Medical Applications of Mapping and Sequencing the Human Genome (Human Genomics)
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1988-04-27 (April 27, 1988)
McKusick, Victor A.
Original Repository: Alan Mason Chesney Medical Archives. Victor Almon McKusick Collection
Reproduced with permission of Anne B. McKusick.
Medical Subject Headings (MeSH):
Human Genome Project
Medical Genetics, Molecular Biology, and the Human Genome Project, 1980-2008
Memorandum from the United States House of Representatives' Subcommittee on Oversight and Investigations [listing the
witnesses on panels to discuss the Human Genome Project] (April 27, 1988)
Medical Applications of Mapping and Sequencing the Human Genome (Human Genomics)
Victor A. McKusick, M.D.,
University Professor of Medical Genetics
Johns Hopkins University School of Medicine
before Subcommittee on Oversight and Investigations of the
Committee on Energy and Commerce,
Wednesday, April 27, 1988
The title of these hearings was given as "Sequencing and Mapping". I reversed the order because, as indicated by the
report of the NRC/NAS committee, mapping should be done first, and sequencing later, although there will be considerable overlap
of the two efforts, and although further technologic developments should proceed immediately, and even though mapping itself
requires technologic development. The reason for "map now -- sequence later" is twofold: the technology of mapping
is adequate for immediate implementation, e.g., for the saturated RFLP map (although further technologic development is necessary
for the contig map), whereas further technical is necessary for most efficient mass sequencing; and 2, the maps, of both types
just mentioned, will facilitate tremendously the complete sequencing.
See Figure 1: a. The RFLP map. B. The contig map.
Genomics is a relatively new term suggested by Dr. Thomas H. Roderick of the Jackson Laboratory, Bar Harbor, Maine for the
field of mapping and sequencing and related analyses of complex genomes, such as that of the human.
As of this date, approximately 1300 expressed genes have been mapped to specific ones of the human chromosomes and for many
of these genes, indeed most, we have at least some information on the precise regional location. In addition to this, approximately
2500 anonymous (function unknown) DNA segments have been mapped to specific sites on the chromosomes. Approximately a third
of these show variation of a type that makes it possible to use them as RFLPs.
See Appendix I: The Human Gene Map newsletter March 25, 1988.
See Figure 2: The rate of growth of human gene mapping, 1968-1988.
II. The medical applications of genome mapping.
In the last 5 years great excitement has been expressed in both the lay and the professional press over the mapping, one after
another, starting with Huntington disease, of more than a dozen genetic disorders:
Huntington disease -- chromosome 4;
Familial adenomatous polyposis of the colon -- chromosome 5;
Cystic fibrosis -- chromosome 7;
Retinoblastoma -- chromosome 13;
Polycystic kidney disease -- chromosome 16;
von Recklinghausen neurofibromastosis -- chromosome 17;
Myotonic dystrophy -- chromosome 19;
Familial Alzheimer disease -- chromosome 21;
Bilateral acoustic neuroma -- chromosome 22;
Duchenne muscular dystrophy -- X chromosome; and others.
The general enthusiasm that greeted these reports was entirely justified. All of these conditions shared in common the characteristic
that at the time the mapping was achieved, there was no clue as to the nature of the fundamental biochemical defect and therefore
it was impossible to devise a specific diagnostic test for carrier detection, preclinical diagnosis or prenatal diagnosis
and impossible to develop any methods of treatment that would serve to correct or counteract the ill effects of that biochemical
defect. A leading and immediate consequence of the mapping of the disorders listed above and other others is that it permits
the elucidation of the fundamental fault and the devising of specific diagnostic methods.
Demonstration of the basic biochemical fault by going directly to the localization of the genes has been referred to as "reverse
genetics". Usually we start from the clinical abnormality and identify an abnormality in some protein, often an enzyme,
and work back to the gene that encodes that protein or enzyme. In all of the conditions listed above it had been impossible
to identify a specific protein that was abnormal -- as stated earlier, the nature of the fundamental defect was unknown --
but by finding where in the DNA the gene is located, one can by the reverse genetics approach determine the normal function
of that segment of DNA, i.e., the protein for which it codes, and proceed from that point to determine what the gene-determined
derangement in that protein is in the disease and how it exerts its pathological effect. This information is critical to
the development of methods of treatment that can correct or ameliorate the disorder at some step between the mutant gene and
the clinical manifestations of the condition.
The diagnostic value of the mapping information lies in the realm of "DNA diagnosis". In all simply inherited (Mendelian)
disorders such as the ones listed earlier, a specific lesion in the chromosomes, i.e., in the DNA, is causative and the diagnosis
can be made by going directly to the DNA for demonstration of that lesion. This can be used for detecting the carrier status
in a disorder such as cystic fibrosis, muscular dystrophy or hemophilia. It can be used for preclinical (i.e., premorbid)
diagnosis in a condition such as Huntington disease, familial adenomatous polyposis of the colon, or bilateral acoustic neuroma
and it can be used for prenatal diagnosis of any of these conditions. Such diagnosis is, of course, a tremendous aid to genetic
counseling in disorders such as cystic fibrosis and in all of these disorders can permit the early institution of therapy
and measures of secondary prevention in disorders such as adenomatous polyposis of the colon.
Gene diagnosis involves what might be called "diagnostic biopsy of the genome". DNA is obtained, for example, from
the white cells in a sample of blood taken from the arm vein and is subjected to the appropriate studies to determine if
the lesion of this or that genetic disorder is present. The presence of the lesion can be determined either (from study of
the DNA in other family members, does the association with specific closely mapped markers that the abnormal gene is present?).
III. Elucidation and specific diagnosis of cancers -- for more accurate prognosis and more effective prevention and cure.
Work in the last decade, particularly the work related to mapping the human genome, establishes beyond all doubt the chromosome
theory of cancer which was advanced by Theodore Boveri in 1914 and by some others before him. The work has furthermore demonstrated
a high order of specificity for the type of DNA change responsible for a given cancer. This means that all cancers are acquired
genetic disorders, somatic cell genetic disorders.
Classically, disease is divided into three categories according to the role of genetic factors:
1. Single gene disorders which show Mendelian pedigree patterns. Most of these conditions are individually rare, but in the
aggregate, since there are many of them, they represent a substantial body of disease. (It is these disorders that are cataloged
in Mendelian Inheritance in Man.)
2. Multifactorial disorders, i.e., disorders in which multiple environmental and genetic factors collaborate in causation.
Examples are common conditions such as hypertension, mental illness, coronary heart disease, and frequent varieties of congenital
malformations. These are discussed in Section C. inasmuch as these are likely to elucidated greatly by genomic information.
3. Abnormalities of chromosome number and structure as in trisomy of chromosome 21, which leads to Down syndrome.
Although in many ways arbitrary, this classification has usefulness and must now be expanded to include a fourth category
of genetic disease -- somatic cell genetic disease -- of which cancers is the main component. In addition, much autoimmune
disease probably has its basis in somatic cell mutation and some congenital malformation are probably the consequence of localized
somatic cell mutations. A somatic mutation theory of aging has been around for quite some time.
Mapping information of two different types (and a correlation of the two) has been responsible for the establishment of the
somatic basis of cancers: the demonstration of specific visible chromosomal changes in specific neoplasm (translocation, inversions
or deletions) and the mapping of specific oncogenes to the same regions. Deletions are often demonstrable with the molecular
markers even when they are not visible microscopically ("microdeletions"). Specific changes in DNA underlie all malignant
growths, even those that have a demonstrable environmental factor in their induction; for example, small cell cancer of the
lung in cigarette smokers has a consistent change in the short arm of chromosome 3.
The lesion in DNA characteristic of each malignancy and/or stage of malignancy can be used for the specific diagnosis of cancers.
Complete mapping and sequencing of the human genome will accelerate the definition of the abnormality that characterizes each
malignancy. Demonstration of the specific DNA lesions will be the means for diagnosis, replacing the presently used, relatively
crude morphologic changes observed under the microscope. More accurate prognosis and more effective prevention and cure can
be expected from the refinement of diagnosis provided by the study of DNA.
C. Elucidation and detection of susceptibilities to common disorders.
Hypertension mental illness, coronary disease and some congenital malformations such a neural tube defects and cleft palate
are examples of common disorders with a multifactorial basis. Methods for identifying the individual genes involved in these
multifactorial disorders have been for the most part imperfect up to this point; indeed, they have been almost nonexistent.
Complete mapping and sequencing of the human genome can be expected to reveal such genes or to open up the methods by which
they can be identified.
D. The medical applications of genome sequencing
a. There are many types of maps of the human genome. The banded chromosomes represent one type of map. The RFLP map and the
contig map (see Figure 1) are others. The cDNA map, which is a map of expressed genes because the cDNAs which are mapped are
prepared from mRNAs, is another useful form of map. But the nucleotype sequence of the human genome is the ultimate map. Complete
sequencing will be necessary to identify all the genes. Of the estimated 50,000 to 100,000 genes of man, only about 4400 are
now identified, and the existence of many of these has only indirectly been deduced (see Figure 3). The sequence of the individual
genes and of the DNA that separates them, i.e., the complete sequence of the human genome, will be the basis for the definition
of the precise derangement in each clinical disorders, a requirement for diagnosis and treatment. Although about 3,000 separate
Mendelian disorders are identified on the basis of clinical and family studies, for less than 400 of these disorders is the
gene that is defective known and for only a few dozen of these is the precise defect in the gene known. (See Appendix II for
a listing of known molecular defects in Mendelian disorders.)
IV. Concluding comments
From the advances of the last few years, the usefulness of gene mapping and the sequencing to clinical medicine has been extensively
demonstrated even though the surface has scarcely been scratched. The applications already in hand adumbrate tremendous usefulness
of the complete map and sequence. The complete map and sequence would be an invaluable tool to medicine and biology for many
years to come.
See Appendix III for a reprint of the series of 4 articles which were published in MEDICINE (January 1986, January 1987, July
1987, January 1988) entitled "The Morbid Anatomy of the Human Genome: a review of gene mapping and clinical medicine".
Medical historians tell us that the anatomical treatise of Vesalius, published in 1543, had a powerful influence on the development
of medicine. It turned physicians from fruitless speculation to a empiricism. It gave the profession of medicine a body of
basic knowledge that was uniquely its own. It provided the basis for Harvey's physiology (1628) and Morgagni's morbid
The map and sequence of the human genome are the new human anatomy. They provide a neo-Vesalian basis for medicine in the