Aims
This course aims to:
• familiarise you with the timelines and key characters in the application of genetics to human health and disease
• introduce some fundamental principles of human heredity
• provide practical experience in investigating human genetic variation
Content
This course will take you on a journey from the fundamental principles of inheritance through to the at-scale genomic analysis underpinning modern approaches to healthcare. The rediscovery of the work of Gregor Mendel at the turn of the 20th century was quickly followed by Archibald Garrod’s description of a disease that followed a Mendelian inheritance pattern (alkaptonuria). Only a small number of single-gene disorders were known for some time afterwards although it was apparent that a great many diseases had at least some genetic basis. While the discovery in 1953 of the structure of DNA by Watson and Crick and the information encoded therein (using Rosalind Franklin’s x-ray crystallography data) promised a new dawn in the understanding of human health and disease, it wasn’t until the completion of the Human Genome Project that the promise of genetic medicine began to be realised.
By the late 1980s, DNA sequencing technology (pioneered by double Nobel prize winner Fred Sanger) had developed to the point where scientists were confident in undertaking the “moon-shot” of determining the sequence of all three billion nucleotides in a reference human genome. While a reasonably-complete sequence was published in the journal Nature in 2003, it was the technological advances in DNA sequencing driven by this project, as much as the information that was revealed, that facilitated advances in individualised care. This technology allowed such initiatives as the 1000 Genomes Project in 2008 (unthinkable in 1990), which sought to investigate human variation and the 100000 Genomes Project in 2015. The latter sought to investigate the genetics of rare disorders and cancer, as well as to create a reference database for future studies. This means that whole genome sequencing can now effectively identify risk alleles, inform management and improve outcomes for an increasing number of disorders.
Presentation of the course
The course will take the form of traditional lectures supported by PowerPoints with practical tasks and quizzes to allow you to apply your knowledge. There will be plenty of space for discussion. In particular, There will be opportunities for you to perform analysis of your own using freely-available on-line resources, so bring a laptop if you want to make the most of the week.
Course sessions
1. A (brief) history of genetics. This will cover the landmarks and personalities.
2. Basic Mendelian principles. It is important that you have a grasp of some basic ideas underpinning inheritance to help you to understand how we can use changes in our DNA to make predictions about disease
3. The large-scale analysis of genes and genomes. In the late 1980s, scientists could determine the sequence a few hundred bases a day, or study how the expression of a single gene varied under different conditions (for example in health versus disease states). Technological innovation driven by the Human Genome Project means that an entire genome can now be sequenced in a few days (for a few hundred pounds) and the activation status of every gene in a cell or tissue can be profiled in an afternoon.
4. Human variation. Any two unrelated individual will differ in 5 million regions in their DNA (most of which will have no effect). We will investigate the kinds of variation that provide the plasticity upon which natural selection acts. We will consider how we are able to filter clinically-relevant data from the background noise.
5. On the last day we’ll focus on the “needle in haystack” challenge of finding genetic changes that can inform prediction, diagnosis and management of disease.
Learning outcomes
You are expected to gain from this series of classroom sessions a greater understanding of the subject and of the core issues and arguments central to the course.
The learning outcomes for this course are:
• explain autosomal dominant, autosomal recessive and sex-linked patterns of inheritance
• demonstrate understanding of the “big ideas” in genetics that have developed over the last
120 years or so
• identify clinically-relevant variants in examples of whole-genome sequencing data
