Module Organisers:
Anton Enright (aje39@cam.ac.uk) & Alex Cagan (atjc2@cam.ac.uk)
Please feel free to contact either Anton or Alex if you have questions about the GGD module.
Introduction
Biological sciences and medicine have changed significantly in the last 20 years since the advent of modern genetics and genomic technologies. Our understanding of the genome and its multi-faceted regulation has improved significantly and created new opportunities for the understanding, diagnosis and treatment of disease. Biology is now a high-throughput data science exploring a genome that is significantly more complicated and nuanced than had been previously thought.
Figure 1: A high-resolution mRNA expression time course of embryonic development in zebrafish. White RJ, Collins JE, Sealy IM, Wali N, Dooley CM, Digby Z, Stemple DL, Murphy DN, Billis K, Hourlier T, Füllgrabe A, Davis MP, Enright AJ, Busch-Nentwich EM.
This course aims to provide a broad and comprehensive overview of these discoveries and their impact from epigenetics, genetics and gene regulation. You will develop a deeper understanding of the genome and its architecture and the modern high-throughput techniques that enable us to utilise genomics and genetics to understand and treat disease.
Figure 2: Spatial Transcriptomics of the Human kidney. Dixon EE, et al. Spatially resolved transcriptomic analysis of acute kidney injury in a female murine model. J Am Soc Nephrol 2022
The Course
The course can be broadly divided into the following sections:
- The Non-Coding Genome: Traditional thinking around the genome centred on protein coding genes and the exome. Since the completion of the Human genome and many other genomes, a new world of regulatory RNAs have been discovered. Here we explore microRNAs, siRNAs piwiRNAs and long-noncoding RNAs and how they interact with mRNAs and proteins and their impact on disease. The roles of these newly discovered non-coding components of the genome and how they interact with the genome itself, proteins and mRNAs, will link into many other aspects of the course content.
- Genetics and Genomics Techniques: We will explore how the causative mutations of diseases can be narrowed down through genome-wide association studies and the challenges such approaches face. We will also look in detail at the specific types of heritability on the sex chromosomes and what this means for disease gene association for X and Y linked conditions. We will also discuss the benefits and uses for animal models of human diseases. We are seeking to update and add content on single-cell and spatial transcriptomics approaches to this course and how these technologies improve our understanding of disease.
- Epigenetics: Modern genomics has revealed that the heritability of many diseases and conditions was not as straightforward as expected. We will explore the missing heritability paradox for common diseases and look at the significant improvements in our knowledge of epigenetic effects and how the genome can pass forward important regulatory marks in response to adverse conditions. We will explore this down to the level of chromatin structure, DNA and histone modifications and long-range regulatory effects on genes through enhancer architecture and the interplay with molecules such as long-noncoding RNAs. Concepts such as imprinting and their importance in our understanding of genome regulation and disease will be covered in detail.
- Mutations and Disease: Our bodies consist of 37 trillion cells and each one is subjected to damage with up to 70,000 mutational damage events each day which are usually repaired. These lectures will focus on somatic mutation, how it arises and its importance for diseases such as cancer, haematological and neurodevelopmental disorders. We will continue this focus into exploring how germline de novo mutations arise and explore the causes and effects of such mutations on disease, including why such mutations become more common as our germline cells age. We will continue this into the developmental origins of health and disease such as how diet and lifestyle in our early years can have significant long term health effects.
- Mitochondrial Diseases: Our mitochondria being inherited maternally are subject to different pressures and mutational profiles and mtDNA mutations are a major cause of disease. In this section we will explore the basis for mitochondrial inheritance and disorders and their presentation in clinical genetics including concepts such as heteroplasmy and how this influences these disorders.
- Degenerative Disorders: Autophagy is when our own cells destroy each other, in these lectures we explore the molecular basis for this process and how it directly feeds into our understanding of significant degenerative disorders such as Huntingdon’s and Parkinson’s diseases.
Research Projects
The projects are usually based on the research interests of the teaching staff. https://www.path.cam.ac.uk/research/cellular-and-molecular-pathology-div...
In addition to the projects within the CMP Division of the Department of Pathology, some research projects are offered by other departments, e.g. The Laboratory of Molecular Biology, the Department of Medicine, The Veterinary School and the Cambridge Institute for Medical Research. These may include topics on clinical genetics, genomics, cancer genomics and novel and experimental diagnostic and sequencing approaches in diseases.
It is possible to do entirely ‘wet’ based projects but also purely computational biology analyses and hybrid projects in-between these two. Please contact potential project supervisors or the module coordinator to discuss options.
Examples of Previous Projects
- Analysis of tRNAs with direct nanopore sequencing
- Direct sequencing of circulating microRNAs Using Nanopores
- Analysis of Exome Sequences from Individuals with Abnormal Sex Development
- Exploration of alternative-splicing in Squamous Cell Carcinoma with next-generation sequencing
Examples of Previous Dissertations
- Delivery of microRNAs as potential cancer therapeutics.
- Preventing Medical Fraud in the Age of Advanced Healthcare: An Examination of Current Practices and Future Solutions.
- Computational approaches to analysing microRNA function in Cancer.