The Anatomy of the Human Genome
A Neo-Vesalian Basis for Medicine in the 21st Century
Victor A. McKusick, MD genes on our chromosomes is part of our microanatomy. When we speak of mapping genes on chromosomes, we use a cartographic metaphor. An equally appropriate anatomic metaphor is the anatomy of the human genome.1-3 Clinical cytogenetics (starting in the late1950s), mapping genes on chromosomes (beginning for autosomes in the late 1960s), and comprehensive DNA sequencing of the genome (initiated in the late 1980s) have provided, in the words of Charles Scriver, MDCM (oral communication, 1982), a neo-Vesalian basis for medicine. The influence on medicine is fully as great as was that of Andreas Vesalius’ de corporis humani Fabrica, which was published in1543 and was the basis of Harvey’s physiology of the circulation (1628) and Morgagni’s morbid anatomy (1761). The history of medical genetics4 can be discussed in 2 parts, the pre-1956 foundations of medical genetics going back to Mendel and the greats of the first half of the 20th century, and the developments in the period since 1956, during which medical genetics has evolved into a full-fledgedclinical and academic field. The objective of this article is to trace the influence of chromosome studies, gene mapping, and DNA sequencing (the Human Genome Project [HGP]) on the evolution of medical genetics since 1956.
Clinical Cytogenetics (Chromosomology)
HE LINEAR ARRANGEMENT OF
Since 1956, the anatomy of the human genome has been described on the basis of chromosome studies, genemapping, and DNA sequencing. The gross anatomy of Andreas Vesalius, published in 1543, played a leading role in the development of modern medicine. The objective of this article is to show that knowledge of genomic anatomy is having a comparably strong and pervasive influence on all of medicine. The research revealing human genome anatomy is reviewed. The insight provided by genome anatomy hasbrought about shifts of focus, both in research and in the clinic, eg, from genomics to proteomic and from the individually rare, single-gene disorders to common disorders. Genomic anatomy permits medicine to become more predictive and preventive. At the same time, diagnosis and treatment are rendered more sensitive, specific, effective, and safe. Hazards in misuse and misunderstanding of theinformation exist. Education of both the public and health professionals is vital if the full benefits of neo-Vesalian medicine are to be realized.
JAMA. 2001;286:2289-2295 www.jama.com
1956 was a watershed year in the history of medical genetics. In that year, the
correct diploid chromosome number of 46 (not 48, as previously thought) was established.5,6 It is remarkable that it was not until 3years after the determination of the double-helical structure of DNA by Watson and Crick7 that the correct number of chromosomes in humans was determined. The advance was significant to medicine, not because of the specific numerology but because of the associated simple improvements in technique that made chromosome analysis feasible in the study of disease and in clinical diagnosis. Medicalgenetics, which really did not exist as a clinical specialty before 1956, was given its own organ, the nucleus, just as cardiology had the heart, neurology the nervous system, etc. Not only was the correct chromosome number established with the improved techniques, but also, in 1959, Jerome Lejeune found the additional small chromosome underlying
mongolism (mercifully renamed Down syndrome)8 andothers described the numerical abnormalities of the sex chromosomes in the Turner and Klinefelter syndromes that same year. In the early 1960s, abnormalities in chromosome number and structure were described in other congenital malformation syndromes, such as trisomies 13 and 18, and in a variety of translocations, deficiencies, mosaics, and, in spontaneously aborted tissue, triploidy. The finding...