Characterizing the physical genome

Abstract

We live in an age in which whole-genome sequences are com- monplace on our hard drives and on other storage media and servers throughout the Internet. It is easy to think of a genome in purely digital terms, that is, as an abstract string of four nucleotides whose secrets can be uncovered largely through the use of software algorithms. But in the nucleus of a cell, the genome has a larger meaning it is a discrete physical entity, organized into chromosomes comprising genomic DNA bound to proteins in a systematic way. This structure is dynamic and participates in many different fundamental processes such as transcription, DNA replication and repair, recombination and chromosome segregation. Genomic DNA may be modified specifically by processes such as methylation, and these modifica- tions can further define functional features of the genome. The genome can be unstable, and this instability underlies the devel- opment of genetic lesions that can lead to cancer. How do transcription factors, DNA modifications and chro- matin structure function in concert to specify the expression of genomic information? How does the genome undergo replica- tion and recombination? How do amplifications and deletions of genomic DNA contribute to different pathological states of cells? Knowing the details of several aspects of genomic structure is clearly important for understanding the functional behavior of the genome. The phenomenal popularity of DNA microarrays has been fueled by their ability to determine global gene expres- sion profiles of RNA. Recently, however, exciting new approaches using DNA microarrays are beginning to provide us with high-resolution views of the physical genome and to clarify how it participates in diverse cellular phenomena. Here we review the use of DNA microarrays in determining the binding- distribution of proteins on the genome, in mapping chemical modifications to chromatin and DNA, in studying DNA replica- tion and repair, and in determining differences in DNA copy number by comparative genomic hybridization to microarrays (array CGH). We also discuss how these and other applications of DNA microarrays may further our understanding of genome dynamics in the future.