SPECIAL COMMUNICATION
The Anatomy of the Human Genome
A Neo-Vesalian Basis for Medicine in the 21st Century
Victor A. McKusick, MD
T
HE LINEAR ARRANGEMENT OF
genes on our chromosomes is
part of our microanatomy.
When we speak of mapping
genes on chromosomes, we use a carto-
graphic metaphor. An equally appropri-
ate anatomic metaphor is the anatomy
of the human genome.1-3 Clinical cyto-
genetics (starting in the late 1950s), map-
ping genes on chromosomes (begin-
ning 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 medi-
cine. The influence on medicine is fully
as great as was that of Andreas Vesalius’
de corporis humani Fabrica, which was
published in 1543 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-fledged clinical and
academic field. The objective of this ar-
ticle is to trace the influence of chro-
mosome studies, gene mapping, and
DNA sequencing (the Human Ge-
nome Project [HGP]) on the evolu-
tion of medical genetics since 1956.
Clinical Cytogenetics
(Chromosomology)
1956 was a watershed year in the his-
tory of medical genetics. In that year, the
©2001 American Medical Association. All rights reserved.
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Since 1956, the anatomy of the human genome has been described on the
basis of chromosome studies, gene mapping, 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 per-
vasive influence on all of medicine. The research revealing human genome
anatomy is reviewed. The insight provided by genome anatomy has brought
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 com-
mon disorders. Genomic anatomy permits medicine to become more pre-
dictive and preventive. At the same time, diagnosis and treatment are ren-
dered more sensitive, specific, effective, and safe. Hazards in misuse and
misunderstanding of the information 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
correct diploid chromosome number of mongolism (mercifully renamed
46 (not 48, as previously thought) was Down syndrome)8 and others
established.5,6 It is remarkable that it was described the numerical abnormalities
not until 3 years after the determina- of the sex chromosomes in the Turner
tion of the double-helical structure of and Klinefelter syndromes that same
DNA by Watson and Crick7 that the cor- year. In the early 1960s, abnormalities
rect number of chromosomes in hu- in chromosome number and structure
mans was determined. The advance was were described in other congenital
significant to medicine, not because of malformation syndromes, such as tri-
the specific numerology but because of somies 13 and 18, and in a variety of
the associated simple improvements in translocations, deficiencies, mosaics,
technique that made chromosome analy- and, in spontaneously aborted tissue,
sis feasible in the study of disease and triploidy. The finding of a rather
in clinical diagnosis. Medical genetics, consistent chromosomal change in
which really did not exist as a clinical
Author Affiliation: McKusick-Nathans Institute of Ge-
specialty before 1956, was given its own netic Medicine, Johns Hopkins University School of
organ, the nucleus, just as cardiology had Medicine, Baltimore, Md.
the heart, neurology the nervous sys- Disclosure: Dr McKusick was a member of the Pro-
gram Advisory Committee for the National Institutes
tem, etc. of Health Human Genome Project 1989-1992 and is
Not only was the correct chromo- a member of the Scientific Advisory Board of Celera
Genomics Inc.
some number established with the Corresponding Author and Reprints: Victor A. McKu-
improved techniques, but also, in sick, MD, McKusick-Nathans Institute of Genetic Medi-
cine, Johns Hopkins Hospital, 600 N Wolfe St, Blalock
1959, Jerome Lejeune found the addi- Bldg, Room 1007, Baltimore, MD 21287-4922 (e-mail:
tional small chromosome underlying mckusick@peas.welch.jhu.edu).
(Reprinted) JAMA, November 14, 2001—Vol 286, No. 18 2289
THE ANATOMY OF THE HUMAN GENOME
cell division when they are extended,
Figure 1. Progress in Mapping of Genes to
Specific Chromosomes Through the Early banding methods made it possible to rec-
Stages of the Human Genome Project ognize small deletions and to interpret
chromosomal rearrangements. Corre-
2500
X-Chromosomal
lation of the specifically interpreted
Autosomal karyotype with phenotype led to the de-
2000 scription of new microdeletion syn-
No. of Genes Mapped
dromes, such as Williams syndrome (on-
1500 line Mendelian Inheritance in Man
[OMIM] 104050), and the related con-
1000 cept (and designation) of contiguous
gene syndromes, eg, DiGeorge syn-
500
drome (OMIM 188400). 12 Further-
more, it allowed the large area of hema-
tologic malignancies that result from
0
68 70 72 74 76 78 80 82 84 86 88 90 reciprocal translocations with creation
19 19 19 19 19 19 19 19 19 19 19 19
Year
of fusion genes to be studied. The Phila-
delphia chromosome was the first of
these; the total number of examples is
chronic myeloid leukemia9 in 1960 now more than 100.13
provided an early confirmation of In the last 20 years, molecular cyto-
Theodor Boveri’s chromosome theory genetics, “chromosome painting,” and
of cancer.10 Named for the city of resi- in situ hybridization for identification
dence of its discoverers and patients of deletions and rearrangements are
following the practice of naming only some of the methods used for char-
hemoglobin variants, the Philadelphia acterizing the karyotype in clinical ap-
chromosome (Ph1) was thought to plications.
represent a partially deleted chromo-
some 21. By improved chromosome Gene Mapping
staining techniques, it was shown in The first gene to be mapped to a spe-
1973 that chromosome 22, not 21, is cific chromosome in any species was
involved and that the change that probably the one for colorblindness. In
causes the abnormally short Ph1 chro- 1911, cytologist E. B. Wilson14 con-
mosome is not a deletion but rather a cluded that the characteristic pedigree
reciprocal translocation between chro- pattern of this trait, described by Pliny
mosomes 9 and 22.11 Earle in Philadelphia, Pa, in 184515 and
The ability to study the chromo- by Friedrich Horner in Zurich, Swit-
somes in cultured cells in the amni- zerland, in 1876, was explained if the
otic fluid inaugurated the field of pre- trait is recessive, the gene is on the X
natal diagnosis of Down syndrome and chromosome, and humans have a fe-
other chromosomal aberrations by am- male-XX/male-XY sex chromosome
niocentesis beginning about 1966. The constitution. In the following de-
characterization in cultured cells of en- cades, a host of disorders were de-
zyme deficiencies in inborn errors of duced to be X-linked from the charac-
metabolism had also progressed to the teristic pedigree pattern, so that by
point that many of these could like- publication of the second edition of
wise be diagnosed prenatally by study Mendelian Inheritance in Man in 1968,12
of amniotic fluid cells. the catalog of X-linked phenotypes had
About 1970, various staining meth- 68 asterisked (seemingly confirmed)
ods were developed that showed band- entries, each presumably related to a dif-
ing of chromosomes. The distinctive pat- ferent gene. The precise localization on
tern of this banding permitted unique the X chromosome of these genes was
identification of each chromosome. not known; the first regional mapping
When combined with methods for was for the linked genes for colorblind-
studying the chromosomes at a stage of ness and G6PD deficiency,16 shown to
2290 JAMA, November 14, 2001—Vol 286, No. 18 (Reprinted) ©2001 American Medical Association. All rights reserved.
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be on the distal end of the long arm of
the X in 1973.17
It was not until 1968, when 68 loci
were already known to be on the X
chromosome, that a gene was mapped
to a specific autosome, ie, the Duffy
blood group gene to chromosome 1.18
This was achieved by Roger Donahue,
then a Johns Hopkins University PhD
candidate in human genetics, through
a linkage study of a chromosome 1 het-
eromorphism (one chromosome 1 was
unusually long and appeared in the pre-
banding karyotypes to have an un-
coiled region near the centromere) that
he had found in his own family.
Progress in gene mapping is shown
in FIGURE 1. The largest part of the
progress in the 1970s19 was through
study of interspecies somatic cell hy-
brids, particularly cells produced by fus-
ing human and mouse cells.20 In cells
derived by cell division from such hy-
brid cells, the full set of mouse chro-
mosomes are retained, whereas indi-
vidual human chromosomes are lost
more or less at random. The presence
or absence of a particular human cell
trait could be correlated with the pres-
ence or absence of a particular human
chromosome in the derivative cells to
determine that the gene for that trait
was located on that chromosome. An
early example (in 1971) was mapping
of the gene that encodes the enzyme
thymidine kinase to chromosome 17.21
Molecular genetics came to gene
mapping about 1980 and contributed
to the field in 3 ways: (1) It provided
DNA probes for analysis of somatic cell
hybrids so that one could “go directly
for the gene” and not require expres-
sion of the human gene in the hybrid
cell. (2) It provided DNA probes (at first
radioactive, later fluorescent) for in situ
hybridization to chromosomes. This di-
rect method for direct mapping was first
made to work reliably for single-copy
genes in 1981. 22 (3) Most impor-
tantly, molecular genetics provided an
abundance of DNA markers that could
be used for family linkage studies.23 Pre-
viously, such studies were seriously
hampered by the pitifully small hand-
ful of available marker traits, ie, a few

blood groups and serum or red blood
cell proteins in which allelic variation
could be demonstrated by immuno-
logic, electrophoretic, or other meth-
ods. The abundant DNA markers first
included restriction fragment length
polymorphisms, followed by variable
number tandem repeats, microsatel-
lites or short tandem repeats, and, most
recently, single-nucleotide polymor-
phisms.
By 1985 when the HGP, as an initia-
tive to sequence completely the DNA of
the human genome, was first formally
proposed, about 700 genes had been
mapped to specific chromosomes and,
for many of these genes, to specific re-
gions of chromosomes. The genes
mapped included those for blood groups,
enzymes, clotting factors, structural pro-
teins, and so on. Importantly, they also
included the genes mutated in mystery
diseases, so termed because at the time
of mapping the nature of the basic de-
fect was unknown. The usefulness of
gene mapping to clinical medicine3 was
particularly evident in connection with
these disorders. It was the availability of
an abundance of DNA markers for fam-
ily linkage studies that advanced clini-
cal application of gene mapping.
The first mystery disease to be mapped
through linkage to DNA markers was
Huntington disease in 1983, located on
the end of the short arm of chromo-
some 4.24 The clinical applicability of the
information was immediately evident. By
the linkage principle, one could now
make diagnoses prenatally and premor-
bidly, provided that DNA of relatives
was available for testing and DNA mark-
ers near the gene were found to be
appropriately heterozygous in specific
individuals. Considerable experience
with the psychosocial problems sur-
rounding predictive DNA testing then
followed.
The other useful application of gene
mapping was for disease gene discov-
ery through positional cloning.25 The
procedure used was to identify mark-
ers (ideally flanking markers) linked to
the disease locus to search the region
for genes and to scrutinize those genes
for a mutation that cosegregates in the
©2001 American Medical Association. All rights reserved.
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THE ANATOMY OF THE HUMAN GENOME
family with the Mendelian disorder.
Sometimes the gene for an enzyme or
other protein had already been mapped
to the region and, thus, was a candi-
date gene; in other cases, a previously
unknown gene was found strictly by its
location in the chromosomal region
identified by linkage mapping of the ge-
netic disorder.
It took 10 years for the gene mutant
in Huntington disease to be isolated by
positional cloning, which occurred in
1993.26 This was partly because of ge-
netic peculiarities of that region of 4p
(ie, many genes and a relatively high rate
of recombination) and particularly be-
cause it was a new type of mutation, an
expanded trinucleotide repeat.
The first 4 successes with positional
cloning were chronic granulomatous
disease27 and Duchenne muscular dys-
trophy28 in 1986 and retinoblastoma
and cystic fibrosis29 in 1989. Cystic fi-
brosis was the first to be elucidated by
positional cloning without the assis-
tance of a cytogenetically visible dele-
tion. In the decade that followed, map-
based gene discovery became a leading
paradigm in biomedical research. All
specialties of medicine used it to study
some of their most puzzling disor-
ders. Once the disease gene and its
mutations were identified, specific
DNA-based diagnostic tests could be de-
signed. Furthermore, scientists were in
a better position to determine patho-
genetic mechanisms, the steps be-
tween gene and phene, ie, between
genotype and phenotype. That infor-
mation can often help investigators de-
vise methods of intervention for treat-
ment or secondary prevention.
The Ultimate Anatomy:
The Sequence of
the Human Genome
As noted earlier, a considerable num-
ber of genes had been mapped before
the HGP was formally proposed. Fur-
thermore, positional cloning for isola-
tion of disease genes had been con-
ceived, and proof of principle had been
provided in 1986.
DNA was discovered in the 19th cen-
tury. That the genetic material is DNA
(Reprinted) JAMA, November 14, 2001—Vol 286, No. 18
was first shown by Avery, McLeod, and
McCarty in 1944 in pneumococcus.30
They found that the so-called transform-
ing factor, which converted one pneu-
mococcus form to another, is DNA.
In 1953, Watson and Crick 7 de-
duced the double-helical structure of
DNA from x-ray diffraction data. The
genetic code of nucleotide triplets, each
specifying a particular amino acid, was
worked out in final detail in 1966. In
the late 1960s, restriction enzymes,
which cut DNA at specific sites and,
thus, could be used as scalpels for the
dissection of the genome, were discov-
ered. In the early 1970s, it was found
that genes (including those of hu-
mans) could be cloned in abundance
by splicing DNA into a bacterial plas-
mid31 and growing the bacteria—the so-
called recombinant DNA technology.
In 1977, improved methods of DNA
sequencing were reported by Maxam
and Gilbert32 and by Sanger et al.33 Re-
markably, the dideoxy method of
Sanger et al remains the technologic
cornerstone of the HGP; the method has
been modified extensively with re-
spect to automation and efficiency but
remains fundamentally the same.
The circular bacteriumlike chromo-
some of the cytoplasmic organelle, the
mitochondrion, was completely se-
quenced, all 16 569 nucleotides, by
Sanger’s group in 1981.34 Thus, some in-
vestigators were emboldened to pro-
pose sequencing the entire nuclear ge-
nome. An early proposal for complete
sequencing, ie, the HGP, came from the
US Department of Energy, which had re-
sponsibilities in the area of the muta-
tional effects of radiation. Importance in
the solution of problems of cancer was
cited by Renato Dulbecco35 as the main
reason to undertake the HGP. Indeed,
genomics has had perhaps its greatest
impact on cancer. Usefulness to the un-
derstanding of birth defects of map-
ping all the genes had been proposed ear-
lier.36 In the 1920s, Haldane pointed out
the usefulness of linkage in diagnosis,
and in his “Croonian Lecture” in 1948
he wrote that the “final aim . . . should
be the enumeration and location of all
the genes found in normal human
2291
THE ANATOMY OF THE HUMAN GENOME
beings.”37 The complete sequence was
needed for finding all the genes.
The HGP was discussed, debated, and
planned between 1985 and 1990 and
had its official start in the United States
on October 1, 1990.38 A National Re-
search Council/National Academy of
Science (NRC/NAS) committee39 on
mapping and sequencing the human ge-
nome was commissioned in late 1986
and reporting in February 1988 sug-
gested that complete mapping and se-
quencing could be achieved in 10 to 15
years at a cost, in add-on funding, of
about $200 million per year. In retro-
spect, this seems in some ways like a
remarkably rash conclusion. Polymer-
ase chain reaction was announced at a
Cold Spring Harbor, NY, meeting in
1986,40 where the status of the gene map
of Homo sapiens was reviewed41 and the
HGP was discussed actively in a rump
session. Yeast artificial chromosomes
were invented in 1987, and bacterial ar-
tificial chromosomes and plasmid ar-
tificial chromosomes were introduced
as other mechanisms for cloning large
DNA segments later. The most poly-
morphic and, therefore, useful link-
age markers, the microsatellites, were
discovered in 1989 and the early 1990s.
In the end, however, the estimates
proved not far off.
The NRC/NAS committee recom-
mended “map first, sequence later”39 be-
cause the sequencing technology was not
yet at an efficient and economical level
and because the maps, both genetic (eg,
of microsatellite markers42) and physi-
cal (eg, of yeast artificial chromosome
clones43), would be useful to the final se-
quencing. Thus, the HGP of the Na-
tional Institutes of Health adopted a
top-down approach when it was initi-
ated October 1, 1990. James D. Wat-
son, PhD, was the first director; he was
succeeded by Francis S. Collins, MD,
PhD, in 1993. The sequencing was
performed clone by clone after the
construction of genetic and physical
maps. Another recommendation of the
NRC/NAS committee was that model or-
ganisms be studied in parallel with the
human.39 Some of the most interesting
and contributory parts of the HGP are
2292 JAMA, November 14, 2001—Vol 286, No. 18 (Reprinted)
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the nonhuman genome projects, ie,
those involving model organisms. Com-
parative genomics is a valuable way to
gain understanding of the structure and
function of the human genome and its
genes.
Expressed sequence tags (ESTs), that
is, complementary DNA created from
messenger RNA by reverse transcrip-
tion, were developed in 199144 as a short-
cut to the coding part of the human ge-
nome. Large EST databases for humans
and many other species have been valu-
able to comparative genomics.
The first free-living organism in which
the genome was completely sequenced
was the bacterium Haemophilus influen-
zae, with 1830137 nucleotides and about
1800 protein-coding genes. This se-
quence was determined by the group of
J. Craig Venter, PhD,45 using a bot-
tom-up approach. The DNA of the cir-
cular bacterial chromosome was bro-
ken into segments by shearing, the
segments were cloned and sequenced at
random, and the individual sequences
were then assembled through recogni-
tion of identity at overlapping ends.
Thereafter, the genomes of a consider-
able number of other microorganisms
were sequenced by the same approach,
including Helicobacter pylori, Mycobac-
terium tuberculosis, and Treponema pal-
lidum. In 1996, baker’s yeast (Saccharo-
myces cerevisiae) was the first nucleated
(eukaryotic) organism to be com-
pletely sequenced.46 The nematode Cae-
norhabditis elegans was the first multi-
cellular organism to be completely
sequenced, in 199847,48 and the com-
plete sequence of the geneticists’ pet, Dro-
sophila melanogaster, was reported in
March 2000. 49 The first 2 were se-
quenced clone by clone and the third by
a combination of the clone-by-clone and
random (“shotgun”) methods.
Following the success with random
sequencing of clones, with subse-
quent assembly, in microorganisms,
Venter and colleagues undertook the
same in humans. They established a pri-
vate company (Celera Genomics Inc)
to work on a factory scale: DNA and
clone preparation, sequencing, and as-
sembly, all assisted by automation and
©2001 American Medical Association. All rights reserved.
computerization. The approach was
validated by the sequencing of Dro-
sophila. The genomes of 5 specific hu-
mans representing 4 different ethnic
backgrounds and both sexes were se-
quenced by Celera. 50 The publicly
funded HGP rose to the competitive
challenge and accelerated its sequenc-
ing, with a coordination of efforts in sev-
eral laboratories in the United States,
United Kingdom, Japan, France, Ger-
many, and elsewhere, under the lead-
ership of Francis Collins.51
The data generated by the publicly
funded HGP are available in public da-
tabases free of charge. The sequence
data generated by Celera collated with
the publicly available data and with an-
notation as well as computer-based
methods of analysis, are available to aca-
demic researchers by subscription and
to pharmaceutical and other nonaca-
demic laboratories at a substantially
higher subscription rate.
At the White House on June 26, 2000,
Collins and Venter announced comple-
tion of initial public and private drafts
of the human sequence. These were
published in mid-February 2001—
the publicly funded results from labo-
ratories in the United States, United
Kingdom, and elsewhere in Nature51
and the results of Celera in Science.50
In each journal, accompanying ar-
ticles described some of the implica-
tions of the new information.
When the complete human genome
sequence was available, the total num-
ber of genes was only about half the
number previously estimated52 and little
more than twice the number in a much
simpler organism such as C elegans. The
increased complexity of the human, as
compared with the worm, for ex-
ample, is achieved by increasing the
number of different proteins encoded
by single genes, through alternative
splicing of messenger RNA, posttran-
scriptional and posttranslational modi-
fications, formation of heteromeric
proteins (ie, proteins combining the
products of 2 or more different genes),
and so on. The estimated 30 000 to
40 000 genes encode more than 10
times that number of proteins. This has
 THE ANATOMY OF THE HUMAN GENOME

resulted in a partial shift of focus from
the gene to proteins and from genom-
ics to proteomics.53-55
Another interesting but not new find-
ing in the sequences published in Feb-
ruary 200150,51 is the nonuniform den-
sity of genes within chromosomes
(genes tend to be concentrated at the
ends of chromosome arms) and be-
archival advantage and that of accessi-
Figure 2. Growth of Mendelian Inheritance
bility in a nonelectronic setting, as well in Man: A Catalog of Human Genes and
as ease of browsing. Genetic Disorders (MIM)12 and Its Online
Throughout its history, MIM (and Version (OMIM)
OMIM) has attempted comprehensive 14 000
cataloging of gene mapping, especially 13 083
OMIM
13 000
any gene related to disease, and com- October 21, 2001
12 000
prehensive cataloging of specific disease-
related mutations. The number of genes 11 000

tween chromosomes. Chromosomes 19 with 1 or more disease-related muta- 10 000

No. of MIM Entries

and 22 are particularly gene-rich and tions passed the 1000 mark about Janu- 9000

chromosomes 13, 18, and 21 are rela- ary 1, 2001.56 FIGURE 3A indicates the 8000
MIM12

tively gene-poor. Related to the latter pace of disease-related gene identifica- 7000
MIM11
observation may be the fact that chro- tion during the last 20 years.53 Figure 3B 6000
MIM10
mosomes 13, 18, and 21 are involved indicates the pace at which specific ge-
5000 MIM9
in the only autosomal trisomies that are netic disorders have been character- MIM8
4000
compatible with live birth. Before ized at the DNA level.53 The total num- MIM7
MIM6
3000
completion of the HGP, the informa- ber of characterized disorders (more MIM5
MIM4
MIM Editions
tion on variation in gene density was than 1600) exceeds the number of dis- 2000 MIM3
MIM2 OMIM
already known on the basis of num- ease-related genes (more than 1200) be- 1000 MIM1

bers of genes mapped and indirectly on
the basis of GC vs AT content; high GC
correlates with high gene count. None-
theless, precise confirmation by the
HGP was useful.
The Morbid Anatomy
of the Human Genome:
How Far Have We Come?
The anatomic metaphor is useful be-
cause it extends to the comparative
anatomy and evolution of the human
genome, as well as to its functional
anatomy, developmental anatomy, and,
particularly in the medical context, to
its morbid anatomy.2
Progress in the last 40 years in de-
fining the morbid anatomy of the hu-
man genome is chronicled in MIM, a
catalog of human genes and genetic dis-
orders (FIGURE 2).12 Computerized
since 1964, MIM was a pioneer in com-
puter-based publication (eg, the first
edition in 1966) and has been avail-
able online as OMIM since 1987. The
periodic print editions, most recently
the 12th, published in 3 volumes in
1998, represent serial cross-sections of
the field of genetic medicine in the last
35 years. OMIM has the advantage of
daily updating, ease of searching, and
ease of linking to related sources of in-
formation, such as that on DNA and
protein structure and that on the re-
lated biomedical literature; MIM has the
©2001 American Medical Association. All rights reserved.
cause many such genes are the site of
mutations causing more than one dis-
tinct disorder, eg, the ␤-globin gene,
which is the site of mutations causing
sickle cell disease, thalassemia, Heinz
body hemolytic anemia, methemoglo-
binemia, erythremia, and so on. In part,
the excess of distinct, molecularly de-
fined disorders over the number of genes
involved is a corollary of the “one gene,
many proteins” phenomenon sup-
ported by the unexpectedly low total
gene counts from analysis of the hu-
man genome sequence.
The counts in Figure 3 include both
germline (heritable) and somatic mu-
tations. They do not include about 100
disease-related genes first identified as
translocation-fusion partners in leuke-
mias and some solid tumors. The counts
do include some genes in which spe-
cific susceptibility or resistance alleles
have been identified through associa-
tion studies.
Where Do We Go From Here?
Clearly, there is much we don’t know,
as reflected in the quotes:
As the radius of knowledge gets longer, the
circumference of the unknown expands
even more.
—Anonymous
How is it that we know so little, given that
we have so much information?
—Noam Chomsky
(Reprinted) JAMA, November 14, 2001—Vol 286, No. 18
1965 1975 1985 1995 2005
Year
Each entry is an essay on a particular phenotype (usu-
ally a disorder) or gene, with extensive bibliographic
references and, in the case of OMIM, links to many
other sources of information.
We may soon have a complete catalog
of the genes, but we do not know all of
the protein products of all of those
genes or the function of all of those pro-
teins, or even a majority of them, in iso-
lation, let alone in concert with oth-
ers. We do not know the worldwide
variation in the genes. We do not know
the correlation between structural varia-
tion in the genes and variation in func-
tion as reflected in the phenotype. These
matters will occupy biology and medi-
cine for a long time to come.
Progress in the HGP has brought sev-
eral paradigm shifts that are relevant to
the neo-Vesalian basis of medicine pro-
vided by this ultimate anatomy of the ge-
nome. A shift from genomics57 to pro-
teomics,55 or at least an extension to
proteomics, comes from the realiza-
tion that several or even many different
proteins can be encoded by a single gene,
as must be the case to account for the
increased complexity of humans as com-
pared with C elegans and Drosophila,
which have one third or one half as many
genes as humans. A shift from map-
based gene discovery to sequence-
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THE ANATOMY OF THE HUMAN GENOME

based gene discovery has occurred be- specific diagnoses at earlier stages. It
cause availability of databases with will surely advance gene therapy. In a
expressed sequence tags or complete se- more general way, genomics is likely to
quence information on many different render medicine more predictive and,
organisms has made research in silico therefore, more preventive. Compre-
(cybergenomics) possible. hensive “genome screens” for recogni-
A shift of emphasis from relatively tion of individual susceptibilities to
rare single-gene disorders to common common disorders can be foreseen. Ge-
disorders of multifactorial causation nomics-based clinical medicine will re-
(complex traits) has occurred, now that quire that primary care physicians be
it is possible that susceptibility alleles competent in the interpretation of gene
that collaborate in causation can be screens and in advising appropriate
identified. Such alleles may be found health measures.
through studies of association be- At the same time, on the traditional
tween the particular disorder and the turf of clinical medicine, diagnosis will
multitude of DNA markers, particu- become more specific and precise, and
larly single nucleotide polymor- treatment also more specific and safer.
phisms, now available. As a conse- Genomics-based individualization of
quence, DNA testing will no longer be medical care aims to achieve the right
limited to specific diagnosis of Mende- treatment for the right patient.59 More
lian disorders but can be extended to precise characterization of the ge-
recognition of vulnerability or resis- nome in common disorders, such as hy-
tance to common disorders. pertension and mental illness, will iden-
tify diagnostic subtypes for which
The Neo-Vesalian Influence different therapies will be more effec-
on 21st-Century Medicine tive. Cancer medicine is at the fore-
As indicated in more detail else- front in the use of genomics to match
where,58 the availability of the human specific diagnosis with specific treat-
genome sequence and information on ment. Morphologically indistinguish-
proteomics related to the sequence is able neoplasms have been shown on
likely to change medicine in many ways. “biopsy” of their altered genomes to be
It will influence reproductive medi- different, suggesting that different treat-
cine, for example, permitting ever more ments are indicated.
Better understanding of individual ge-
nomic constitutions should permit drug
therapy to get away from the one-size-
fits-all approach. It should allow selec-
tion of drugs likely to be more effec-
tive in the treatment of a given disorder
in a given individual. Even though a
particular drug may be effective in the
treatment of a disorder in a particular
patient, the genomic constitution of the
patient may place him or her at an in-
creased risk of adverse drug reaction.
Identifying such risks is part of pick-
ing the right treatment for the right pa-
tient and can reduce the very consid-
erable toll of iatrogenic morbidity and
mortality.
As reflected in the large investments
in genomics by pharmaceutical firms, ge-
nomics is anticipated to lead to identi-
fication of new drug targets, ie, genes and
gene products involved in physiologic
processes that can be enhanced or down-
regulated by custom designed drugs,
pharmacogenomics. 5 9 Genomics-
based drug development should lead to
entirely new medications for disorders
not now treatable and to more effective
and safer replacements for current drugs.
In summary, chromosome analysis,
gene mapping, and complete sequenc-
ing of the genome provide an anatomic
basis for all aspects of clinical medicine.

Figure 3. Pace of Disease Gene Discovery and Molecular Characterization of Clinical Disorders, 1981-2000

A No. of Genes Discovered With Disease-Related Mutations B No. of Clinical Disorders Characterized at the Molecular Level
175 200
(6)
(12) (6)
150

150
125 (5) (11)
(13)
100
(8)
No.

No.

(8) 100
75 (8) (9)
(6)
50 (2)
50

25
(1) (1)
(1) (1)
0 0
82 84 86 88 90 92 94 96 98 00 82 84 86 88 90 92 94 96 98 00
19 19 19 19 19 19 19 19 19 20 19 19 19 19 19 19 19 19 19 20
Year Year

Reprinted with permission from Peltonen L, McKusick VA. Dissecting human disease in the post-genomic era. Science. 2001;291:1224-1229.53 A, The number of
disease genes discovered by the end of 2000 was 1112, including both germline and neoplasia-related somatic mutations. This number does not include all the genes
identified as translocation gene-fusion partners in neoplastic disorders. Numbers in parentheses indicate genes with disease-related polymorphic alleles (susceptibility
genes). B, The number of clinical disorders characterized by the end of 2000 was 1430. This number does not include the many neoplastic disorders caused by translocation-
related fusion genes.

2294 JAMA, November 14, 2001—Vol 286, No. 18 (Reprinted) ©2001 American Medical Association. All rights reserved.

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As with any powerful new develop-
ment, there are hazards of misuse of in-
formation or techniques. Privacy and
confidentiality are issues of impor-
tance. A serious risk may be public mis-
understanding that will prevent maxi-
mum benefit to be realized from the
information. Blind fear of anything ge-
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