples. I found that tumours had a lower mtDNA content than normal controls, and the content correlated with tumour stage and driver gene choices. Moreover, most tumour samples showed a significant depletion of mtDNA expression levels. Altogether, these results provide insights into mitochondrial heteroplasmy, content and expression in tumour development across distinct mouse genomes and their potential role in cancer susceptibility, transformation timing, and driver gene choice. In the second part of the thesis, I aimed to identify and connect selection events on fast-evolving cis-regulatory elements, on slower-evolving gene expression levels, and their contribution to phenotypic adaptations. Using African mole-rats as a model, renowned for their unique phenotypic adaptation traits like cancer resistance and hypoxia tolerance, I aimed to uncover gene expression patterns underlying these traits, which have mainly been characterised at the level of candidate genes in individual species. I profiled gene expression in heart and liver tissues across two mole-rat species and two rodent outgroups, using a phylogenetic comparative approach to identify genes whose expression levels have undergone selection events (shifts) within the mole-rat clade and specific genera. I found that genes with shifted expression patterns are associated with known functional adaptations in naked mole-rats, such as lower oxidative stress, response to stress, and fatty acid metabolism. Additionally, a significant portion of shifted genes were shared between the two tissues with a high correlation in their shift magnitude. Furthermore, I integrated cis-regulatory element shifts with expression shifts, revealing a coordinated selection of gene regulation and expression. Employing a phylogenetic comparative approach offers new insights into the interplay between gene expression, regulation, and phenotypic evolution in mammals. These findings shed light on the molecular mechanisms driving the evolution of unique traits in mole-rats and potentially other mammalian species.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Daunesse, Maëlle

Advisors dc:contributor.advisor

• Flicek, Paul
• Goldman, Nick

• Comparative genomics
• Mammalian evolution
• Gene expression
• Gene regulation
• Mitochondrial genome
• Heteroplasmy

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4d8e37eb-79eb-4114-9ef7-43e1ff294aed/download
• https://creativecommons.org/licenses/by-nc-sa/4.0/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.114721

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/378226