Timeline: A History of the Human Genome Project

Author(s): Leslie Roberts

Source: Science , Feb. 16, 2001, New Series, Vol. 291, No. 5507 (Feb. 16, 2001), pp. 1195-
1200
Published by: American Association for the Advancement of Science

Stable URL: https://www.jstor.org/stable/3083473

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 I I AI - . -

1953 1984
i (April) James (May) Charles Cantor and David
Watson and Francis
Schwartz of Columbia University develop
Crick discover the
pulsed field electrophoresis (Cell).
double helical struc-
ture of DNA (Nature). (July) MRC scientists decipher the
complete DNA sequence of the
1972 I Epstein-Barr virus, 170 kb
(October) Paul Berg and co-workers I (Nature).
create the first recombinant DNA mole-
cule (PNAS).
4 (May) Robert Sinsheimer
1977 hosts a meeting at the University of
T Allan Maxam and Walter Gilbert California (UC), Santa Cruz, to discuss
(below) at Harvard University and the feasibility of sequencing
Frederick Sanger at the U.K. Medical the human genome.
Research
Council (MRC) (December) Kary Mullis and
independently colleagues at Cetus Corp.
.:.., 'C : develop meth- develop PCR, a technique to
ods for sequenc- replicate vast amounts of
ing DNA (PNAS, DNA (Science).
February; PNAS,
December).

TV

/i:I
Va;; ~,
j

1992 (October) The G

moves from Los
(April) After a dispute with then-NIH
NIH's and DOE's t
director Bernadine Healy over patenting
partial genes, Watson resigns as head of
NCHGR.
1994
(September) Jeffr

(June) Venter leaves NIH to set up The of Iowa, Cohen o

Institute for Genomic Research (TIGR), a publish a comple
nonprofit in Rockville, Maryland. William the human genom
Haseltine heads its sister company, spacing of 0.7 cM
Human Genome Sciences, to commercial-
ize TIGR products. 1995
(May to August
(July) Britain's Wellcome Trust enters the colleagues at UC
HGP with $95 million. develop improv
(PNAS, May); M
(September) Mel Simon of Caltech and Fuller at Amersh
colleagues develop BACs for cloning mostable polym
(PNAS).
* (July) Venter
I' (October) U.S. Fraser of TIGR a
and French Smith of Johns
teams complete lish the first se
the first physical free-living o
maps of chromo- Haemophilus
somes: David { 1.8 Mb (Scien
Page of the
Whitehead ....... (September)
ment funds s
Institute and colleagues (above) map the
Y chromosome (Science); Daniel Cohen of groups for a
the Centre d'Etude du Polymorphisme over 5 years
Humain (CEPH) and Genethon and col- University of
leagues map chromosome 21 (Nature). University.

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 .11X1. ?. I.i-- m

V (June) Leroy (Octobe

Hood (b
Smith of the system
California In
Technology fluores
(Caltech) a
leagues cleotides (Science).
announce th
automated DNA seque
machine Applied Biosystems Inc. puts the first auto-
(Nature).
mated sequencing machine, based on
(September) Charles DeLisi Hood's technology, on the market.
begins genome studies at
DOE, reallocating 1988
$5.3 million from (February) In a pivotal report, the NRC
the fiscal year endorses the Human Genome Project
1987 budget. (HGP), calling for a phased approach and
a rapid scale-up to $200 million a year of
1987 new money.
(February) Walter Gilbert
resigns from the U.S. (March) Prompted by advisers at a
National Research Council meeting in Reston, Virginia, James
(NRC) genome panel and Wyngaarden, then director of the
announces plans to start Genome Corp., National Institutes of Health (NIH),
with the goal of sequencing and copy- decides that the agency should be
righting the human genome and selling a major player in the HGP, effec-
data for profit. tively seizing the lead from DOE.

'he GenBank database officially (September) DOE initiates six pilot

n Los Alamos to NCBI, ending projects, funded at $5 million total,
)OE's tussle over control. to sequence the ends of BAC clones.

(October) An international consor-

) Jeffrey Murray of the University
tium publicly releases the com-
plete genome sequence of the
hen of Genethon, and colleagues
yeast S. cerevisiae (Science).
)mplete genetic linkage map of
genome, with an average marker
(November) Yoshihide Hayashizaki's
3.7 cM (Science). -4

group at RIKEN completes the first set

I of full-length mouse cDNAs.

igust) Richard Mathies and

:t

1997
at UC Berkeley and Amersham
(January) NCHGR is promoted to the
iproved sequencing dyes o
National Human Genome Research
:
y); Michael Reeve and Carl CI :Y

Institute; DOE creates the Joint Genome

,mersham develop ther- Institute.
)olymerase (Nature, August).
T (September) Fred Blattner, Guy
enter and Claire
FIGR and Hamilton Plunkett, and University of

ohns Hopkins pub- '. Wisconsin, Madison, colleagues

complete the DNA sequence
st sequence of a
of E. coli, 5 Mb (Science).
ving organism,
ophilus influenzae,
b (Science).
: (September) Molecular
Dynamics introduces the
.mber) The Japanese govern- MegaBACE, a capillary
funds several sequencing sequencing machine.
Is for a total of $15.9 million
i years: Tokai University, 1998
rsity of Tokyo, and Keio (January) NIH announces a new project to
find-SNPs.

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nt scientists develop a (September) Olson, Hood, Botstein, and
d DNA sequencing with Cantor outline a new mapping strategy,
in-terminating dideoxynu- using STSs (Science).
ce).
(September) DOE and NIH start a joint com-
ems Inc. puts the first auto- mittee on the ethical, legal, and social
ng machine, based on implications of the HGP
)gy, on the market.
(October) NIH office is elevated to the
National Center for Human Genome
pivotal report, the NRC Research (NCHGR), with grant-awarding
uman Genome Project authority.
or a phased approach and
p to $200 million a year of 1990
* Three groups develop capillary elec-
trophoresis, one team led by
) Prompted by advisers at a Lloyd Smith (Nucleic Acids
Ig in Reston, Virginia, James Research, August), the second
aarden, then director of the by Barry Karger (Analytical
lal Institutes of Health (NIH), Chemistry, January), and the
is that the agency should be third by Norman Dovichi
)r player in the HGP, effec- (Journal of Chromatography,
seizing the lead from DOE. September).

I i

(October) NIH and DOE throw HGP into * (October) DOE

overdrive with a new goal of creatinglaborative
a project
"working draft" of the human genome tobysequence the
2001, and they move the completion genome
date of the
for the finished draft from 2005 to 2003.
puffer fish, Fugu
rubripes, by Marc
(December) Sulston of the 2001.
Sanger Centre and Robert
Waterston of Washington - (Decembe
University and colleagues com- tional consor
plete the genomic sequence of pletes the s
C. elegans (Science). the first pla
thaliana, 12
1999
(March) NIH again moves up (December) HGP and Celera's plans for
the completion date for the joint publication in Science collapse;
rough draft, to spring 2000. HGP sends its paper to Nature.
Large-scale sequencing efforts
are concentrated in centers at 2001
Whitehead, Washington University, * (February)
Baylor, Sanger, and DOE's Joint The HGP con-
Genome Institute. sortium pub-
lishes its
(April) Ten companies and the Wellcome working draft
Trust launch the SNP consortium, with in Nature (15
i plans to publicly release data quarterly. February),
and Celera
(September) NIH launches a project to publishes its
sequence the mouse genome, devoting draft in
$130 million over 3 years. Science (16
February).

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 The Human n e r
Genome Project ...i jIJ m> [r cS
PATENT SKIRMISHES
From the outset, the proposal to map and sequence the
human genome has sparked controversy and evoked "I am horrified."
Jamesthe
strong emotions. The following quotes capture how Watson, Science, 11 October 1991, on NIH's plans to patent

debate has shifted over the years. J. Craig Venter's partial genes

"There is no coherent government policy [on gene

EARLY DEBATES patents] and we need one-quick-since the sequence
is just pouring out. It would be a big mistake to leave
"It endangers all of us, especially the young this one to the lawyers." David Galas, Science, 11 October 1991
researchers." David Botstein, Science, 27 June 1986
VENTER ANNOUNCES CELERA
"The idea is gathering momentum.
"It strikes me that this is a cream-skimming approach. It's
I shiver at the thought." David Baltimore, Science, 27 June 1986
clearly an attempt to short-circuit the hard problems
"The idea of trudging through the genomeand defer them to the [research] community at a very
sequence
substantial cost." Robert Waterston, Science, 15 May 1998
by sequence does not command wide and enthusiastic
support in the U.K." Sydney Brenner, Science, 8 August 1986
"I think it's great."
David Cox, Science, 15 May 1998
"The total human sequence is the grail of human genetics."
Walter Gilbert, Science, 27 June 1986
"Every time we talk, we move [the deadline] up."
Robert Waterston, Science, 19 March 1999,
"It is clearly no longer a question of whether the project
ought to be done, but of how fast it will be done." on the new goal to produce a rough draft
Russell Doolittle, Science, 13 February 1987
"The scientific community thinks this is just a
business
"I'm surprised consenting adults have been caught in public project, and the business community
talking about it [sequencing the genome].... It makes noit's just a science project." J. Craig Venter,
thinks
sense." Robert Weinberg, New Scientist, 5 March 1987 Science, 18 June 1999

"The sequence of the human genome would "Why should I play by their rules when I am
be perhaps
the most powerful tool ever developed to not getting
explore thea cent of federal money? Let me get
mysteries of human development and this straight. I am being criticized for doing the
disease."
Leroy Hood, Issues in Science and Technology,work and
Spring giving it away free, but not giving it
1987
away fast enough?" J. Craig Venter, interview with
WALTER GILBERT DECLARES HE WILL
L. Roberts, 2 September 1999
COPYRIGHT AND SELL DNA DATA

"The idea of the company is to be a service to THE DRAFT NEARS COMPLETION

the biotech and pharmaceutical industries and to the

"The change is so fundamental it is hard for
research community.... [The sequence data] would be made
even scientists to grasp." Maynard Olson, interview
available to everyone-for a price." with L. Roberts, 16 November 1999
Walter Gilbert, Science, 24 July 1987
"Ten, 15 years from now, nobody is going to care
"This information is so important that it cannot be
about all this fuss and bother. They're going to care
proprietary." C. Thomas Caskey, Science, 24 July 1987
that we got the ... human sequence done.... And all
this back and forthing over who did what and what
"If a company behaves in what scientists believe is a socially
responsible manner, they can't make a profit." strategy was used and which money was public
Robert Cook-Deegan, Science, 24 July 1987 and which was private is probably going to sink
below the radar screen. And hallelujah."
THE PUBLICATION OF THE "FIRST" GENETIC MAP
Francis Collins, interview with L. Roberts, 19 August 1999
"What they have accomplished is important ... But it is
not what we believe should be properly called "We've
a map.called the human genome the blueprint, the
... We would never have dreamed of making Holy Grail, all sorts of things. It's a parts list. If I gave
such
you the parts list for the Boeing 777 and it has 100,000
a publication with our data set, which is substantially
larger than theirs, because we still parts,
have I don't think you could screw it together, and you
certainly
significant gaps." Ray White, Science, 6 November 1987 wouldn't understand why it flew." Eric Lander,
Millennium Evening at the White House, 14 October 1999
"A map is a map. Our map has holes, we make no bones
about it.... It is not Ray White's ideal, but so"Free
what?"
will will not go out of style once the
Helen Donis-Keller, Science, 6 November 1987 sequence is done." Francis Collins, interview with
L. Roberts, 11 November 1999
"It's a real shame that the only two groups in the world
who are doing this haven't communicated and shared "The prevailing view is that the genome is going to
probes." Leroy Hood, Science, 6 November 1987 revolutionize biology, but in some ways, it's overhyped. In
SUPPORT BUILDS the end, the real insights are coming from individuals
studying one gene at a time in real depth." Gerald Rubin,
"You can't be against getting this information; it is too
interview with E. Pennisi, May 2000
fundamental." Charles Cantor, Science, 12 February 1988
"If there is anything worth doing twice, it's the human
"The argument against DOE is that while they talk about
genome." David Haussler, interview with E. Pennisi, July 2000
peer review, it is not clear that they do it.... [About NIH,]
you can't have a lead agency that doesn't want to do it." "Biology will never be the same."
Bruce Alberts, Science, 12 February 1988
John Sulston, interview with E. Pennisi, February 2000

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 I a
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 THE HUMAN GENOME: NEWS

Allele Alternative versions of aHomologous

gene or genes Genes with
other similar structures and
segment
of a chromosome functions

Intron Region
Alternative splicing Different ways of a gene's DNA that
of combining a is not translated
gene's exons to make variants of into a protein
the complete protein
Amplification Repeated copyingJunkof
DNA a piece
Stretches of
of DNA DNA
that do not code for genes;
most of coding
Annotate Identify the locations and the genome consists
regionsof so-calledof
junk DNA
genes in a genome and determine
Kilobase what they
(kb) Unit of do equal to 1000 bases
DNA length
Assembly Putting sequenced fragments oflocation
-Locus Chromosomal DNA of ainto
gene or other piece
their correct chromosomal positions
of DNA
BAC Bacterial artificial chromosome: bacterial
Megabase (Mb) DNA
Unit of DNA length equalspliced
to 1 million bases
with a medium-sized fragment of a genome (100 to 300
PCR Polymerase
kb) to be amplified in bacteria and sequenced chain reaction: a technique for ampli-
fying a piece of DNA quickly and cheaply
Bioinformatics The study of genetic and other biological
Physical map A map of thetechniques
information using computer and statistical locations of identifiable
markers spaced along the chromosomes; a physical
BLAST A computer program that identifies homologous
map may also be a set of overlapping clones
genes in different organisms, such as human, fruit
fly, or nematode Plasmid Loop of bacterial DNA that replicates inde-
pendently of the chromosomes; artificial plasmids
Centimorgan (cM) A unit of genetic distance, deter-
can be inserted into bacteria to amplify DNA for
mined by how frequently two genes on the same
sequencing
chromosome are inherited together
Polymorphism A variation in DNA sequence within a
Centromere The difficult-to-sequence central region of
population
a chromosome
Proteome The full complement of proteins produced by
Coding DNA Sequences transcribed into protein struc-
a particular genome
tures; also called exons
Proteomics The study of the full set of proteins encod-
Contig Contiguous sequence of DNA created by assem-
ed by a genome
bling overlapping sequenced fragments of a chromo-
some (whether natural or artificial, as in BACs) Pseudogene A sequence of DNA similar to a gene but
nonfunctional; probably the remnant of a once-
Cosmid DNA from a bacterial virus spliced with a small
functional gene that accumulated mutations
fragment of a genome (45 kb or less) to be amplified
and sequenced Regulatory region A segment of DNA that controls
whether a gene will be expressed and to what degree
Directed sequencing Successively sequencing DNA from
adjacent stretches of chromosome Repetitive DNA Sequences of varying lengths that
occur in multiple copies in the genome; it represents
Draft sequence Sequence with lower accuracy than a much of the genome
finished sequence; some segments are missing or in
the wrong order or orientation Restriction enzyme An enzyme that cuts DNA at specif-
ic sequences of base pairs
EST Expressed sequence tag: a unique stretch of DNA
within a coding region of a gene; useful for identify- RFLP Restriction fragment length polymorphism: genetic
ing full-length genes and as a landmark for mapping variation in the length of DNA fragments produced
by restriction enzymes; useful as markers on maps
Exon Region of a gene's DNA that encodes a portion of its
protein; exons are interspersed with noncoding introns Scaffold A series of contigs that are in the right order
but are not necessarily connected in one continuous
Finished sequence Sequence in which bases are identi- stretch of sequence
fied to an accuracy of no more than 1 error in 10,000
and are placed in the right order and orientation Shotgun sequencing Breaking DNA into many small
along a chromosome with almost no gaps pieces, sequencing the pieces, and assembling the
fragments
FISH Fluorescence in situ hybridization: a method for
pinpointing the location of a piece of DNA sequence SNP Single-nucleotide polymorphism: common, single-
on a chromosome base-pair variations in DNA

Functional genomics The study of genomes to determine Structural genomics The effort to determine the 3D
the biological function of all the genes and their products structures of large numbers of proteins using both
experimental techniques and computer simulation
Gene expression Conversion of the information encoded
in a gene first to messenger RNA and then to a proteinSTS Sequence tagged site: a unique stretch of DNA
whose location is known; serves as a landmark for
Gene prediction Predictions of possible genes made by
mapping and assembly
a computer program based on how well a stretch of
Telomere The free end of a chromosome
DNA sequence matches known gene sequences
Genetic linkage map A map of the relative positions ofTranscription factor A protein that binds to regulatory
genes and other regions on a chromosome, deter- regions and controls gene expression
mined by how often loci are inherited together Transcriptome The full complement of activated genes,
Genome The entire chromosomal genetic material of or mRNAs or transcripts, in a particular tissue at a
an organism particular time

Genomics The comprehensive study of whole sets of YAC Yeast artificial chromosome: yeast DNA spliced
genes and their interactions rather than single genes with a large fragment of a genome (up to 1000 kb)
or proteins to be amplified in yeast cells and sequenced
16 FEBRUARY 2001 VOL 291 SCIENCE www.sciencemag.org

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