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A 60-Year Tale of Spots,
Maps, and Genes
Victor A. McKusick
Institute of Genetic Medicine, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21287-4922
Annu. Rev. Genomics Hum. Genet. 2006.
7:1–27
The Annual Review of Genomics and Human
Genetics is online at
genom.annualreviews.org
This article’s doi:
10.1146/annurev.genom.7.080505.115749
c 2006 by Annual Reviews.
Copyright All rights reserved
1527-8204/06/0922-0001$20.00
Key Words
gene mapping, genetic nosology, medical genetics, OMIM
Abstract
This is an account of almost 60 years’ experience in the clinical
delineation of genetic disorders, mapping genes on chromosomes,
and cataloging human disease–related genes and genetic disorders.
The origins of medical genetics as a clinical specialty, of the Human
Genome Project, of genomics (including the term), and of HUGO
are recounted.
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In 1997, Victor McKusick received the
Albert Lasker Award for Special Achievement in Medical Science. The award recognized his “lifelong career as a founder of
the discipline of medical genetics, a pioneer
in human gene mapping, a champion of the
Human Genome Project, and the creator of
Mendelian Inheritance in Man.” We asked Dr.
McKusick to recall for us some of his experiences in these four areas—The Editors
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Portrait: Herbert Abrams, 1990. In the background (left to right): set of successive editions of Mendelian Inheritance in Man (52),
“the Amish madonna photograph,” Heritable
Disorders of Connective Tissue (45), and Cardiovascular Sound in Health and Disease (46).
The chair came from Dr. J.E. Moore’s office and was used for many years by Dr.
McKusick (usually in white coat) in conducting patient conferences in the Moore
Clinic.
BACKGROUND
My identical twin brother Vincent and I grew
up on a dairy farm in Maine in a family that
valued scholastic achievement. Our elementary schooling (it was called grade school) was
in a one-room schoolhouse where the same
teacher taught us seven of eight years. Following that we went off to high school in the
neighboring village where we pursued a classic
“college prep” course with four years of Latin,
three years of French, much English literature
and composition, and much history and math
(algebra, geometry, and trigonometry, but no
calculus), with no biology, no chemistry, and
no physics.
My formal exposure to science and to genetics came late, at Tufts University, where I
was a premed student for three academic years
(2 1/2 calendar years), from September 1940
to January 1943. My twin and I split up when
we went to college, he to Bates and I to Tufts,
partly to avoid competing with each other for
scholarship support but also because our career goals had diverged. Vincent had been
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McKusick
long set for the law; my goals were altered by
an experience that Vincent did not share. At
the age of 15 I developed an abscess of the left
axilla and a superficial spreading ulcer of the
right elbow that would not heal. After many
attempts to culture the causative organism(s) I
ended up in the Massachusetts General Hospital where I spent 10 weeks in the summer of
1937—incredible in this age of brief hospitalizations. There a microaerophilic streptococcus was cultured that had escaped detection
previously in Maine because of its fastidious cultural requirements. I got sulfanilamide
(“Prontosil”), which had become available the
year before. The lesions of axilla and elbow,
which had been present for more than eight
months, healed and stayed healed. In the process I saw much of medicine and decided that
it was the field for me.
At Tufts, the biology, chemistry, and
physics of the premed curriculum were fascinating to me, and I suspect I did better than
many of my classmates who had been exposed
to these subjects in high school and were perhaps blasé as a result. In my last semester
at Tufts I took an elective course in genetics with Professor Paul A. Warren, an inspiring teacher, who made the topic of classic
Mendelism exciting.
After the Pearl Harbor attacks on December 7, 1941, while I was in my second year at
Tufts, the United States entered the war. To
preserve my deferment as a premed student,
I did a semester at Tufts in the summer of
1942, and finished up my third academic year
by January 1943. In the fall of 1942 I learned
that Johns Hopkins Medical School was accepting applications from undergraduate students who had not yet received a college degree, for an entering class in March 1943. For
Johns Hopkins this was a shift, forced by the
wartime exigencies, away from the requirement of a bachelor’s degree that had existed at
the school since its opening in 1893.
I was strongly attracted to Johns Hopkins
because of a cover story in Time magazine
in January 1939. It focused on the Hopkins
professor of the history of medicine, Henry
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Sigerist, and his views on socialized medicine.
At the same time it recounted the saga of the
founding of Johns Hopkins and of its Institute
of the History of Medicine. The only medical
school application I submitted was for Johns
Hopkins and I was accepted to matriculate in
March 1943. Part of my “reverse snobbery”
is that I am a college dropout. I do not have
a bachelor’s degree. I have only one earned
degree, the MD from Johns Hopkins (1946),
but a goodly collection of honorary doctorates from universities in the United States and
abroad, including Tufts.
After completing four academic years of
medical school in three calendar years, my
class graduated from Johns Hopkins Medical School in March 1946. I then embarked
on an internship in internal medicine at the
Johns Hopkins Hospital, April 1, 1946 to July
1, 1947. I had fully expected that after medical
school and a certain amount of postdoctoral
training I would go back to Maine to enter the
general practice of medicine. That was not to
be, because of my ambitions for the internship
on the prestigious Osler Medical Service with
its tradition of training for academic medicine,
and because of career-changing developments
during my years of hospital training.
The most important influence directing
me into medical genetics was a teenager
named Harold Parker. He became my patient in June 1947 near the end of my Osler
internship and was my introduction to the
polyps-and-spots syndrome. In the next two
years, four other patients with this combination came my way, three of whom were
members of one family, indicating autosomal
dominant inheritance. Hearing that Harold
Jeghers in Boston also had 5 cases, I joined
forces with him to write up these 10 cases for
publication in two successive issues of the New
England Journal of Medicine in late December
1949 (33). This syndrome of jejunal and other
intestinal polyps and melanin spots of the lips,
buccal mucosa, and digits was subsequently
named the Peutz-Jeghers syndrome, first in a
paper from the Mayo Clinic in 1954 (7). Peutz
(97) had described the combination in a large
Dutch family in 1921. Peutz’s was not the first
report, however; Jonathan Hutchinson first
described the pigmentary changes in identical twins in 1896 (32), and in 1919 F. Parkes
Weber (116) reported that one of the twins
had died of intestinal obstruction.
I was tutored in the genetic interpretation
of the polyps-and-spots syndrome by Professor Bentley Glass, then at the Homewood
Campus of Johns Hopkins University. He dissuaded me from genetic linkage as the basis
of the association of polyps and spots and indicated that pleiotropism of a single mutant
gene was much more likely, even though at
the time we did not know what the mechanism
of the association might be. Indeed, the precise connection between the two features remains unclear to this day, even though the mutant gene and specific mutation(s) have been
identified.
Meanwhile, I was becoming a cardiologist. First, as a junior assistant resident on the
Osler Medical Service, I read electrocardiograms in the Johns Hopkins Heart Station
under the tutelage of Elliott V. Newman.
Then, from 1948 to 1950, I worked in a
cardiovascular unit at the U.S. Marine Hospital in Baltimore under Luther L. Terry,
who subsequently achieved fame as the surgeon general of the United States Public
Health Service who pointed the accusative
finger at cigarettes. While there I was involved
in doing cardiac catheterizations and studied the movement in the heart borders by a
new method called electrokymography, in the
course of which I became intimately familiar
with the mechanics of cardiac function. Based
on work done during that period, publications
came out on chronic constrictive pericarditis
(41, 42), on successful reversion of ventricular fibrillation occurring as a complication
of right heart catheterization (109), on the
electrocardiographic effects of lithium chloride (then used as a salt substitute) (43), and
on other topics. The reversion of “v.fib” (109)
may have been in part attributable to the use
of Xylocaine (Astra), which was subsequently
known as lidocaine. This agent was in trial
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as a local anesthetic in our cardiac catheterization laboratory. The case may have been
the first instance of its use for treatment of an
arrhythmia.
On July 1, 1950, I returned to Johns
Hopkins and the Osler Medical Service, first
as a senior assistant resident in 1950–1951
and then as the chief resident (“the Resident
Physician”) from 1951 to 1952. Thereafter, I
stayed on the junior faculty, engaging in the
combination of research, teaching, and patient care that I continue to the present.
In my first years on the Johns Hopkins
University faculty, I pursued two research
projects in parallel. One was the study of heart
sounds and murmurs by the method of sound
spectrography, which had been developed at
the Bell Telephone Laboratory for analyzing
speech sound (“visible speech”) and which I
adapted to the heart sound field, renaming
it spectral phonocardiography (87, 88). (The
frequency spectrum of the heart sounds was
demonstrated by the recordings.) The ultimate output from those studies was a monograph entitled Cardiovascular Sound in Health
and Disease (1958) (46). It was a comprehensive
treatise on heart sounds and murmurs and on
clinical auscultation, illustrated with spectral
phonocardiograms. Preparing the first chapter, on the history of the field, gave me much
pleasure. I have insisted that the best way to
“get on top” of a field is to know how it got
where it is now from where it was at the beginning. In each of the fields in which I have
worked I have explored its history. Related to
the heart sound field, for example, I wrote a
short biography of Osborne Reynolds (89),
who devised the Reynolds number, which is
relevant to the generation of turbulence in
fluid flow and therefore of heart murmurs. In
genetics, my historical writings include a history of medical genetics, which is the initial
chapter of successive editions of Emery and
Rimoin’s Principles and Practice of Medical Genetics (72), as well as biographical pieces on
Jonathan Hutchinson (40), Frederick Parkes
Weber (49), Walter Stanborough Sutton (47),
and Marcella O’Grady Boveri (64).
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The second project I pursued in parallel in my first years on the junior faculty
of Johns Hopkins University was a comprehensive study of the Marfan syndrome and
four other disorders in the category I labeled heritable disorders of connective tissue, namely, Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, and Hurler syndrome (the prototype of
the mucopolysaccharidoses). This work culminated in the monograph Heritable Disorders of Connective Tissue (first edition, 1956)
(45). [Subsequent editions appeared in 1960,
1966, and 1972, and my former fellow Peter
Beighton (3) edited a multiauthor fifth edition
in 1993.]
Encountering Marfan syndrome in my
clinical work in cardiology, and having been
schooled in the principle of pleiotropism, it
was not difficult to be impressed with the
probability that the various features of that
disorder—in the skeletal system, in the eye,
in the aorta—could be due to a mutationdetermined defect in one element of connective tissue wherever it occurred in the body.
I collected all the Marfan patients I could
and studied them extensively, often retrospectively on the basis of hospital records, and
studied the families firsthand insofar as possible. The Johns Hopkins Hospital was a superb site for such studies because of strong
departments of ophthalmology, pediatric and
adult cardiology, orthopedics, and other specialties that patients consult in connection
with the various syndromal features of Marfan syndrome. Because of pleiotropism, such
syndromes are often like the elephant being
examined by multiple blind men. Conspicuous features in one organ system may bring
the patient to the attention of one specialist
to the exclusion of others.
I am mainly an autodidact in genetics. As
a junior faculty person at Hopkins in the
1950s, I had access to faculty knowledgeable in genetics, particularly Bentley Glass,
and association with others who like me were
would-be geneticists, including Barton Childs
and Abraham Lilienfeld. The four of us with
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others referred to ourselves as the GaltonGarrod Society. The first edition of Curt
Stern’s textbook Principles of Human Genetics (110) was influential in my education in
genetics. Stern incorporated much information from classic genetics when dealing with
phenomena for which evidence in man was
limited.
MEDICAL GENETICS AS A
DISTINCT CLINICAL
DISCIPLINE
Medical genetics was institutionalized at
Johns Hopkins on July 1, 1957. My boss,
A. McGehee Harvey (69, 70), chair of the
Hopkins Department of Medicine, asked me
to take over the direction of a multifaceted
chronic disease clinic that had been developed by J. Earle Moore in about 1952. The
arrangement I made with Dr. Harvey was that
I would develop a Division of Medical Genetics within the Department of Medicine based
in this clinic, which was renamed in honor of
Dr. Moore. I argued that genetic disease is
the ultimate in chronic disease. The objective
of the new division was to serve in relation
to hereditary disorders the same role that the
established subspecialty divisions such as cardiology, gastroenterology, and endocrinology
performed in relation to particular systems:
teaching, research, and exemplary patient care
(58, 67).
I became known as a cardiologist because
of my writings in the field in the 1950s, before
I became known as a geneticist. Some thought
I was committing professional suicide in leaving cardiology to focus on rare and “unimportant” genetic disorders. They asked why I
switched from cardiology to genetics. Actually
it was a matter of phasing down cardiology and
ramping up genetics after 1957. The genetics of heart disease was a focus of our Moore
Clinic program at the beginning, and our National Institutes of Health (NIH) support for
research and training came from the National
Heart Institute until the National Institute
of General Medical Sciences was founded in
the early 1960s. I continued involvement in
the Heart Sound Laboratory until 1962. In
1961, I did a major study of Buerger disease in
Korea in comparison with cases in the United
States (79a). This re-established the condition
as a distinct entity as opposed to being merely
precocious atherosclerosis.
The newly renamed Moore Clinic was fertile soil for planting a medical genetics unit.
It had evolved out of a world-class venereal disease clinic that had developed longterm follow-up mechanisms for studying the
late manifestations of syphilis, such as the
neurologic and cardiovascular, and the efficacy of pre-penicillin therapies such as bismuth, mercury, and arsenicals. Dr. Moore’s
clinic had close links to the Johns Hopkins
School of Hygiene and Public Health (now
the Bloomberg School of Public Health), including the statistics and epidemiology departments and the Department of Public
Health Administration, which was involved
in the Master of Public Health program for
public health officers, who rotated through
the clinic. It had good funding in connection
with its new role in the area of chronic disease,
including training grant funds, which at that
time could be used for noncitizens.
Paradoxically, an advantage of the Moore
Clinic for developing a medical genetics unit
with a triple function in research, teaching,
and patient care was its cramped quarters. On
the second floor of the Carnegie Dispensary
Building of the Johns Hopkins Hospital, facilities for patient visits, offices for staff and fellows, and cytogenetics and biochemical laboratories were crowded into a limited space that
was made to do and fostered collaborations.
Education in the Moore Clinic
A postdoctoral training program was immediately instituted. Several postdoctoral fellows already recruited by Dr. Moore as fellows in chronic disease were proselytized to
medical genetics. These included E.A. (Tony)
Murphy, who was subsequently a long-time
member of the medical genetics faculty with
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responsibility particularly in the area of statistical genetics. Samuel H. (“Ned ”) Boyer
IV had come to me in 1956 as a fellow in
cardiology. I proselytized him also to genetics (or he became infected by the contagious
“genetics bug”) and he went off to the Galton Laboratory in London for an exciting
year (1957–1958) with Lionel Penrose, Harry
Harris, C.A.B. Smith, and others. His associations with Harris were especially significant
and started him off on the study of biochemical polymorphism including G6PD and the
hemoglobins that absorbed his attention for
the next 30 years.
Other fellows were attracted to the Moore
Clinic both from the United States and
from abroad. Early postdoctoral fellows from
Britain included David A. Price Evans, who
as a postdoc did the classic study of the pharmacogenetics of isoniazid metabolism (17) [at
that time the concept and the term pharmacogenetics had scarcely been invented, by Arno
Motulsky (93) and Friedrich Vogel (115)].
They also included Malcolm A. FergusonSmith, who in February 1959 started the
first cytogenetics laboratory in the Moore
Clinic (which may have been the first clinical cytogenetics laboratory in a U.S. hospital); and David J. Weatherall, who worked
first with Boyer and then established collaborations with the hematology division under C. Lockard Conley and with the Department of Biophysics under Howard Dintzis
to pursue his interest in hemoglobinopathies
and particularly thalassemia that he had
acquired in Southeast Asia while “in the
Forces.”
Many who came to the Moore Clinic for
fellowship training were undifferentiated internists or pediatricians. Others were already
specialized in neurology, cardiology, orthopedics, and other fields; several were dentists.
Donald F. Patterson, from the University of
Pennsylvania, was a veterinarian who subsequently did for animal medical genetics what
we were doing in human medicine.
A PhD program in human genetics was
established in the 1960s. Alan E. H. Emery
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(from England), David L. Rimoin (from
Canada), and Samia Temtamy (from Egypt)
were notable examples of postdocs from a
medical background who added a PhD degree on the basis of work in the Moore Clinic.
The PhD students included some with only
a bachelor’s degree such as Roger Donahue,
who achieved the first autosomal gene assignment (13).
In the early stages of the Moore Clinic
program’s development, a distinguished human geneticist spent one month in residence
each year. The first of these was Curt Stern,
PhD, who lived in the hospital (“under the
Dome”) and gave a total of 12 lectures, on
Monday, Wednesday, and Friday in each week
of January 1959. These lectures, held in Hurd
Hall, the main auditorium of the hospital,
were well attended. Several department chairmen attended most lectures. Using six blackboards tightly covered with handwritten notes
as his only visual aid, Stern conveyed very
well the excitement of the field. The second lecturer-in-residence was Harry Harris
from London, adding a biochemical genetics
slant to Stern’s classic genetics. C.A.B. Smith,
also from London, followed with mathematical and statistical genetics, including linkage analysis, which was by then a research
emphasis of the new Division of Medical
Genetics.
The Bar Harbor Course
An important part of the educational program
of the Moore Clinic in its early years (and
of the genetics program at Johns Hopkins to
this day) was the annual two-week course at
Bar Harbor, Maine, organized jointly by Johns
Hopkins University and The Jackson Laboratory ( JAX). The annual session in July 2006
was the 47th, the course having been inaugurated in 1960 (22, 24, 56, 84).
The title in its first seven annual sessions
and in the even-numbered years, 1968 to
1978, inclusive, was Short Course in Medical
Genetics. On odd-numbered alternate years
beginning in 1967, the course focused on the
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mouse and was entitled Short Course in Experimental Mammalian Genetics. According to that
plan, it should have been a “mouse course”
in 1979, but by that time developments in
somatic cell and molecular genetics had advanced to the point that the same methods
were being used in the study of mouse and
man, and the human had become amenable to
experimental genetics to an extent not previously possible. Lecturers on a particular topic
would often move back and forth between
mouse and man (or other species) in an almost
seamless way. The mouse-human somatic cell
hybrid system was a metaphor for what had
happened in the field. In 1979, the course
was in its twentieth annual session and that
year was the fiftieth anniversary of the JAX—
more reasons to have a combined celebratory
course. The title of the course in 1979 was
changed to Short Course in Medical and Experimental Mammalian Genetics, and such has been
the title ever since.
In the early decades of the Bar Harbor
Course the faculty was approximately one
third each from Hopkins, the JAX, and other
institutions. In recent times, the faculty, which
for a decade or more has numbered about 40,
are one fourth from Hopkins, one fourth from
the JAX, and one half from other institutions.
More than 90 different individuals from Johns
Hopkins, more than 120 from the JAX, and
more than 290 from other institutions have
taught in the course.
The students numbered 45 the first year;
the number passed the 100 mark in the 1970s,
and has been 120 per year for some time.
In all, with the completion of the 2006 session, more than 4800 students have passed
through the course. They represent a wide geographic distribution. The students, always a
highly heterogeneous group, were of higher
average age in the first decade because established clinical specialists, medical and biological educators, and even medical deans sought
out the new information for aid in their clinical work, research, teaching, and curriculum
planning.
Patient Care in the Moore Clinic
From the beginnings of the Moore Clinic
in 1957, patients in all age groups, from
womb to tomb, were cared for. The family was considered the unit of clinical practice as much as the individual patient. From
the first, the Moore Clinic cared for many
of my previously identified patients and families with heritable disorders of connective
tissue. The development of a chromosome
laboratory by Malcolm A. Ferguson-Smith
in 1959 brought referrals. Early on, it may
have been unclear in the mind of the public
and perhaps many physicians how unlikely it
was to find a visible chromosomal abnormality in disorders that were “running in families.” Thus, physicians referred many patients
to the Moore Clinic for chromosome studies, and many other patients were self-referred
(58).
Research in the Moore Clinic
Many research topics were pursued by members of the clinic staff. Each postdoctoral fellow had an “arbeit,” many of which were
inspired by patients seen in the clinic. The
overarching emphasis of the research was
twofold: genetic nosology (53, 54, 60) and
gene mapping. For the pursuit of both of these
areas, the Division of Medical Genetics was
organized into five sections, each headed by a
faculty member who had started out as a postdoctoral fellow. The biochemical genetics section was represented by Samuel H. Boyer IV;
the cytogenetics section by Ferguson-Smith,
and later Digamber Borgaonkar and others;
the immunogenetics section by Wilma Bias;
the mathematical and statistical genetics section by E. A. Murphy; and the clinical genetics
section by myself. It is evident that these represented the areas of expertise necessary for
studying inherited diseases and the areas of
expertise necessary for characterizing marker
traits for linkage studies, for analyzing family linkage data, and, of course, for defining
phenotypes.
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Genetic Nosology
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Defining the multiple distinct forms of the
mucopolysaccharidoses in the 1960s and early
1970s is a good example of genetic nosology
in the Moore Clinic (83). Close collaboration with Elizabeth Neufeld of the NIH, who
was responsible for the cellular and biochemical differentiations, was notably useful (82).
The mucopolysaccharidoses provided nice examples of locus heterogeneity (e.g., the Sanfillippo syndromes) and allelic heterogeneity
or allelic series (e.g., Hurler syndrome and
Scheie syndrome) (82).
Also in the 1960s, skeletal dysplasias became an area of both clinical and research
nosologic interest because of their relationship to the heritable disorders of connective
tissue, because of studies of dwarfism in the
Amish (78, 79), which we initiated in 1963,
and because of collaboration with Little People of America, Inc., which began in 1965
when I first attended the annual national convention of this fraternal organization of persons of short stature. Skeletal dysplasias became a major interest of many who were
my fellows in that period including David
Rimoin, Judith G. Hall, and Charles Scott,
who like me became honorary life members
of Little People of America.
The studies of the Old Order Amish
demonstrated how observations in genetically
isolated populations could contribute to the
nosology of genetic disease (81). Our expectation that “new” recessive disorders would
be found in this inbred population was richly
fulfilled (80). The first phenotype we studied in detail in the Amish was dwarfism (78,
79, 81), which was said to be unusually frequent. It was clear that this was not likely to be
achondroplasia, which is dominant. Indeed,
two forms of recessive dwarfism were found
in the Amish of Lancaster County, Pennsylvania, where our studies started. One, the Ellisvan Creveld (EvC) syndrome, or six-fingered
dwarfism, had been described in 1940 through
the collaboration of a Scottish and a Dutch
professor of pediatrics (15). When we re-
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McKusick
ported on the Amish EvC in 1964 (78), we had
a total of 50 cases, living and dead. Because
about 50 cases had previously been reported,
by one fell swoop we doubled the world’s reported cases of the disorder. The existence of a
large number of Amish cases almost certainly
due to the same mutation permitted a useful
analysis of the range of the phenotype.
EvC syndrome in the Amish became a favorite with writers of biology textbooks as
an example of founder effect. The “Amish
Madonna,” an Amish mother with her affected daughter demonstrating the polydactyly of this disorder, appeared in several
textbooks after her debut in my Human Genetics (first edition, 1964) (50).
The second form of recessive dwarfism
that we found in the Amish was a previously
unknown entity that we designated cartilagehair hypoplasia (CHH) because of the striking
changes in cartilage and hair (79). It has since
become known also as metaphyseal chondrodysplasia, McKusick type. Whereas EvC
was limited to the Lancaster County Amish
deme, CHH was also frequent in Amish in
other parts of North America, e.g., Ohio,
Indiana, and Ontario.
In the initial study of CHH (79), 77 affected persons in 53 Amish sibships were
identified. This cohort represented an intellectually exciting opportunity to describe
from scratch a previously unrecognized disorder, including its various and variable
features, including immunologic deficiency
(105), chronic neutropenia (36), anemia,
megacolon, lymphoma in unusual sites, herpes and other viral infections, and so on.
We and others described a large number
of other “new” disorders among the Amish,
which were cataloged in Medical Genetics Studies of the Amish (59), published in 1978, and in a
special issue of the American Journal of Medical
Genetics in 2003 (21). The new disorders identified in the first decade of our Amish studies
included the McKusick-Kaufman (77), Byler
(9), Troyer (11), and Mast (10) syndromes, the
last three named for affected Amish families.
The causative mutations in all four of these
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disorders have now been characterized by the
positional cloning approach (8, 96, 108, 111).
A noteworthy finding of the Amish studies was the demonstration that the Amish in
Lancaster County, Pennsylvania, in Holmes
County, Ohio, and in Elkhart and Lagrange
Counties, Indiana, represent partially separate
demes. The separateness, resulting from different immigration histories, was indicated by
differences in the frequency of family names,
in blood group frequencies, and in specific
genetic disorders (59). It was as though the
Amish immigrants were streaked like bacteria east-west across the waist of America, with
colonies springing up first in eastern Pennsylvania and then successively in Ohio and in
Indiana. In effect, a bioassay of the genomes
of the founder immigrants was provided by
the findings in their descendants.
Occurrence of CHH in all Amish demes
suggested a high frequency of the mutant allele in the parent population. The Finns, who
have no known geneologic connection with
the Amish, were also found to have a relatively high frequency of CHH (37, 38). Remarkably, the same mutation in the RMRP
gene (OMIM 157660.0001) turned out to be
responsible for CHH in both the Finns and
the Amish (104), suggesting that the mutation is ancient or, alternatively, recurrent. In
either case, the demographic histories of the
Finns and the Amish, which have some parallels, must have favored a high mutant allele
frequency through founder effect and random
genetic drift.
In 1963, during a visit to Hopkins, Charles
Dent told me of Nina Carson’s work (8a,b)
describing a Marfan look-alike disorder. Subluxation of the lenses and Marfan-like skeletal
changes were associated with excretion of homocystine in the urine and disastrous thrombotic accidents. Carson had detected the disorder in a urine chromotography survey in an
institution for the mentally retarded in Northern Ireland. I then recalled a family I saw
in 1960 in which three siblings appeared to
have Marfan syndrome with dislocated lenses
and “typical” skeletal features. One of the sib-
lings died at age 18 of thrombosis of carotid
arteries and a second of coronary occlusion
at age 21. During Dent’s visit, we confirmed
that the surviving sibling had homocystine in
the urine. Thereafter, Neil Schimke and I undertook a mail follow-up study of all cases
of nontraumatic ectopic lentis in the files of
the Wilmer Institute at Johns Hopkins and
many other eye clinics. Urine was mailed to
Baltimore for assay. With this approach and
others, 20 families were assembled for study
(105a). Ascertained not on the basis of mental retardation but on the basis of ectopia
lentis, the series showed that mental retardation is not a consistent feature of homocystinaria (one patient achieved a PhD). Homocystinuria differed from Marfan syndrome in
recessive inheritance and by thrombotic (not
aortic) complications as the prime cardiovascular problem.
Other notable nosologic output from the
Moore Clinic included The Genetics of Hand
Malformations (113a), Samia Temtamy’s PhD
thesis; isolated growth hormone deficiency as
an autosomal recessive trait by Rimoin et al.
(104a); microcephaly-chorioretinopathy syndrome (OMIM 251270) (86a); and cranioectodermal dysplasia (OMIM 218330) (35a).
Genetic nosology was the topic of oneweek-long conferences, entitled “Clinical Delineation of Birth Defects,” held at the Johns
Hopkins Hospital for five consecutive years,
from 1968 to 1972. Genetic disorders in all
areas of medicine were reviewed, with presentation of papers, morning and afternoon,
and with a noon case conference introducing a
large number of patients illustrating particular disorders that fell into the area of focus
in that day’s lectures. The conferences and
the publications emanating from them gave
my colleagues in all departments of the Johns
Hopkins Hospital a chance to present their
experiences with rare or not so rare genetic
disorders.
The importance of clear delineation of
distinct genetic clinical entities was emphasized by the conferences, such definition being necessary for proper prognostication and
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management in individual cases as well as for
genetic counseling. Such delineation was also
necessary to achieve “pure culture” groups
of cases for determining the basic defect and
pathogenic mechanisms. Three main principles of clinical genetics that underlie genetic
nosology—pleiotropism, variability, and genetic heterogeneity—were discussed with numerous examples. My lecture on the first day
of the first conference in May 1968, entitled
“On lumpers and splitters: the nosology of
genetic disease” (54), addressed the issue of
genetic heterogeneity and others. The proceedings of the conferences, both the papers
presented and full reports of the noon conference patients, were published as a series of
Birth Defects “Blue Books” by the March of
Dimes, which funded the conferences. See, for
example, the 396-page monograph on skeletal dysplasias (4) that came out of the two days
of the first (1968) conference devoted to that
topic.
A certain excitement, and as Robert Gorlin
put it, charisma, accompanied the conferences
that came from the intellectual challenges
of differential diagnosis and consideration of
the nature of basic defects and developmental mechanisms. James German commented
that if he had known that clinical genetics
could be so exciting he might not have left his
clinical position at Cornell-New York Hospital to go to the New York Blood Center a
few years earlier. These conferences gave academic respectability to the disciplines of syndromology and dysmorphology. No longer
could these fields be considered mere postage
stamp collecting.
At all the conferences, a number of “living
eponyms” were present, e.g., Dent, George
Fraser, François, Gardner, Klinefelter, Lamy,
Laron, Menkes, and Noonan. Many, including Gorlin and Opitz, became eponymically
established on the basis of these conferences.
In the five conferences I count a total of 40
such “living eponyms,” some of whom did not
yet know they were such.
By necessity, the naming of genetic disorders, including the appropriateness of
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eponyms, came up for discussion at the conferences on the Clinical Delineation of Birth
Defects. Incidentally, the possessive form of
eponyms was consistently eschewed in the
conference publications. Use of the nonpossessive form was already established in my
own writings. Although I wrote “Marfan’s
syndrome” in March 1955 (44), it was always
“Marfan syndrome” beginning with the first
edition of Heritable Disorders of Connective Tissue (1956) (45). In all my writings since then,
such as the annotated annual reviews of medical genetics (74, 76) and Mendelian Inheritance in Man (1966–1998) (52), the nonpossessive eponyms have been maintained. J. Earle
Moore had inculcated me in this usage. He
had adopted it from Morris Fishbein’s guidelines for the journals published by the American Medical Association. I have felt that the
nonpossessive form makes eminently good
sense for reasons that I have spelled out in
the “front material” of successive editions of
Mendelian Inheritance in Man (52). Most genetics journals, notably the American Journal
of Human Genetics, now follow the rule of the
nonpossessive form of eponyms. Some journals, including the New England Journal of
Medicine, persist in the use of the possessive.
Gene Mapping
I am not certain why, in the late 1950s, I
became enthralled with mapping genes on
human chromosomes. Certainly I was impressed with the gene mapping that had been
done in other species such as Drosophila and
the mouse. The maps gave a concreteness to
the genes. In the 1950s I was also impressed
by the reports of human autosomal linkages
(of unknown chromosomal location) by Jan
Mohr in 1951 (91), by Renwick & Lawler
in 1955 (100a), and by Newton Morton in
1956 (92), and I had some vague sense of
the probable significance of such linkages to
clinical medicine, as had been pointed out by
J.B.S. Haldane (25) and by others. I had begun thinking along the lines of linkage studies
and had applied for grant support for such
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studies before Curt Stern, during his onemonth stay in the Moore Clinic in 1959,
encouraged me, pointing out that the arrangement of genes on our chromosomes is an important feature of our anatomy. The anatomic
metaphor is something I have since used extensively (62, 63, 66, 71, 73). Sometimes I
have mixed the anatomic and cartographic
metaphors, as in the title of a 1981 lecture:
“The human genome through the eyes of
Mercator and Vesalius” (63). I entitled a long
four-part review of gene mapping in clinical
medicine “The morbid anatomy of the human
genome” (66), and another review in 2001
“The anatomy of the human genome, a neoVesalian basis for medicine in the 21st century” (71).
One of my first ventures into genetic linkage was done with Ian Porter (98, 99), who
was a postdoctoral fellow in the Moore Clinic
from 1960 to 1962. This was a study of the
genetic interval between the locus for G6PD
deficiency and that for colorblindness (CB).
[The only X chromosome linkage interval that
had previously been estimated was that between CB and hemophilia, by J.B.S. Haldane
and C.A.B. Smith in 1947 (26).] Both G6PD
and CB are X-linked polymorphic traits. The
study was begun with a survey of CB in
African American boys in a Baltimore elementary school. The frequency of CB is less
in that ethnic group than in Caucasians, perhaps 3.5% compared with 7% in European
Americans. The colorblind boys were then
tested for G6PD deficiency to identify a group
of families in which both traits were segregating. An attempt was made to test all males in a
given sibship and to test the maternal grandfather of the affected males. The grandfather
provided information on the linkage phase of
the two traits in his double-carrier daughters:
If the mother of the boys in the test generation had the two traits in coupling, her father was either doubly affected or completely
unaffected. If the mother had the two traits
in repulsion, her father was either colorblind
or G6PD deficient but not both and not neither. The Porter family studies indicated a
close relationship of the G6PD and CB loci,
with about 5% recombination between them.
This close positioning was confirmed by other
mapping and molecular studies of the generich telomeric region of the long arm of the
X chromosome.
Linkage work in the Moore Clinic in the
1960s was greatly abetted by collaboration
with James H. Renwick, first of Glasgow and
then of London, who spent several months
each year in the Moore Clinic. With Jane
Schulze & David Bolling, he wrote one of the
first computer programs for linkage analysis
(100, 101, 102). That program was used in the
analysis of the CB-G6PD linkage by Porter
et al. (98, 99) and the analysis of possible linkage of XG and CB by Renwick & Schulze
(102). Renwick was involved in several other
Moore Clinic linkage studies (2), including assignment of the Duffy blood group locus to
chromosome 1 in 1968 (13). A notable contribution by Renwick in the same period was
the introduction of the useful term synteny
(and syntenic), meaning “on the same chromosome” as opposed to linkage (and linked).
It was in a superb review of human gene mapping (99a), in which he introduced and defined the term synteny, which he derived from
the Greek syn = together and taenia = ribbon. He took to task two groups (104b,c)
who the previous year had reported that lactic
acid dehydrogenase (LDHB; OMIM 150100)
and peptidase–B (PEPB; OMIM 169900) are
“linked” on the basis of somatic cell hybrid
studies. Renwick pointed out that the somatic
cell hybrid method can prove synteny but not
linkage (in the strict genetic sense). In fact,
it turned out that LDHB and PEPB are on
different arms of chromosome 12.
Mann et al.’s (39) discovery of the Xlinked blood group antigen Xg(a) in 1962 led
to a flurry of investigations in families with
X-linked disorders. These excluded linkage
for almost all loci tested (102), a finding not
now surprising because of the known location
of the XG locus near the end of the short arm
of the X chromosome (14a), which is one of
the larger ones of the human complement.
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Even though syntenic to XG, they were not
genetically linked to XG.
Several of our autosomal linkage studies in
the 1960s came to naught largely because of
the pitifully small collection of marker traits
then available. Disappointingly negative autosomal linkage studies included those of Marfan syndrome (107) and of the large kindred with symphalangism (112) that the noted
neurosurgeon Harvey Cushing described and
named in 1915 (12). [The Cushing article with
large fold-out pedigree was in the first volume of Genetics, which also carried Calvin
Bridges’s classic paper (6) on nondisjunction
as proof of the chromosome theory of heredity.] Both Marfan syndrome (OMIM 154700)
and symphalangism (OMIM 185800) were
later mapped when DNA markers became
available, and the mapping information was
used to determine the basic defect in the
genes encoding fibrillin-1 (FBN1; OMIM
134797) and noggin (NOG; OMIM 602991),
respectively.
Positive results of linkage studies from the
Moore Clinic in the 1960s included mapping of the interval between nail-patella syndrome and the adenylate kinase locus (106);
Renwick & Lawler (100a) had already linked
nail-patella syndrome to the ABO locus.
[Ferguson-Smith et al. (18, 19) later assigned
the NP/ABO/AK1 gene cluster to 9q34.1.]
Harper et al.’s (28) demonstration that secretor status of the fetus can be determined by
studying amniotic fluid meant that one could
do prenatal diagnosis of myotonic dystrophy,
whose close linkage to secretor (and lutheran)
we confirmed (29). The most exciting result
in the 1960s was the first assignment of a
specific locus to a specific autosome, Duffy
blood group to chromosome 1, by Donahue
et al. in 1968 (13). Donahue was a PhD candidate in human genetics and although his thesis topic was in another area he studied his
own karyotype and found a heteromorphism
of the chromosome 1 pair. One chromosome
of the pair was longer than the other and
in the preparations of that just-prebanding
era looked as though it had an uncoiled seg-
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ment subjacent to the centromere. Donahue
had both the wit and the gumption to do a
linkage study: the wit to recognize the heteromorphism as a probably normal variant
transmitted as an autosomal dominant, and
the gumption to collect blood for chromosome and marker studies from members of
a far-flung family and perform the chromosome and marker testing.The lod score calculable for the linkage of the blood group with
the heteromorphic chromosome 1 that Roger
Donahue found in himself and some other
members of his family was low. However, the
assignment was confirmed by other workers
studying the same heteromorphism (118) and
other markers in the centromeric region of
1q.
From the paltry collection of positive results from much mapping work it is clear why
in 1967 I welcomed with enthusiasm Weiss
& Green’s (117) development of the method
of interspecies somatic cell hybridization as
it was an alternative method for assigning
genes to specific chromosomes or regions of
chromosomes. It substituted the variation between the two species in the hybrid for the
variation between the paternal and maternal
alleles in family studies. It was not necessary, for example, to have a polymorphism
of a given enzyme such as thymidine kinase
to map it to chromosome 17, in one of the
first applications of the method to chromosome mapping (90). And it is clear why I welcomed equally or even more enthusiastically
the use of DNA markers [at the beginning,
restriction fragment length polymorphisms
(RFLPs)] for linkage study, as spelled out especially clearly by David Botstein, Ray White,
Mark Skolnick, and Ron Davis in a seminal
paper that introduced the term RFLP in 1980
(5).
The annual or biennial Human Gene
Mapping (HGM) workshops initiated in 1973
were Frank Ruddle’s idea. He was a pioneer in
the use of interspecies somatic cell hybridization for assigning genes to specific chromosomes in mouse and man. As noted, I was active in the linkage approach to gene mapping
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in the human. A regular member of the
faculty of the Bar Harbor Short Course in
Medical Genetics, Ruddle solicited my collaboration in the organization of the HGM
workshops. He trusted that I would be able
to arrange funding from the March of Dimes,
which funded the Bar Harbor Course and the
Clinical Delineation of Birth Defects conferences, and on whose medical advisory committee I had served since 1959. The idea of
the HGM workshops was enthusiastically received by the March of Dimes and was implemented by Dr. Daniel Bergsma, vice president
for professional education. The first HGM
workshop was held in New Haven under the
leadership of Ruddle in 1973. The dates and
organizers of the subsequent conferences are
indicated in Figure 1.
The HGM workshops served an important function in the collation of gene map
information both published and unpublished
over a period of two decades. Persons attending the workshops submitted abstracts of
unpublished works. Committees comprising
persons who worked on the mapping of particular chromosomes vetted the published and
unpublished information accumulated since
the previous conference. Reports of the chromosome committees were published by the
March of Dimes as part of its Birth Defects series and appeared as a supplement to the journal Cytogenetics and Cell Genetics. The workshops had a committee on comparative gene
mapping, as well as a committee on nomenclature that attempted to standardize names
of genes and gene symbols and establish conventions for indicating the cytogenetic band
location of genes.
The HGM workshops were a forerunner for the Human Genome Organisation
(HUGO); indeed, in its conferences and
standing committees (that on nomenclature,
for example), HUGO assumed most of their
functions. Abandonment of the workshops,
as they had been known for 18 years, occurred after the London workshop of 1991.
The change met with the displeasure of
many of the HGM workshop faithful who
Figure 1
had come to value greatly the charm, comradery, and effectiveness of the previous workshops. The annual or biennial five-day-long
endeavor represented hard work by the participants, who took great pride in the finished
product.
By June 1976, at least one gene locus had
been assigned to all 22 autosomes and the X
and Y, testis determining factor (TDF) being
the first gene assigned to the Y chromosome.
The same milestone, at least one gene known
on each chromosome, was achieved at about
the same time in the mouse. In 1977, Ruddle
and I published a review in Science entitled
“The status of the human gene map” (85).
In 1986, in the immediate pregenomics era, I
gave another status report (65). By then, about
600 genes had been assigned to specific chromosomes and in most cases to specific regions
of chromosomes.
THE ROLE OF THE POLIO
VACCINE IN THE
DEVELOPMENT OF MEDICAL
GENETICS
The efficacy and safety of the Salk polio vaccine was announced by The National Foundation for Infantile Paralysis on April 12, 1955.
Known also as the March of Dimes (MOD),
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the organization considered that its goal had
now been achieved and looked around for new
worlds to conquer. It settled on birth defects
and arthritis as appropriate fields in which to
work. (Arthritis was abandoned after a few
years.)
The polio vaccine was important to the
development of medical genetics because the
MOD could now turn its considerable expertise in fundraising and public information
to medical genetics. The polio foundation
had already fostered the early development
of molecular genetics by supporting Max
Delbrüch, for example; James D. Watson was
a National Foundation fellow when he went to
work in a Copenhagen polio virus laboratory,
later switching to the Cavendish Laboratory
at Cambridge.
I claim some credit for establishing with
the National Foundation the principle that
birth defects fall into the domain of medical
genetics. When I heard of the MOD’s shift in
focus, I sent a copy of the first (1956) edition of Heritable Disorders of Connective Tissue (45) to Thomas M. Rivers, Rockefeller
Institute researcher, who was vice president
of research at the MOD. Rivers was a loyal
Hopkins medical alumnus, with training in
pediatrics at the Johns Hopkins Hospital. I
think it was through him that I was invited to
join the MOD medical advisory committee in
1959.
The shift of the powerful MOD organization to the field of birth defects (read “medical
genetics”) had its effect on education, clinical
care, and research. In education, the MOD
was the sole funder of the Bar Harbor Short
Course for its first 25 sessions, from 1960 to
1984, and to this day provides some support.
In clinical care, the effect of the MOD was evidenced in the annual conferences on the Clinical Delineation of Birth Defects held at Johns
Hopkins from 1968 to 1972 and elsewhere
thereafter, and was supported exclusively by
the MOD. In research, the role of the MOD
was evidenced by the HGM workshops from
1973 to 1991, which for much of that period
were supported by the MOD.
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THE HUMAN GENOME
PROJECT
From early on, several of us who were enthusiasts and aficionados of gene mapping championed the usefulness of mapping all the genes
in the human. For example, in August 1969
at the International Conference on Birth Defects sponsored by the MOD in The Hague
(55), I proposed that mapping all the genes
would be a useful approach to understanding the basic derangements in birth defects.
In part, the proposal reflected the exuberant
mind-set that followed the first moon landing
by Apollo 11, carrying Neil Armstrong and
Buzz Aldrin, on July 10, 1969.
In 1980 (61) I suggested that it should be
possible to map all the genes by the end of the
last ventade (20 years, parallel to decade) of
the twentieth century, i.e., by the year 2000. It
was not clear by what methods mapping could
be achieved and it was not clear precisely how
the use of this complete information would
help the understanding of birth defects and
their diagnosis and management. Of course,
it is molecular genetics that has permitted the
complete mapping of the genes, and it is positional cloning of genes mutant in “mystery
diseases” that has represented a major, but not
the only, way in which gene mapping has permitted elucidation of the molecular defects of
birth defects.
As Walter Gilbert pointed out to me during the deliberations of the National Research Council/National Academy of Sciences (NRC/NAS) committee on mapping
and sequencing the human genome (94), complete sequencing would be necessary just to
find all the genes.
The Human Genome Project as an endeavor to completely sequence the human
genome was first formally proposed in 1985 by
Robert Sinsheimer, by Charles DeLisi, by Renato Dulbecco (14) (who championed complete sequencing as an approach to understanding cancer), and by others.
In May 1986, the Cold Spring Harbor symposium was entitled “The Human
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Genome.” By that time the Human Genome
Project was a hotly debated topic, with parties
both favoring and opposing it. A rump session, chaired by Paul Berg and Walter Gilbert,
was held to discuss the proposed project for
complete sequencing. James Watson raised
the question of why the Department of Energy should be undertaking the project, the
implication being that the NIH would be
more appropriate. One reason given by one
of the moderators was that if multiple agencies were involved there would be more total funding for the project. From the first,
however, a justification of the Department of
Energy’s involvement lay in the responsibility that agency had for studying the biologic
effects of radiation.
At that Cold Spring Harbor symposium in
1986, I gave a paper on the status of the human
gene map (65). I think it was an eye-opener to
molecular biologists. It was also at that Cold
Spring Harbor symposium, or soon thereafter, that Brian Crawford, of Academic Press,
suggested that I edit a new journal on mapping and sequencing. I was reluctant to undertake this, but was reassured when Ruddle
agreed to join me as coeditor-in-chief. We
proposed to name the journal Genome, a term
attributed by the Oxford English Dictionary
to the German botanist Hans Winkler (1920)
and formed by combining the words GENe
and chromosOME. However, we found that
we had been scooped by the Canadian Journal of Genetics and Cytology (1959–1986), which
had chosen to rename that journal Genome.
Although one cannot copyright the title of a
book or a journal, we shied away from Genome.
In July 1986, over beer after an evening session of the editorial board of the new journal, Thomas H. Roderick of the JAX proposed
Genomics as the title.
During the next year, plans for Genomics
were laid and the first issue was published in
September 1987. The inaugural editorial in
the first issue was entitled “Genomics: a new
discipline, a new name, a new journal” (86).
Nine years later, a stock-taking editorial was
entitled “Genomics: an established discipline,
a commonly used name, a mature journal”
(34).
During the period of 1986–1988, the question of whether complete sequencing of the
human DNA could be done and should be
done continued to be actively discussed. A vocal few opposed it as being extravagantly expensive and not representing true science, or
at least having questionable usefulness. The
idea that it was not science was born particularly out of the hypothesis-driven research
mindset. The Human Genome Project, as has
since been often pointed out, represents discovery and hypothesis-generating research.
A major factor in the federal government’s
funding of the Human Genome Project was
the report prepared by the NRC/NAS committee on mapping and sequencing the human genome, which was commissioned in late
1986 and reported out in February 1988 (94).
The committee was chaired by Bruce Alberts
and made up of the following, in addition
to me: Botstein, Brenner, Cantor, Doolittle,
Hood, Nathans, Olson, Orkin, Rosenberg,
Ruddle, Tilghman, Tooze, and Watson. Because of his involvement with commercial development of sequencing apparatus, Michael
Hunkapiller resigned early from the committee to avoid conflict of interest.
The report of the committee concluded
that the project should be done; that it could
be completed in 15 years at an annual budget of $200 million; that “map first, sequence
later” was the appropriate approach because
the mapping of DNA markers and cloned
fragments would provide a useful scaffolding
for sequencing, and particularly because sequence technology at that time was not very
efficient; that the sequence of other genomes
should be determined in parallel with that of
the human; and so on.
Clearly, the report of the NAS/NRC committee (94) influenced Congress’s funding of
the Human Genome Project, which was to be
done jointly by the Department of Energy and
the NIH. The NIH project was officially initiated October 1, 1990, with James Watson as
the first director of the National Center for
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Human Genome Research (NCHGR). On
January 1, 1993, Francis S. Collins took over
as director of the center, which was given institute status as the National Human Genome
Research Institute.
The Human Genome Project was being
discussed and planned by scientists in other
countries as well, and in 1988 HUGO was
founded as a coordinating agency for the
global effort. Sydney Brenner, James Watson,
Lee Hood, and others proposed HUGO at the
1988 Cold Spring Harbor symposium, and at
a rump session I was invited to serve as organizing president. I was selected, I suppose,
because of my role in the international HGM
workshops, all of which I had attended, and
on the basis of which I had maintained an ongoing record of the status of the human gene
map.
The first task was to assemble a founding council to write a mission statement
and bylaws for HUGO. At Watson’s suggestion, the first meeting of the council
in September 1988 was held in Montreux,
Switzerland, to give HUGO an international
cachet, and HUGO was incorporated in
Geneva, hence the spelling organisation in its
name. HUGO was subsequently incorporated
also in Delaware to facilitate handling of funds
in the United States. The Montreux founding
meeting was attended by 31 scientists, including 5 Nobelists (Dausset, Dulbecco, Gilbert,
Jacob, and Watson), from 19 countries (66a).
Funding of HUGO in its beginning and
for several years thereafter was provided
by the Howard Hughes Medical Institute
(HHMI) through the agency of its vice president, George F. Cahill, Jr. The HHMI also
supported the development of OMIM (see
below) beginning in 1985 and for six or
seven years thereafter. It had supported in
part the last several biennial HGM workshops. Thus, in relation to these three developments, HHMI played the same role as had
the March of Dimes in relation to the Bar Harbor Course, the Conferences on the Clinical
Delineation of Birth Defects, and most of the
HGM workshops.
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The objectives and functions of HUGO
related to intellectual property rights, ethical issues, research materials, information
sharing, and nomenclature standardization.
HUGO was never conceived as a funding agency; it has always been a coordinating agency for the various genome projects
funded by national governments.
After my term as founder president, I
served as cochair of the HUGO ethics committee and was a member of the ethics
committee for the NCHGR. At the outset,
Watson wisely decided that funding should
be provided in the budget of the NCHGR for
the study of what he termed ELSI, for ethical,
legal, and societal implications, or issues (presumably he and his staff devised this felicitous
acronym).
Following the “map first, sequence later”
recommendation of the NRC/NAS committee, the effort at the beginning of the
NIH program was to construct genetic maps
(marker maps) and physical maps (contig
maps) of the genome, such as yeast artificial
chromosome (YAC) maps—a top-down approach. In contrast, Craig Venter and Hamilton Smith used a bottom-up approach to
achieve for the first time the complete sequence of the genome of a free-living organism, H. influenzae, reported in 1995 (20).
The single chromosome of the bacterium was
fragmented into many pieces. In a shotgun
approach, fragments were cloned as bacterial artificial chromosomes (BACs) and the
DNA was sequenced several times over to
increase the likelihood that all the BACs
were sequenced at least once. Then the complete sequence was assembled using overlaps of ends of BAC clones. In the next few
years, this approach was used for sequencing
many other organisms including Drosophila
and man.
I first learned of Venter’s work in genomics
through his 1991 report on the sequencing and mapping of complementary DNAs
(cDNAs), which he called expressed sequence
tags (ESTs) (1). I had been impressed by the
potential usefulness of going directly to the
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functional part of the genome as a shortcut
in the effort to “map all the genes.” Complete sequencing of the H. influenzae genome
was done in The Institute for Genomic Research (TIGR) in Rockville, Maryland, which
Venter founded in 1992. In 1998, when he
founded the company Celera to undertake the
complete sequencing of the human genome,
Venter asked me to join the Celera scientific advisory board. I found participation as a
board member stimulating because of the association with Hamilton (“Ham”) Smith and
Venter and with the other members of the
board, as well as the excitement of the undertaking. The Venter enterprise was severely
criticized by many who saw a threat to the
open and free (i.e., at no cost) access to the sequence data. See, for example, the discourse
by Sulston & Ferry (113). It was obvious
that complete sequencing of the large human
genome was a major undertaking. One approach was an industrial one funded in the
way industry is customarily funded, i.e., sale
of the product. The business plan of Celera
called for licensing of access to the data and
the computer programs for their analysis. The
second approach was to parcel out the effort
to multiple laboratories in multiple countries
with funding from governmental and foundation sources. Open and free access was important, perhaps essential, to the approach by
international consortium.
I did not sense that a commercial approach
was unethical, and in retrospect I conclude
that the “completion” of the Human Genome
Project was accelerated by the competition
that the private effort introduced. Venter assembled an array of computer equipment, second only to that at NASA, to analyze the
data produced by large banks of sequencers.
The name Celera (as in acCELERAte) and
the company’s motto “Discovery cannot wait”
indicate the Venter style of urgency that accompanied the effort. An announcement of
the Venter map and of the map created by
the international consortium led by Francis
Collins was made at the White House on June
26, 2000. The two maps were published sepa-
rately in Science (114) and Nature (35), respectively, in February 2001.
MENDELIAN INHERITANCE IN
MAN (MIM) AND ITS ONLINE
VERSION (OMIM)
OMIM (95) is the internet version of
Mendelian Inheritance in Man (MIM) (52), a
catalog of human genes and genetic disorders
that I began in the early 1960s as a catalog
of mendelizing phenotypes. The subtitle of
the first 10 of the 12 book editions published
to date was “Catalogs of Autosomal Dominant, Autosomal Recessive and X-linked Phenotypes.” The first phenotype catalog, that for
X-linked traits (48, 51), was assembled to answer the question of the genetic constitution
of the X chromosome. The second, the recessive catalog, was prepared as a resource in connection with study of recessive disorders in the
Amish (81). The autosomal dominant catalog
was then undertaken for the sake of completeness. Mendelian Inheritance in Man was first
published in book form in 1966 (52). For the
eleventh (1994) and twelfth (1998) editions
(68a), the subtitle was changed to “Catalogs
of Human Genes and Genetic Disorders,” a
reflection of progress in the field from phenotypic characterization of hereditary disorders
to DNA definition.
Mendelian Inheritance in Man has been
maintained on the computer since 1964. With
the first print edition in 1966, it was a pioneer
in computer-based publication. In the 1980s,
MIM was prepared for online presentation,
with a search engine that enhanced its usefulness. Online access, as OMIM, was provided
generally beginning in 1987, first from the
Welch Medical Library at Johns Hopkins and
since December 1995 from the National Center for Biotechnology Information (NCBI) of
the National Library of Medicine (27).
The conception of Mendelian Inheritance in
Man was rooted in the annual annotated reviews of medical genetics my colleagues and I
prepared in six successive years, 1958–1963,
inclusive (74, 76). Soon after the genetics
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program in the Moore Clinic was founded
on July 1, 1957, an effective journal club
was initiated with the ambitious intention of
comprehensive review of the current literature relevant to medical genetics. These reviews, published each year as one month’s issue of the Journal of Chronic Diseases, ranged
in length from 121 pages (1958) to 202 pages
(1959). Photographic illustrations and short
clinical reports from our own experience were
included. For example, when Holt & Oram
(31) reported the syndrome that now bears
their names, we suggested the use of the
eponym and provided the second report of
the Holt-Oram syndrome in a mother and
daughter (figure 45 in Reference 74). Reviews
of each of the two three-year periods were
collected in book form: 1958–1960 (74) and
1961–1963 (76).
In 1962, in the Quarterly Review of Biology,
I published a monograph entitled On the X
Chromosome of Man (48). This reviewed the
exciting information then developing on the
role of the sex chromosomes in sex determination and on the mechanism of X chromosome
dosage compensation as reflected in the Lyon
hypothesis. The monograph, which was also
published in somewhat modified book form
in 1964 (51), sought to answer the question
of what genetic information is carried by the
X chromosome by listing all of the X-linked
traits. For each trait the preferred designation, a description of the trait, and detailed information on its genetics, with bibliographic
references to support the statements, were
given—the format subsequently used for entries in Mendelian Inheritance in Man.
The last of the six annual reviews of medical genetics for the Journal of Chronic Diseases
was that for the year 1963 (75). By that time
the usefulness of genetic studies in the Amish
had come to my attention through the unpublished manuscript of John Hostetler’s Amish
Society, and through a story in a drug company “throw away” about a physician in Lancaster County, Dr. David Krusen, who had
many Amish patients, including some with
dwarfism. We expected that studies in the
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Amish would reveal new recessive disorders
(80), and in preparation for the studies we assembled a catalog of known recessive disorders. Rather than continuing annual reviews,
we were attracted to the idea of creating a
comprehensive catalog of Mendelian phenotypes, such as we had done for X-linked and
autosomal recessive phenotypes, to which additions could be made as new phenotypes were
described and information on the “old” phenotypes became available. Thus, a catalog of
autosomal dominant traits was added. In early
1964 the catalogs were “put on the computer”
(the mainframe at the Homewood campus of
Johns Hopkins University) to avoid introducing errors in the file with updating, and to
simplify indexing and publication; the word
processor was not yet available.
The first three editions of MIM (1966,
1968, and 1971) were in all uppercase font because of limitations of the printer available for
preparing the camera copy for photo-offset
publication. Beginning with the fourth edition (1975), automatic typesetting has provided conventional type styles.
I did the lion’s share of the authoring and
editing of MIM for all print editions, ably
aided by editorial assistants, particularly Carol
Bocchini, who has worked on MIM full time
since 1979 and has served as writer/editorial
director of OMIM since 1998. In the ninth
(1990) and the tenth (1992) editions, the title page indicated “with the assistance of
Clair A. Francomano, MD, and Stylianos
E. Antonarakis, MD.” To these was added
Peter L. Pearson, PhD, in the eleventh edition (1994); and Antonarakis, Francomano,
Orest Hurko, MD, Alan F. Scott, PhD, David
Valle, MD, and others in the twelfth edition (1998). Since 1998, a distributed authorship/editorship has been achieved, with the
involvement of an estimated eight full-time
equivalents working as writers and editors at
Hopkins and elsewhere. Since 1986, Joanna
Strayer Amberger, now OMIM project manager, has had charge of bibliographic review,
assignments to writers and editors, and upkeep of the gene map and other tables. Ada
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Hamosh (27) has been the scientific director
of the OMIM project for several years.
From 1973 to 1985, I was chair of the Department of Medicine of the Johns Hopkins
University School of Medicine and physicianin-chief of the Johns Hopkins Hospital. I reveled in the teaching of medical students and
residents. From the distinguished careers in
genetics of several of those students and residents, it appears that through teaching in a
framework of classic Oslerian medicine I may
have helped bring genetics into mainstream
medicine.
I did not find the administrative responsibilities of the University’s largest academic
department excessively onerous, nor those of
the clinical department of the Johns Hopkins
Hospital—despite the fact that during that
12-year period there was a major rebuilding of the hospital, a reorganization of the
Osler residency program into four firms, and
a decentralization of hospital administration
into six clinical functional units. Planning for
the structural rebuilding required my input
as department chairman. The rebuilding resulted in a major change from a departmentby-department pavilion-type layout to a horizontal layering of the inpatient units of each
department through several buildings, as well
◦
as a 180 switch of the front door from N.
Broadway to N. Wolfe St. in 1979.
On the clinical side of the Department of
Medicine, in 1975 I reorganized the Osler
residency, and the inpatient hospital units on
which the residents worked, into four firms
(57), each with its chief (assistant chief of service) and main in-hospital unit. Later, Robert
M. Heyssel, then president of the Johns
Hopkins Hospital, reorganized the hospital’s
administration into six “Functional Units,”
essentially six separate hospitals, of which
the Department of Medicine was one, each
with a functional unit director, the chair of
the clinical department, who was responsible for its administration, budget, and nursing
personnel (30).
Despite these busy and important hospital
responsibilities, and those related to direct-
ing a large research-oriented university department, I enjoyed the 12 years as chair. As
chairman from 1973 to 1985, I could still continue the academic triathlon of teaching, patient care, and research I have now engaged
in for 60 years. I mention all this here because the continuous updating of MIM, one of
my main contacts with genetics research while
I was chairman, had to be done in evenings
and weekends. It was a pleasant respite from
hospital and university business. Keeping up
MIM, building the human gene map through
the HGM workshops and the literature, and
organizing and directing the annual two-week
course at Bar Harbor assured that I did not fall
behind in the science and practice of medical
genetics. On the urging of Dean Richard S.
Ross, I stepped down from the chairmanship
in 1985, two years earlier than was mandated
by the rule of retirement at age 65. This, as it
turned out, was a fortunate move because I was
free to participate in the planning of the Human Genome Project (1986–1990) and in the
launching of OMIM (1987), the journal Genomics (1987), and HUGO (1988), as well as
to produce a book version of Mendelian Inheritance in Man at two-year intervals from 1986
(seventh edition) to 1994 (eleventh edition).
Two areas of particular focus in the assembly of MIM (and OMIM) have been (a) the
nature of the basic defects of hereditary disorders, and (b) the chromosomal map location
of the mutant genes that underlie them. For
40 years an attempt has been made to be comprehensive in recording information in these
two domains. The two domains are more
closely related than I had expected; chromosome mapping of mutant phenotypes became a main approach (“positional cloning”)
to defining basic defects of “mystery diseases”
in the last quarter century.
In the third book edition of MIM (1971),
a tabulation of known autosomal linkages
and chromosomal assignments was published
in the “front material”; it occupied only
a single page. In subsequent print editions, chromosome-by-chromosome tables of
mapped genes have been presented, and the
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same table, kept up on an ongoing basis, has
been accessible in the NCBI internet version, OMIM. The last print edition (1998)
devoted 116 pages to the tabular synopsis
of the human gene map and I estimate that
the January 2006 map in OMIM would require at least 256 printed pages in the same
layout.
The nature of the basic defects in hereditary disorders was tabulated beginning in the
fourth edition (1975), with a listing of enzymopathies and one of structural protein variants (polymorphism) as part of the “front material.” The known amino acid substitutions
in hemoglobin variants were cataloged from
the beginning; for example, the first edition
(1966) listed the amino acid changes in a
dozen or more variants of the β-globin chain.
The second edition (1968) had a comprehensive tabulation of known amino acid changes
in variant hemoglobins, which was appended
to the entry for the particular globin type.
This was the forerunner of the practice of
listing descriptions of individual allelic variants after the entry for the gene. The allelic
variants are given a unique entry number of
10 digits formed by adding .0001 and so on
to the six-digit entry number for the gene.
Allelic variants numbered in this way were
first listed in the seventh print edition (1986).
Thus, the common mutation responsible for
cystic fibrosis, deletion of amino acid residue
phenylalamine-508, carries the entry number
602421.0001. [602421 is the entry number for
the CFTR gene, which is mutant in cystic fibrosis; 219700 is the number of the entry describing the phenotype(s) and genetics of cystic fibrosis.]
With the accelerating identification of mutant genes and specific DNA changes in genetic disorders, the number of entries with
listed allelic variants has increased rapidly (1a).
As of May 1, 2006, OMIM had identified
1871 genes in which at least one diseaserelated mutation had been described. Because
many genes are the site of different (allelic)
mutations causing multiple distinct phenotypes, the total number of phenotypes for
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which the molecular basis had been identified as residing in one of these 1871 genes was
3112.
All genes that have been identified as the
site of disease-related mutations have been
mapped to specific chromosomal sites. Therefore, the “Disorder” field in the tabular presentation of the gene map, which can be accessed online directly from the OMIM entry
for a particular gene, lists the distinct disorders that are known to be related to mutation
in that gene.
The successive English book editions of
MIM [along with the Spanish (1976), Russian
(1976), and Mandarin (1996) editions] constitute a four-foot shelf of books. (Each of the
English editions has a different color of cover.
I am probably the only author that people
used to ask not what my next book will be
on, but rather what color my next book will
be.) The successive 12 editions (1966–1998)
represent serial cross sections of the medical genetics field over more than 30 years.
Economic considerations make a multivolume (the 1998, or twelfth edition, is in three
volumes) print edition less practical; internet
access to OMIM, which is updated essentially
daily, makes the periodic print edition less
necessary. Nonetheless, the historian in me
grieves the loss of the historical record that
can be retrieved more easily from the successive print editions.
For the first eight editions of MIM (1966–
1988), the individual entries were assembled, organized, and updated in a diachronic
(“through time”) or historical mode, rather
than the descriptive or synchronic (“one point
in time”) mode characteristic of encyclopedias
and textbooks. The historical approach is that
used by the Oxford English Dictionary, which
has other parallels to MIM. Beginning with
the ninth edition (1990), many long entries
in OMIM were reorganized into topical sections, within each of which the diachronic sequence was usually retained. For a long time,
at least 10 years, most new entries have been
organized in topical sections at the time of
creation.
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The heavy use of OMIM is reflected by
the large number of users who visit the internet site daily. The wide use and depth of
information in OMIM is reflected by the following statistics on May 18, 2006: approximately 15,300,000 references to OMIM are
listed by Google. (Google has approximately
16,300,000 references to the Encyclopedia
Britannica and 33,200,000 to the Oxford English Dictionary.) Every phenotype and every
gene discussed in OMIM appears to be indexed in Google, as well as many symptoms,
signs, laboratory tests, and so on.
In a letter to the editor of the New England
Journal of Medicine, the correspondent (23) described a clinical case conference in which the
diagnosis was not made by a distinguished
visiting professor, but by a resident. When
asked how she made it, the resident said
she consulted Google using the signs, symptoms, and test findings. A Boston pediatricianbioinformatician tells me that when he makes
teaching rounds he tells his students and residents to consult Google and OMIM for help
with diagnostically puzzling cases.
The clinical usefulness of OMIM in clinical diagnosis is indicated by the above anecdote. Its usefulness in research is evident
in the fields of gene mapping and identification of basic molecular defects. OMIM
is also useful in teaching. In 1993, I published “Medical Genetics: A Self-Instruction
Guide and Workbook Based on (Online)
Mendelian Inheritance in Man” (68). This
consisted of a set of questions the answers
to which could be found in OMIM, with the
help of the search engine available at that
time.
CONCLUDING COMMENT
This personal account spans almost 60 years
from the polyps-and-spots syndrome to the
present. It seems appropriate that it should
finish with a discussion of OMIM, which
chronicles the phenomenal advances that represent the present scientific and clinical base
for the discipline of medical genetics and also
much of our understanding of the genetics and
genomics of our species.
ACKNOWLEDGMENT
To my wife, Dr. Anne B. McKusick, I am indebted for support, encouragement, and frequent
advice that began 60 years ago when she matriculated at Johns Hopkins Medical School.
She attests to the accuracy of the present account and has done her best to keep me from
exaggeration and braggadocio.
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Annual Review of
Genomics and
Human Genetics
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Contents
Volume 7, 2006
A 60-Year Tale of Spots, Maps, and Genes
Victor A. McKusick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Transcriptional Regulatory Elements in the Human Genome
Glenn A. Maston, Sara K. Evans, and Michael R. Green p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29
Predicting the Effects of Amino Acid Substitutions on Protein
Function
Pauline C. Ng and Steven Henikoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p61
Genome-Wide Analysis of Protein-DNA Interactions
Tae Hoon Kim and Bing Ren p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81
Protein Misfolding and Human Disease
Niels Gregersen, Peter Bross, Søren Vang, and Jane H. Christensen p p p p p p p p p p p p p p p p p p p p p 103
The Ciliopathies: An Emerging Class of Human Genetic Disorders
Jose L. Badano, Norimasa Mitsuma, Phil L. Beales, and Nicholas Katsanis p p p p p p p p p p p p p 125
The Evolutionary Dynamics of Human Endogenous Retroviral
Families
Norbert Bannert and Reinhard Kurth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 149
Genetic Disorders of Adipose Tissue Development, Differentiation,
and Death
Anil K. Agarwal and Abhimanyu Garg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175
Preimplantation Genetic Diagnosis: An Overview of Socio-Ethical
and Legal Considerations
Bartha M. Knoppers, Sylvie Bordet, and Rosario M. Isasi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201
Pharmacogenetics and Pharmacogenomics: Development, Science,
and Translation
Richard M. Weinshilboum and Liewei Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 223
Mouse Chromosome Engineering for Modeling Human Disease
Louise van der Weyden and Allan Bradley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
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The Killer Immunoglobulin-Like Receptor Gene Cluster: Tuning the
Genome for Defense
Arman A. Bashirova, Maureen P. Martin, Daniel W. McVicar,
and Mary Carrington p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
Structural and Functional Dynamics of Human Centromeric
Chromatin
Mary G. Schueler and Beth A. Sullivan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301
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Prediction of Genomic Functional Elements
Steven J.M. Jones p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 315
Of Flies and Man: Drosophila as a Model for Human Complex Traits
Trudy F.C. Mackay and Robert R.H. Anholt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
The Laminopathies: The Functional Architecture of the Nucleus and
Its Contribution to Disease
Brian Burke and Colin L. Stewart p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Structural Variation of the Human Genome
Andrew J. Sharp, Ze Cheng, and Evan E. Eichler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 407
Resources for Genetic Variation Studies
David Serre and Thomas J. Hudson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
Indexes
Subject Index p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 459
Cumulative Index of Contributing Authors, Volumes 1–7 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 477
Cumulative Index of Chapter Titles, Volumes 1–7 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 480
Errata
An online log of corrections to Annual Review of Genomics and Human Genetics chapters
may be found at http://genom.annualreviews.org/
vi
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