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Source: S. T. Cole et al., Massive gene decay in the leprosy bacillus, Nature 409 (2001), p. 1007.

The reduced DNA content, fewer functional genes, and the large number of pseudogenes suggest that, evolutionar-ily, the genome of M. leprae has undergone massive decay through time, losing DNA and acquiring mutations that have inactivated many of its genes. Furthermore, the genome of M. leprae has undergone extensive rearrangement; comparison with the genome of M. tuberculosis has identified at least 65 gene segments that are arranged in different order and distribution.

The mechanisms responsible for gene decay and genomic rearrangement in M. leprae are not known, although the loss of proofreading ability in the bacterium's DNA polymerase III (the enzyme responsible for most bacterial DNA replication, see Chapter 12) may contribute to a high rate of mutation and the large number of pseudogenes. Because the leprosy bacterium resides in a highly specialized habitat (human nerve cells), it may have lost the need for many enzymatic functions found in other bacteria. When a function is no longer required for survival, genes encoding that function usually accumulate mutations and deletions.

Regardless of the mechanism for gene inactivation and loss, this genomic decay helps explain some of the bacterium's unique properties. Genes for many metabolic enzymes and structural proteins have been lost, which may explain why the bacterium cannot be cultured on synthetic media containing traditional carbon sources; it may also account for the bacterium's slow growth, with a doubling time of 14 days, compared with a doubling time of 20 minutes for E. coli.

A comparison of M. leprae's genome with those of other related bacteria has identified a few unique genes that may contribute to its pathogenesis. The study of these genes has opened the door to an improved understanding of leprosy, better diagnostic tests, and the development of new drugs for the disease.

The information gleaned from sequencing the genome of M. leprae illustrates the power of genomics, which is the focus of this chapter. Genomics is the field of genetics that attempts to understand the content, organization, function, and evolution of genetic information contained in whole genomes. Genomics consists of two complementary fields: structural genomics and functional genomics. Structural genomics determines the organization and sequence of the genetic information contained within a genome, and functional genomics characterizes the function of sequences elucidated by structural genomics. A third area, comparative genomics, compares the gene content, function, and organization of genomes of different organisms.

The field of genomics is at the cutting edge of modern biology; information resulting from research in this field has made significant contributions to human health, agriculture, and numerous other areas. It has also provided gene sequences necessary for producing medically important proteins through recombinant DNA technology. Comparisons of genome sequences from different organisms are leading to a better understanding of evolution and the history of life.

We begin this chapter by examining genetic and physical maps and methods for sequencing entire genomes. Next, we explore functional genomics—how genes are identified in genomic sequences and how their functions are defined. Some of the genomes that have been sequenced are then examined in detail. We end the chapter by briefly considering the future of genomics.

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