Doctors can now sequence a patient’s entire DNA, but they often cannot tell which of the thousands of genetic typos they find actually cause disease. This project aims to solve that problem for inherited adult neurological disorders by building a detailed map of which genes are switched on in specific regions and cell types of the human brain. The core challenge is that most DNA mutations are harmless, and the brain is extraordinarily complex. Without knowing which genes are normally active in a given brain cell, a doctor cannot judge whether a mutation in that gene matters. This researcher will measure gene expression in 12 brain regions from donated tissue and in lab-grown brain cells made from patients’ skin cells, using a technique called RNA-seq that captures all the RNA a cell is making at once. If successful, the work will create a public reference map that doctors can use to interpret a patient’s genome and reach a diagnosis for rare neurological diseases. It could also reveal which genes are disrupted in common conditions, pointing toward new drug targets. The project is primarily fundamental science—building a basic understanding of gene regulation in the human brain—but that understanding is a prerequisite for turning genome sequencing into a reliable diagnostic tool.
View original technical description
We all inherit an instruction manual for making the human body and this is encoded in our DNA. Unfortunately, spelling mistakes or mutations in our DNA can increase our risk or even directly cause certain disorders including disorders, which mainly affect the brain and nervous system in adults. Recognising the mutations that cause these disease can be difficult. This is because we all carry many mutations within our DNA most of which are probably harmless and because the brain is a very complicated organ. However, it is important that doctors and researchers find ways of assessing the importance of specific mutations so that we can improve the way in which we diagnose people with rare inherited neurological diseases and so that we can find new ways to treat these conditions. This is particularly important now that more people are being offered testing to look for mutations in their DNA and that technological advances mean that we can potentially test all of a patient's DNA (not just a small part). One way to try and decide whether mutations in the DNA are contributing to neurological diseases is by understanding more about which parts of the DNA are expressed in the human brain and the impact that changes in the DNA have on the expression of particular genes (the basic building blocks of the DNA) in the brain. In order to check this, researchers need to make measurements about the genetic variation an individual carries and link this information to the genes they express in their brain cells. Although making these types of measurements in the brain is very difficult, it is possible and this is the aim of this project. One of the challenges is accurately measuring the amount of each of the genes expressed in specific parts of the brain and even in the specific types of cells in the brain. I will try and overcome this challenge in two ways. Firstly, I will study gene expression data from 12 different regions of the human brain and central nervous system taken from people who have donated their brain to a brain bank. Secondly, I will study cell types found in human brain that have been made in culture. These cells start as a patient's skin cells, but are then converted into induced pluripotent stem cells, a very special kind of cell that can be used to make lots of different types of cells in the human body including brain cells. This project also uses a new technology for measuring all the genes expressed in a single cell type or tissue sample. This technology is called "RNA-seq" or "whole transcriptome sequencing" and it allows researchers to measure all kinds of genes at the same time. It also allows us to measure the relative amounts of alternative versions of the same gene, and to measure these quantities in such a way that the influence of genetic risk factors can be more sensitively detected by directly comparing the relative amounts in individuals who happen to have both a "good" and a "bad" copy of a given genetic variant. In order to make more sensitive measurements about some types of RNA I will also be making measurements from two main parts of the cell, called the nucleus and cytoplasm. By making all these measurements about the way genes are expressed in the human brain and brain cells, I will create a very detailed map of gene expression in the human brain together with a map of how this expression is controlled. Most importantly, I will work with other doctors and researcher and use the detailed map to try and help reach a diagnosis in specific patients. In this way, I will find out whether having detailed information on the expression and regulation of genes in the human brain really does help us to better diagnose and understand inherited brain diseases.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know