Grantee: MRC Human Genetics Unit (Western General Hospital), Edinburgh, United Kingdom
Researcher: Wendy A. Bickmore, Ph.D.
Grant Title: Putting the Genome on the Map
Grant Type: Research Award
Program Area: Centennial Fellowship
Amount: $1,000,000Putting the Genome on the Map
The scale of the human genome is staggering. Our 80,000 genes account for only a small part of the delicate thread of three thousand million bases of sequence that we carry on our chromosomes. Encoded within this part of the sequence are the Instructions for making a complete set of proteins that drive all of the processes in our cells. We have almost no idea about what functions, if any, the rest of the sequence might have. Determining the sequence of the human genome - both that of the genes and that of the non-coding regions - is going to tell us much about our biology. However, there is also a lot that we will not be able to fathom from the sequence of the human genome alone. We need to broaden our horizons when thinking about the map of the human genome and the richness of information that we want it to contain. We need to understand how chromosome environment can perturb gene function every bit as effectively as mutation within gene sequence and how chromosomal elements that maintain the integrity of our genome are so intimately embedded within the way in which sequence is packaged inside of our cells.
The map of the human genome as we understand it today must undergo a Copernican transformation if it is to achieve these goals. The genome is not a linear string of letters but a dynamic and three dimensional complex of DNA with proteins and RNA. It is the cartography skills of the map-maker that we need to equip ourselves with to understand this level of human genome organization. We must use our eyes - aided by the light microscope and fluorescent coloured tags - to examine the spatial and temporal distribution of the DNA and proteins that make up our genomes and to portray this in map form.
Our work has shown that genes are clustered within restricted domains of chromosomes both in man and in other vertebrate animals. We have also seen that different types of chromosome have preferred spatial locations within the nucleus so that our genes can find themselves in different sorts of microenvironment depending on their location in the DNA sequence. We have disrupted the normal chromosome context of specific parts of the genome in a controlled way by stripping away some but not all of the proteins from human chromosomes. On these partially denuded and consequently greatly expanded, chromosomes we have been able to trace the topology of parts of the human DNA sequence for the first time. The geometric tracery of the genome that we have revealed challenges us to investigate how the pattern of interaction of sequence with protein, and the folding path of the sequence with its curves and sharp bends, is integrated with genome function and how this pattern can be copied so that the full spectrum of genetic information is passed from cell to cell and from parent to child.
To understand the significance of different distributions of sequence within the nucleus we have to know what the nucleus is made of. Using a genetic screen, we are taking advantage of the current maps of the human and mouse genome to identify which of our genes code for proteins whose destiny is to become part of the nucleus or even parts of chromosomes themselves. This experiment has suggested that as many as one in ten of our genes fall into this category - a total of 8,000 genes. Clearly, much of the coding capacity of our genome is devoted to coding for proteins that make their way back to the nucleus and participate in forming a complex environment for the genome to operate within.
There is a feeling that the completion of the human genome sequence will somehow strip some of the mystery from mankind - that we will be reduced to a mere list of bases - pages and pages of As, Gs, Cs and Ts. Our growing awareness of the complex organization of the human genome in time and space makes it quite apparent that a linear DNA sequence, regardless of its extraordinary length, will be an inadequate description of the human genome. As our new map-making adventure proceeds we hope to be better placed not only to understand our own genome's biology but also better placed to devise specific artificial chromosome environments in which to deliver genes for the amelioration of genetic disease. In the next millennium we hope that our work and that of many others will put the map of the human genome into a new dimension.