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ABSTRACT

The Morbid Anatomy of the Human Genome is a list of mapped loci for which there is a known clinical association (Fig. 1-1). It is derived from the Synopsis of the Human Gene Map which was published in the 7th edition of MMBID and which is available with Online Mendelian Inheritance in Man (OMIM), a continuously updated catalog of genetic disorders and genes (http://www.ncbi.nlm.nih.gov/omim). The gene map and morbid map are periodically published as part of Mendelian Inheritance in Man (Johns Hopkins University Press, 12th edition, 1998).

INTRODUCTION

Genetics is the study of inheritance, genomics is the study of genomes,1 and mutations, or nucleotide changes, occur at the interface between the two. Mutations are the source of genetic variation and diversity, and by their effect some are pathogenic while others are neutral. By definition, the majority of mutations documented in this eighth edition of The Metabolic and Molecular Bases of Inherited Disease are pathogenic.

As the genome projects enter the final stages of their structural phases, they will yield integrated chromosomal, genetic, and physical maps for the host organisms. In the poststructural era, genomics will continue as “functional genomics”; a new term describing the old domains of, for example, embryology, physiology, biochemistry, and pathology. Meanwhile, structural genomics will benefit from cross-referencing of genes in different species2 and, in this regard, “expression genomics”3 is relevant because it will include systematic analysis and documentation of gene expression in organisms while revealing patterns of host gene expression, in natural and mutant states, and in organs, tissues, and cell types during development and at maturity of the organism. All of this presupposes knowledge of individual genes and the corresponding knowledge bases. Genomes, mutations, and the Internet have come together.4

If a typical human locus contains 100 different alleles—a reasonable estimate based on current information—then the human genome containing an estimated 35,000–120,000 genes or, for the sake of argument, 80,000 genes5 will harbor at least 8 million different alleles. Informatics is necessary to capture, record, and distribute information of this magnitude about variation in the human or any other genome. The HUGO Mutation Database Initiative6 (http://ariel.ucs.unimelb.edu.au:80/~cotton/mdi.htm) is a significant initiative to catalogue, store, and deploy data about genetic variation, primarily human in nature. Mutation databases will thus be essential resources for the era of functional genomics.

ALLELES

The tools for mutation detection,7-9 which include scanning and diagnostic methods, are enhancing the rate of discovery which, in the human genome, already exceeds the ability of the print literature to keep pace. Mutational databases thus serve both as tools for biologic taxonomy and as respositories for essential genetic data. Accordingly, “in silico genetics” is the latest step in the journey of modern human genetics whose milestones, as Victor McKusick has noted, include cytogenetics, somatic cell ...

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