A Dictionary of Genetics phần 10 pptx

532 APPENDIX C: CHRONOLOGY
I. Zaenen and four colleagues discover the tumor-inducing plasmid of the
crown gall bacterium.
K. M. Murray and N. E. Murray manipulate the recognition sites for restriction
endonucleases in lambda (λ) bacteriophage so that its chromosome can be used
as a receptor site for restriction fragments from foreign DNAs. Lambda thus
becomes a cloning vehicle.
A. Tissieres, H. K. Mitchell, and U. M. Tracy find that heat shocks result in
the synthesis of six new proteins in Drosophila. These are also synthesized by
tissues that do not have polytene chromosomes.
B. Dujon, P. P. Slonimski, and L. Weill propose a model for recombination
and segregation of mitochondrial genomes in Saccharomyces cerevisiae. Accord-
ing to it, mtDNA molecules are present in the zygote cell in multiple copies.
These pair at random, and during any mating cycle a segment from one parent
can exchange with that from a second parent mtDNA yielding recombinant
units.
R. D. Kornberg proposes that chromatin is built up of repeated structural units
of 200 base pairs of DNA and two each of the histones H2A, H2B, H3, and
H4. These structures, which are later called nucleosomes, are isolated by
M. Noll. A. L. Olins, and D. E. Olins publish the first electron micrographs of
chromatin spreads from nuclei that show nucleosomes.
B. Ames develops a rapid screening test for detecting mutagenic and possibly
carcinogenic compounds.
S. Brenner describes methods for inducing, isolating, and mapping mutations
in the nematode Caenorhabditis elegans.
R. W. Hedges and A. E. Jacob discover in E. coli that ampicillin-resistance genes
can be transferred between plasmids that show no DNA homology. The agent
responsible is a mobile DNA sequence, which they named a transposon.
J. Ott invents the first computer program (LIPED) for the efficient computa-
tion of lod scores.
C. A. Hutchison and three colleagues demonstrate the maternal inheritance of

mitochondrial DNA in horse-donkey hybrids.
G. L. Stebbins publishes Flowering Plants: Evolution Above the Species Level,
which brings a modern framework of cytogenetics and systematics to the study
of plant evolution.
A. Claude, C. de Duve, and G. Palade receive Nobel Prizes for their contribu-
tions to cell biology.
1975 G. Ko
¨
hler and C. Milstein perform experiments with mouse cells that show
that somatic cell hybridization can be used to generate a continuous “hybrid-
oma” cell line producing a monoclonal antibody.
Molecular biologists from around the world meet at Asilomar, California, to
write a historic set of rules to guide research in recombinant DNA experi-
ments.
The NIH Recombinant DNA Committee issues guidelines aimed at eliminating
or minimizing the potential risks of recombinant DNA research.
L. L. Goldstein and M. S. Brown demonstrate that normal fibroblasts have
binding sites for low-density lipoproteins, whereas fibroblasts from humans ho-
mozygous for the hypercholesterolemia gene lack these receptors.
APPENDIX C: CHRONOLOGY 533
M. Grunstein and D. S. Hogness develop the colony hybridization method for
the isolation of cloned DNAs containing specific DNA segments or genes.
A. T. C. Carpenter identifies recombination nodules in Drosophila melanogas-
ter. She points out the correlation between the number of RNs and the number
of meiotic exchanges.
D. Pribnow determines the nucleotide sequences of two independent bacterio-
phage T7 promoters, and compares these and other known promoter sequences
to form a model for promoter structure and function.
E. M. Southern describes a method for transferring DNA fragments from agar-
ose gels to nitrocellulose filters. The filters are subsequently hybridized to ra-

dioactive RNA and the hybrids detected by autoradiography.
W. D. Benton and R. W. Davis describe a rapid and direct method for screen-
ing plaques of recombinant lambda bacteriophages that involves transfer of
phage DNA to a nitrocellulose filter and detection of specific DNA sequences
by hybridization to complementary labeled nucleic acids.
F. Sanger and A. R. Coulson develop the “plus and minus” method for deter-
mining the nucleotide sequences in DNA by primed synthesis with DNA poly-
merase.
M. C. King and A. C. Wilson point out that 99% of the proteins that have
been studied in humans and chimpanzees have identical amino acid sequences.
They conclude that the biological differences between these two species must
be largely the result of mutations that involve regulatory rather than structural
genes.
G. Morata and P. A. Lawrence show in Drosophila that the engrailed mutation
allows cells of the posterior wing compartment to mix with those of the ante-
rior compartment. Therefore, the normal allele of this gene functions to define
the boundary conditions between the sister compartments of the developing
wing.
B. Mintz and K. Illmensee inject XY diploid cells from a malignant mouse
teratocarcinoma into mouse blastocysts that then are transferred to foster
mothers. Cells derived from the carcinoma appear in both somatic and germ
cells of some F
1
males. When these are mated, some F
2
mice contain marker
genes from the carcinoma. The experiments demonstrate that the nuclei of
teratocarcinoma cells remain developmentally totipotent, even after hundreds
of transplant generations during which they functioned in malignant cancers.
S. L. McKenzie, S. Henikoff, and M. Meselson isolate mRNAs for heat-shock

proteins and show that they hybridize to specific puff sites on the Drosophila
polytene chromosomes.
L. H. Wang and three colleagues locate within the RNA genome of the Rous
sarcoma virus the segment responsible for its oncogenic activity.
G. Blobel and B. Dobberstein put forth the signal hypothesis.
R. Dulbecco, H. Temin, and D. Baltimore receive Nobel Prizes for their studies
on oncogenic viruses.
1976 H. R. B. Pelham and R. J. Jackson describe a simple and efficient mRNA-
dependent in vitro translation system using rabbit reticulocyte lysates.
W. Fiers and 11 colleagues complete their analysis of MS2 RNA. This is the
first virus to have its genome sequenced from beginning to end.
534 APPENDIX C: CHRONOLOGY
R. V. Dippell shows in Paramecium that kinetosomes contain RNA (not DNA)
and that RNA (not DNA) synthesis accompanies kinetosome reproduction.
N. Hozumi and S. Tonegawa demonstrate that the DNA segments coding for
the variable and constant regions of an immunoglobulin chain are distant from
one another in the chromosomes isolated from mouse embryos, but the seg-
ments are adjacent in chromosomes isolated from mouse plasmacytomas. They
conclude that somatic recombination during the differentiation of B lympho-
cytes moves the constant and variable gene segments closer together.
W. Y. Kan, M. S. Golbus, and A. M. Dozy are the first to use recombinant
DNA technology in a clinical setting. They develop a prenatal test for alpha
thalassemia utilizing molecular hybridization techniques.
P. M. Nurse, P. Thuriaux, and K. Nasmyth elucidate the genetic control of the
cell division cycle in Schizosaccharomyces pombe. Among the genes that control
mitosis are those that encode cyclin-dependent kinases.
M. F. Gellert and three colleagues discover DNA gyrase to be the enzyme that
converts a relaxed, closed, circular DNA molecule into a negatively supercoiled
form.
W. Y. Chooi shows that ferritin-labeled antibodies raised against proteins (iso-

lated from rat ribosomes) bind to the terminal knobs of fibers extending from
Miller trees (isolated from the ovarian nurse cells of Drosophila). This observa-
tion proves that Miller trees are rRNA transcription units and shows that at
least some ribosomal proteins attach to a precursor rRNA molecule before its
transcription is completed.
B. G. Burrell, G. M. Air, and C. A. Hutchison report that phage phiX174
contains overlapping genes.
Formal guidelines regulating research involving recombinant DNA are issued
by the National Institutes of Health in the United States.
H. Boyer and R. Swanson found Genentech, an event which marks the begin-
ning of the biotech industrial revolution.
A. Efstratiadis and three colleagues are the first to enzymatically generate eu-
karyotic gene segments in vitro. They synthesize double-stranded DNA mole-
cules that contain the sequences transcribed into the mRNAs for the alpha and
beta chains of rabbit hemoglobin.
J. T. Finch and A. Klug propose that the 300 A
˚
threads seen in electron micro-
graphs of fragmented chromatin are formed by the folding of DNA-nucleo-
some filaments into solenoids.
L. H. Miller and three colleagues conclude that the Duffy blood group antigens
(Fy
a
and Fy
b
) serve as receptors for the merozoites of Plasmodium vivax and
that individuals of blood group Fy
−
/Fy
−

are resistant to P. vivax infections be-
cause their red cells lack these receptors.
1977 A. Knoll and E. S. Barghoorn find microfossils which they interpret as undergo-
ing cell division in rocks 3,400 million years old. This discovery pushes back
the age of life on earth to the lower Archean eon.
J. B. Corliss and R. D. Ballard aboard Alvin, a deep-diving minisubmarine, dis-
cover communities of hyperthermophilic bacteria, tube worms, clams, and
other organisms, living in the Galapagos rift.
E. M. Ross and A. G. Gilman show that adenylcyclase is regulated by a protein
that binds GTP. This G protein is purified three years later and shown to be a
heterotrimer.
APPENDIX C: CHRONOLOGY 535
K. Itakura and six colleagues chemically synthesize a gene for human somato-
statin and express it in E. coli. This leads to the commercial production of the
first artificial human protein, somatostatin.
S. M. Tilghman and eight colleagues clone the first protein-encoding gene
(mouse beta-hemoglobin) using bacteriophage lambda as a vector.
C. Jacq, J. R. Miller, and G. G. Brownlee describe the presence of “pseudo-
genes” within the 5S DNA cluster of Xenopus laevis oocytes.
J. C. Alwine, D. J. Kemp, and G. R. Stark prepare diazobenzyloxymethyl
(DBM) paper and describe methods for transferring electrophoretically sepa-
rated bands of RNA from an agarose gel to the DBM paper. Specific RNA
bands are then detected by hybridization with radioactive DNA probes, fol-
lowed by autoradiography. Since this method is the reverse of that described
by Southern (1975) in that RNA rather than DNA is transferred to a solid
support, it has come to be known as “northern blotting.”
F. Sanger and eight colleagues report the complete nucleotide sequence for the
DNA genome of bacteriophage phiX174.
E. W. Silverton, M. A. Navia, and D. R. Davies determine the three-dimen-
sional structure of the human immunoglobulin molecule.

M. Leffak, R. Grainger, and H. Weintraub show that “old” histone octamers
remain intact during DNA replication and that “new” octamers consist entirely
of proteins synthesized immediately before replication.
C. Woese and G. E. Fox conclude from their studies of the nucleotide se-
quences of the 16S rRNAs of certain newly discovered microorganisms that
they should be placed in a domain separate from the other bacteria (the
Archaea).
W. Gilbert induces bacteria to synthesize useful nonbacterial proteins (insulin
and interferon).
A. M. Maxam and W. Gilbert publish the “chemical method” of DNA se-
quencing.
R. J. Roberts and P. A. Sharp lead groups that discover split genes in adenovirus
2. R-loop mapping by L. Chow and S. Berget shows the position of intron
loops. Intervening noncoding segments are then described for genes that encode
animal proteins, namely, the rabbit beta-globin gene (A. Jeffreys and R. A.
Flavell) and the chicken ovalbumin gene (R. Breathnach, J. L. Mandel, and
P. Chambon).
J. Weber, W. Jelinek, and J. E. Darnell report that alternative splicing of non-
consecutive DNA segments in the adenovirus-2 genome can produce multiple
mRNAs.
J. F. Pardon and five colleagues use neutron contrast matching techniques to
demonstrate that in nucleosomes the DNA segment that attaches to the his-
tone octamer is on the outside of the particle.
J. Sulston and H. R. Horvitz work out the postembryonic cell lineages for
Caenorhabditis elegans.
J. Collins and B. Holm develop cosmids for cloning large DNA fragments.
F. Lee and C. Yanofsky explain the mechanism of attenuation that takes place
in the tryptophan operon of E. coli.
R. S. Yalow receives a Nobel Prize for developing the radioimmunoassay proce-
dure.

536 APPENDIX C: CHRONOLOGY
1978 R. M. Schwartz and M. O. Dayhoff compare sequence data for a variety of
proteins and nucleic acids from an evolutionarily diverse assemblage of pro-
karyotes, eukaryotes, mitochondria, and chloroplasts. Their computer-gener-
ated evolutionary trees identify the times during evolution when protoeukaryo-
tic organisms entered into symbiosis with mitochondria and chloroplasts (about
2 and 1 billion years ago, respectively).
W. Gilbert coins the terms intron and exon.
T. Maniatis and seven colleagues develop a procedure for gene isolation, which
involves construction of cloned libraries of eukaryotic DNA and screening these
libraries for individual sequences by hybridization to specific nucleic acid
probes.
M. S. Collett and R. L. Erickson report that the product of the src gene of the
Rous sarcoma virus is a protein kinase.
W. Bender, R. Spierer, and D. Hogness describe a method for sequencing genes
they call chromosome walking.
E. B. Lewis concludes that the component genes in the bithorax complex have
related functions in Drosophila segmentation and that they evolved from a
smaller number of ancestral genes by their duplication and subsequent special-
ization.
C. Coulondre and three colleagues show that sites in the DNA of E. coli identi-
fied as mutational hot spots contain the modified pyrimidine, 5-methylcyto-
sine.
V. B. Reddy and eight colleagues publish the complete nucleotide sequence for
simian virus 40 and correlate the sequence with the known genes and mRNAs
of the virus.
Y. W. Kan and A. M. Dozy demonstrate the value of using restriction-frag-
ment-length polymorphisms as linked markers for the prenatal diagnosis of
sickle-cell anemia.
C. A. Hutchison and five colleagues demonstrate that it is possible to introduce

specific mutations at specific sites in a DNA molecule.
E. H. Blackburn and J. G. Gall demonstrate that telomeres from Tetrahymena
pyriformis consist of short DNA sequences (one strand containing AACCCC,
the other TTGGGG) repeated tandemly 30 to 70 times.
R. T. Schimke and three colleagues show that cultured mouse cells exposed to
methotrexate develop resistance by amplifying the genes that encode the en-
zymes that serve as the target for the drug.
W. Arber, H. O. Smith, and D. Nathans share the Nobel Prize in Physiology
or Medicine for the development of techniques utilizing restriction endonucle-
ases to study the organization of genetic systems.
P. D. Mitchell receives the Nobel Prize in Chemistry for his contribution to
the understanding of biological energy transfer through the formulation of the
chemiosmotic theory.
1979 J. G. Sutcliffe determines the complete 4,362 nucleotide pair sequence of the
plasmid cloning vector pBR322.
J. C. Avise, R. A. Lansman, and R. O. Shade successfully use restriction endo-
nucleases to measure mitochondrial DNA sequence relatedness in natural pop-
ulations.
APPENDIX C: CHRONOLOGY 537
The National Institutes of Health relax guidelines on recombinant DNA to
allow viral DNA to be studied.
S. Perdix-Gillot reports giant nuclei that are over 1 million–ploid in the cells
of the silk gland of Bombyx mori.
B. G. Barrell, A. T. Bankier, and J. Drouin report that the genetic code of
human mitochondria has some unique, nonuniversal features.
E. F. Fritsch, R. M. Lawn, and T. Maniatis determine the chromosomal arrange-
ment and structure of human globin genes utilizing recombinant DNA tech-
nology.
J. R. Cameron, E. Y. Loh, and R. W. Davis discover transposable elements in
yeast.

N. Wexler and a group of Venezuelan colleagues begin a study of natives who
are living in three fishing villages on the shore of Lake Maracaibo. Huntington
disease is prevalent in this population, and eventually an eight-generation pedi-
gree is constructed that contains over 11,000 people. Analyses of DNA samples
of this group lead to the localization and eventual sequencing of the HD gene
by MacDonald and coworkers in 1993.
D. V. Goeddel and nine colleagues construct a gene that encodes human
growth hormone (HGH) using recombinant DNA technology. The synthesized
gene is expressed in E. coli under the control of the lac promoter and a polypep-
tide having the properties of HGH is synthesized.
M. R. Lerner and J. A. Steitz report the discovery of small nuclear ribonucleo-
proteins (snurps).
1980 L. Olsson and H. S. Kaplan produce the first human hybridomas that manufac-
ture a pure antibody in laboratory culture.
A. Hershko, A. Ciechanover, I. A. Rose, and three other colleagues demon-
strate that proteins destined to be destroyed undergo ATP-dependent conjuga-
tion to a specific protein (APF-1). They later show that APF-1 is ubiquitin and
that it delivers doomed proteins to the 26S proteasome where they are broken
down into short peptides for reuse.
The United States Supreme Court rules that genetically modified microorgan-
isms can be patented. General Electric, on behalf of A. Chakrabarty, obtains a
patent for a genetically engineered microorganism capable of consuming oil
slicks.
D. Lowe describes stromatolites from the Archean of Western Australia. They
contain 3.8 billion-year-old fossils that resemble cyanobacteria.
J. W. Gordon and four colleagues produce the first transgenic mice by direct
injection of cloned DNA into the pronucleus of a fertilized egg.
M. R. Capecchi describes a technique for efficient transformation of cultured
mammalian cells by direct microinjection of DNA into cells with glass micropi-
pettes.

C. Woese and 10 colleagues publish the secondary structure for 16S ribosomal
RNA.
D. Botstein and three colleagues describe the method of using restriction frag-
ment length polymorphisms to construct genetic linkage maps of the human
genome.
538 APPENDIX C: CHRONOLOGY
W. F. Doolittle and C. Sapienza and, independently, L. E. Orgel and F. H. C.
Crick point out that the genomes of all species are littered with DNA segments
that contribute nothing to the fitness of the species and persist only because
they are efficient replicators. These authors name this collection of DNA seg-
ments selfish DNA and suggest that these DNAs represent the ultimate para-
sites.
H. Gronemeyer and O. Pongs demonstrate that, in Drosophila melanogaster sali-
vary glands, beta ecdysone binds directly to sites on polytene chromosomes
where ecdysone-inducible puffs occur.
C. Nu
¨
sslein-Volhard and E. Wieschaus describe the isolation and characteriza-
tion of zygotic segmentation mutations of Drosophila melanogaster.
L. Clark and J. A. Carbon clone the gene that corresponds to the centromere
of yeast chromosome 3.
A. R. Templeton provides a new theoretical framework for speciation by the
founder effect.
Nobel Prizes in Physiology and Medicine go to G. D. Snell, J. Dausset, and
B. Benacerraf for their contributions to immunogenetics.
P. Berg, W. Gilbert, and F. Sanger receive Nobel Prizes in Chemistry for their
contributions to the experimental manipulation of DNA.
1981 R. C. Parker, H. E. Varmus, and J. M. Bishop demonstrate that the tumorigenic
properties of the Rous sarcoma virus are due to a protein encoded by the v-src
gene. Cells from various vertebrates contain a homologous gene, c-src. The two

genes differ in that v-src has an uninterrupted coding sequence, whereas c-src
contains seven exons separated by six introns.
L. Margulis publishes Symbiosis in Cell Evolution. Here she summarizes the
evidence for the theory that organelles such as mitochondria, chloroplasts, and
kinetosomes evolved from prokaryotes that lived as endosymbionts in the an-
cestors of modern-day eukaryotes.
R. Lande proposes a new model of speciation based on sexual selection on
polygenic traits. This model results in a revival of interest in sexual selection.
J. D. Kemp and T. H. Hall transfer the gene of a major seed storage protein
(phaseolin) from beans to the sunflower via a plasmid of the crown gall bacte-
rium Agrobacterium tumefaciens, creating a “sunbean.”
T. R. Cech, A. J. Zaug, and P. J. Grabowski report the discovery of a self-
splicing rRNA in Tetrahymena thermophila. This is the first demonstration that
a macromolecule other than a protein can act as a biological catalyst.
W. F. Anderson and three colleagues determine the three-dimensional struc-
ture of the cro repressor at 2.8 A
˚
resolution.
G. Hombrecher, N. J. Brewin, and A. W. B. Johnson demonstrate that the
ability of Rhizobium bacteria to nodulate legumes and fix atmospheric nitrogen
is due to plasmid-linked genes.
P. R. Langer, A. A. Waldrop, and D. C. Ward develop a procedure for synthe-
sizing biotinylated DNA probes that hybridize normally with complementary
DNA, providing an anchor for streptavidin-linked, color-generating systems.
S. Anderson and 13 colleagues work out the complete nucleotide sequence and
genetic organization of the human mitochondrial genome.
APPENDIX C: CHRONOLOGY 539
H. Sakano and three colleagues discover two segments in the heavy chain im-
munoglobulin gene of the mouse, which serve as recognition sites for a somatic
DNA recombinase.

M. E. Harper and G. F. Saunders demonstrate that single-copy genes can be
mapped on human mitotic chromosomes utilizing an improved in situ hybrid-
ization technique.
J. Banerji, S. Rusconi, and S. Schaffner show that the transcription of the beta-
globin gene is enhanced hundreds of times when this gene is linked with certain
SV40 nucleotide sequences that they name “enhancer sequences.”
J. G. Gall and four colleagues localize histone mRNAs that are being tran-
scribed on the lampbrush chromosomes of salamander oocytes.
M. Chalfie and J. Sulston identify among the touch-insensitive mutants of
Caenorhabditis elegans five genes that affect a specific set of six sensory neu-
rons.
K. E. Steinbeck and three colleagues demonstrate that the resistance of a weed,
Amaranthus hybridus, to triazine herbicides is controlled by a chloroplast gene
that encodes a polypeptide to which the herbicide binds. Resistant strains of
the weed produce a modified gene product that fails to bind triazine.
J. D. Walker sequences the eight genes of the E. coli atp operon. These encode
the protein subunits of ATP synthase.
1982 Eli Lilly and Company markets a Genentech-licensed, recombinant, human in-
sulin. This is the first product generated by this new technology.
E. P. Reddy and three colleagues report that the genetic change that leads to
the activation of an oncogene carried by a line of human bladder carcinoma
cells is due to a single base substitution in this gene. The result is the incorpora-
tion of valine instead of lysine in the 12th amino acid of the protein encoded
by the oncogene.
P. Goelet and five colleagues determine the complete nucleotide sequence for
the RNA genome of the tobacco mosaic virus.
P. M. Bingham, M. G. Kidwell, and G. M. Rubin show that P strains of Dro-
sophila contain 30 to 50 copies per genome of a transposable P element. This
is the cause of hybrid dysgenesis. Then A. C. Spradling and Rubin demonstrate
that cloned P elements, when microinjected into Drosophila embryos, become

integrated into germ-line chromosomes and that P elements can be used as
vectors to carry DNA fragments of interest into the Drosophila germ line.
E. R. Kandel and J. G. Schwartz utilize the gill-withdrawal reflex in Aplysia to
study the molecular control of memory formation. They eventually show that
the long-term facilitation of sensory neurons requires the activation of cAMP-
responsive memory genes.
S. B. Prusiner shows that the infectious agent that causes scrapie is a protein,
which he calls a prion.
A. Klug receives the Nobel Prize for his contributions to the analysis of crystal-
line structures of biological importance, especially virus particles, tRNA, and
nucleosomes.
1983 E. A. Miele, D. R. Mills, and F. R. Kramer construct the first recombinant
RNA molecule by inserting a synthetic foreign deca-adenylic acid into a variant
of the RNA genome of phage Q beta via the action of the Q beta replicase.
540 APPENDIX C: CHRONOLOGY
H. J. Jacobs and six colleagues report the presence of promiscuous DNA in the
sea urchin.
T. Hunt and four colleagues demonstrate that sea urchin eggs contain a mater-
nal mRNA which encodes a protein that is synthesized after fertilization and
is cyclically destroyed and resynthesized during cleavage divisions. They name
the protein cyclin.
I. S. Greenwald, P. W. Sternberg, and H. R. Horvitz demonstrate that the lin-
12 mutant of Caenorhabditis functions as a developmental control gene.
M. Oren and A. J. Levine isolate and identify a cDNA of the p53 mRNA from
a SV-40-transformed mouse cell line.
S. D. Gillies and three colleagues show that a tissue-specific enhancer is located
in the first intron of the heavy-chain immunoglobulin gene.
W. Bender and seven colleagues sequence genes in the bithorax complex of Dro-
sophila and show that spontaneous mutations by bx, Ubx, and bxd are associ-
ated with insertions of transposable elements.

M. P. Scott and six colleagues sequence another group of segment identity
genes and work out the organization of the Antennapedia locus.
G. N. Godson and four colleagues clone the gene that encodes the circumspo-
rozoite protein of Plasmodium knowlesi, and they show that the protein con-
tains a repetitive epitope that serves as a decoy to the host immune system.
C. Guerrier-Takada and four colleagues show that ribonuclease P consists of
one protein and one RNA subunit and that the latter is the catalytic subunit.
L. Montagnier in France and R. Gallo in the United States lead teams that
independently publish accounts of the discovery of the virus that causes AIDS.
M. Kimura and T. Ohta estimate 1.8 × 10
9
years as the time of divergence
of eukaryotes and prokaryotes through comparative studies of the nucleotide
sequences of 5S rRNAs from humans, yeasts, and bacteria.
M. Rassoulzadegan and six colleagues isolate a recombinant DNA clone from
the polyoma virus that immortalizes cultured fibroblast cells from rat embryos.
They also show that only the amino-terminal portion of the protein encoded
by the viral gene carries the immortalizing function.
R. F. Doolittle and six colleagues demonstrate that the simian sarcoma virus
oncogene, v-sis, is derived from the gene encoding a platelet-derived growth
factor.
E. Hafen, M. Levine, and W. J. Gehring work out a technique for in situ hy-
bridization of labeled DNA probes to RNA transcripts in frozen tissue sections.
They succeed in localizing transcripts of homeotic genes to specific regions of
developing Drosophila embryos.
R. Mann, R. C. Mulligan, and D. Baltimore genetically engineer the Moloney
murine leukemia virus so that it can be used safely as a vector in gene transfer
experiments with mammalian hosts.
B. McClintock receives the Nobel Prize for her discovery of transposable ge-
netic elements.

1984 D. C. Schwartz and C. R. Cantor show that pulsed field gradient electrophore-
sis can be used to separate DNA fragments as large as 2,000 kbp. This method
overcomes the limitation of agarose gel electrophoresis, which can only sepa-
rate molecules of much smaller sizes (50 kbp or less).
APPENDIX C: CHRONOLOGY 541
J. Gitschier and eight colleagues report the cloning of the gene encoding the
antihemophilic factor in humans.
C. G. Sibley and J. E. Ahlquist show from DNA-DNA hybridization data that
humans are more closely related to chimpanzees than to any other hominoid
and estimate that the species diverged 5 or 6 million years ago.
R. F. Pohlman, N. V. Fedoroff, and J. Messing determine the nucleotide se-
quence of the maize transposable element Activator.
F. S. Collins and four colleagues identify mutations upstream of the gamma-
globin gene that cause it to be switched on in adults.
W. McGinnis and six colleagues discover and name the conserved homeobox
sequence in Drosophila homeotic genes, and they find that the mouse also con-
tains genes that influence segmentation and possess homeoboxes.
J. C. W. Shepherd and four colleagues show that yeast mating-type regulatory
proteins contain homeoboxes.
T. A. Bargiello and M. W. Young clone and sequence period, the first gene
known to control a biological clock.
M. Davis and T. Mak identify and clone the genes for the T cell receptor.
N. K. Jerne, G. Ko
¨
hler, and C. Milstein receive the Nobel Prize in Medicine
for their contributions to immunology.
R. B. Merrifield is awarded a Nobel Prize in Chemistry for his work in auto-
mated peptide synthesis.
1985 J. R. Miller, A. D. McLachlan, and A. Klug report the isolation and character-
ization of a zinc finger protein from Xenopus oocytes. This protein binds to the

5S RNA gene and controls its transcription.
M. P. Williamson, T. F. Havel, and K. Wu
¨
thrich publish the first atomic resolu-
tion structure of a protein, a bull seminal proteinase inhibitor, using nuclear
magnetic resonance spectroscopy.
The universal code theory has to be amended because codons that serve as
termination signals according to the “universal” genetic code are found to en-
code amino acids in certain ciliates and bacteria. For example, in Stylonychia
lemnae UAA and UGA encode glutamine (S. Horowitz and M. A. Gorowsky)
and in Mycoplasma capricolum UGA encodes tryptophan (F. Yamao).
C. M. Newman, J. E. Cohen, and C. Kipnis demonstrate mathematically that
the punctuated shifting equilibrium patterns of species formation seen in the
fossil record are to be expected on traditional grounds and do not require spe-
cial mechanisms to explain them.
C. W. Greider and E. H. Blackburn isolate a telomerase from Tetrahymena
pyriformis.
O. Smithies and four colleagues report the successful insertion of DNA se-
quences into human tissue culture cells by homologous recombination at the
beta-globin locus. This is an early example of transfection.
J. D. Boeke and three colleagues discover the first retroposons in Saccharo-
myces.
S. M. Mount and G. M. Rubin determine the complete nucleotide sequence of
a Drosophilia copia element and conclude that it is a retroposon.
542 APPENDIX C: CHRONOLOGY
A. J. Jeffries, V. Wilson, and S. L. Thien develop the DNA fingerprint tech-
nique and point out its potential use in forensic science.
R. K. Saiki, K. B. Mullis, and five colleagues report the use of the polymerase
chain reaction to allow enzymatic amplification in vitro of specific beta-hemo-
globin gene fragments.

H. L. Carson concludes from a study of the ecological genetics of the Hawaiian
Drosophilidae that the evolution of this group is driven by sexual selection
which ensures the choice of mates with the greatest Darwinian fitness.
M. S. Brown and J. L. Goldstein receive the Nobel Prize for identifying the
low-density lipoprotein receptor pathway and for demonstrating that familial
hypercholesterolemia is a genetic defect in this pathway.
1986 M C. Shih, G. Lazar, and H. M. Goodman show that the nuclear genes that
encode chloroplast glyceraldehyde-3-phosphate dehydrogenase of higher plants
are direct descendants of the genes from the symbionts that gave rise to the
chloroplast. Later during evolution, these genes were transferred from the chlo-
roplast to the nuclear genome.
L. E. Hood and three colleagues invent the first automated DNA sequencer.
As these machines are perfected, the sequencing of genomes becomes thou-
sands of times faster, and the Human Genome Project is greatly facilitated.
T. C. James and S. C. R. Elgin identify HP1 (heterochromatin protein 1) in
Drosophila melanogaster.
A. Tomlinson and D. F. Ready report the discovery of sevenless, a mutation in
Drosophila that controls the developmental fate of a specific cell in the omma-
tidium.
A. G. Amit and three colleagues determine the three-dimensional structure of
an antigen-antibody complex at a resolution of 2.8 A
˚
.
F. Costantini, K. Chada, and J. Magram demonstrate that cloned normal beta-
hemoglobin genes can be experimentally substituted for defective thalassemia
genes in the mouse. They inject cloned normal genes into the fertilized thalas-
semic eggs. The mice that develop possess red blood cells that can synthesize
normal beta-hemoglobin chains. These transgenic mice transmit this ability to
their offspring.
J. Nathans, D. Thomas, and D. S. Hogness isolate and characterize the human

visual pigment genes.
M. Noll and four colleagues identify a gene (paired) that encodes a protein
with a DNA-binding site (the paired domain). This domain is later identified
in mammalian regulatory proteins. Noll’s group shows that regulatory genes
often contain multiple conserved domains and suggests that genes which share
one or more of these domains form networking families that program the early
development of multicellular organisms.
R. Benne and five colleagues discover RNA editing in trypanosomes.
H. M. Ellis and H. R. Horvitz isolate genes in Caenorhabditis elegans that cause
the programmed death of specific cells.
The complete nucleotide sequence and gene organization of the chromosomes
from chloroplasts is determined for two plant species. In the case of the liver-
wort, Marchantia polymorpha, the genome contains 121 kilobase pairs (K. Ohy-
ama and 12 colleagues), while the genome of tobacco, Nicotiana tabacum, con-
tains 155 kilobase pairs (K. Shinozaki and 22 colleagues). Some chloroplast
genes are found to contain introns.
APPENDIX C: CHRONOLOGY 543
E. U. Selker and three colleagues characterize the phenomenon of repeat-
induced point mutation (RIP) in Neurospora.
V. F. Semeshin and five colleagues observe new bands and interbands at the
site where a transposable element had inserted into a Drosophila polytene chro-
mosome.
R. Levi-Montalcini and S. Cohen receive the Nobel Prize in Physiology for
their studies on growth factors.
E. Ruska receives the Nobel Prize in Physics for designing the first electron
microscope.
1987 M. R. Kuehn and four colleagues introduce a human gene into the mouse to
allow its study in a convenient laboratory rodent. They employ a mutant allele
of the gene encoding HPRT and use a retrovirus as a vector to insert it into
cultured mouse embryonic germ cells. These are then implanted into mouse

embryos to form chimeras. Strains of mice carrying the human gene are ob-
tained from these chimeras.
C. Nu
¨
sslein-Volhard, H. G. Frohnho
¨
fer, and R. Lehmann show that a small
group of maternal effect genes exist in Drosophila that determine the polarized
pattern of development of the embryo.
E. P. Hoffman, R. H. Brown, and L. M. Kunkel isolate dystrophin, the protein
encoded by the musculardystrophy locus.
D. C. Wiley and five colleagues determine the three-dimensional structure of
HLA-A2, a human class I histocompatibility molecule.
D. C. Page and eight colleagues clone a segment of the human Y chromosome
that contains a gene which encodes a factor influencing testis differentiation.
Within the Y chromosome fragment is a 1.2 kb ORF that appears to encode a
zinc finger protein.
R. L. Cann, M. Stoneking and A. C. Wilson compare the extent of sequence
divergence in the mtDNA of individuals belonging to geographically distinct
human populations. They erect a genealogical tree that suggests that all
mtDNAs can be traced back to a common African maternal ancestor.
C. J. O’Kane and W. J. Gehring successfully utilize enhancer traps to identify
the positions in Drosophila embryos of elements that are functioning to activate
the transcription of specific genes.
D. T. Burke, G. F. Carle, and M. V. Olson describe a technique for cloning
large segments of exogenous DNA by means of yeast artificial chromosomes.
R. E. Dewey, D. H. Timothy, and C. S. Levings show that cytoplasmic male
sterility in maize is due to a protein encoded by the mitochondrial genome.
K. H. Wolf, W. H. Li, and P. M. Sharp report for various plant species that
the rates of nucleotide substitutions in chDNAs are on average five times

slower than the rates shown for nuclear genes.
J. E. Anderson, M. Ptashne, and S. C. Harrison describe the three-dimensional
structure of the lambda (λ) bacteriophage repressor-operator complex.
S. Tonegawa wins the Nobel Prize for his elucidation of the genetic mechanism
that generates antibody diversity.
1988 W. Driever and C. Nu
¨
sslein-Volhard demonstrate that the bicoid gene encodes
a protein that is distributed in an exponential concentration gradient along the
anteroposterior axis of the embryo.
544 APPENDIX C: CHRONOLOGY
P. M. Macdonald and G. Struhl show that a 625-nucleotide segment in the
trailer of a message encoded by the maternal polarity gene bicoid is responsible
for the anterior localization of this mRNA in the Drosophila oocyte.
W. H. Landschulz, P. F. Johnson, and S. L. McKnight discover the leucine
zipper and propose that it functions as a DNA binding site.
W. Herr and 10 colleagues discover a new DNA-binding domain (POU) en-
coded by a family of homeotic genes. Many POU genes are expressed only in
the nervous system.
R. R. Brown and seven colleagues clone the human androgen receptor gene
and show that mutations within it cause the hereditary androgen insensitivity
syndrome.
D. C. Wallace and seven colleagues report that a human, maternally inherited
disease, Leber’s hereditary optic neuropathy, is caused by a mutation in mito-
chondrial DNA.
H. H. Kazazian and five colleagues discover two cases of hemophilia A due
to insertions of truncated transposable elements. They subsequently isolate a
complete transposable element that is a likely progenitor of one of these inser-
tions. They show the transposon resides on chromosome 22 and that homolo-
gous elements occur in chimpanzee and gorilla at the same genomic location.

This finding suggests that the element has been occupying the same chromo-
somal site since the evolutionary divergence of humans, chimpanzees, and go-
rillas 7 million years ago.
V. Sorsa publishes a two-volume monograph that reviews the encyclopedic
literature concerning polytene chromosomes and presents electron microscope
maps of Drosophila salivary-gland chromosomes.
The first U.S. patent is issued for a genetically altered animal. Harvard Univer-
sity receives the patent for “oncomice,” developed by P. Leder and T. Stewart.
S. L. Mansour, K. R. Thomas, and M. R. Capecchi describe a general strategy
for gene targeting in the laboratory mouse.
1989 W. Driever and C. Nu
¨
sslein-Volhard show that in Drosophila the protein en-
coded by the bicoid gene acts by switching on the hunchback segmentation gene.
B. Zink and R. Paro show by immunostaining that a protein encoded by the
Polycomb (Pc) gene binds to a limited number of discrete sites along the Dro-
sophila polytene chromosomes. The sites include the Antennapedia complex
and the bithorax complex, which contain genes known to be repressed by Pc.
S. Field and O. Song develop the yeast two-hybrid system for identifying pro-
tein-protein interactions, based on the properties of the GAL4 protein of S.
cerevisiae. This system is later modified by various lab groups as a screen to
identify protein sequences encoded by genomic or cDNA libraries which inter-
act with a known protein.
J. J. Brown and three colleagues determine the structure of the “Dotted” trans-
poson of maize.
L. H. Hartwell and T. A. Weinert introduce the concept of controls called
“checkpoints” that ensure the order of events in the cycle of cell division.
L C. Tsui and 24 colleagues identify the cystic fibrosis gene, predict the amino
acid sequence of the protein it encodes, and determine the nature of its most
common mutant allele.

APPENDIX C: CHRONOLOGY 545
M. Srivastava and four colleagues clone and sequence the cDNA for human
nucleolin.
J. R. Williamson, M. K. Raghuraman, and T. R. Cech present the guanine quar-
tet model of telomere structure.
D. B. Kaback, H. Y. Steensma, and P. De Jonge show that crossing over on the
shortest chromosome of yeast is two times higher than the average for the
whole genome. They conclude that this ensures that at least one crossover will
occur in every bivalent, a necessity for proper segregation of the homlogs dur-
ing the first meiotic division.
Y. Q. Qian and five colleagues show that the Antennapedia homeobox protein
binds to DNA through a helix-turn-helix motif.
F. D. Hong and seven colleagues determine the structure of the retinoblastoma
gene. The RB transcript is encoded in 27 exons dispersed over about 200 kilo-
base pairs of genomic DNA.
M. Horowitz and five colleagues determine the structure of the human gluco-
cerebrosidase gene. They also sequence a nearby pseudogene. Mutations in the
functional gene are the cause of Gaucher disease.
J. M. Bishop and H. E. Varmus receive the Nobel Prize in Medicine for their
studies on the oncogenes of retroviruses.
T. R. Cech and S. Altman receive the Nobel Prize in Chemistry for their dem-
onstration that certain RNAs have enzymatic functions.
1990 W. French Anderson describes the first successful example of human gene ther-
apy. Lymphocytes from a four-year-old girl suffering from adenosine deaminase
deficiency are grown in culture and later incubated with a retroviral vector
carrying a normal gene that encodes the missing enzyme. The transformed cells
are reinjected into the patient, where they multiply and correct the disease.
M. K. Bhattcharyya and four colleagues show that one of the mutations (Wrin-
kled seed) used by G. Mendel in his classic experiments is due to the insertion
of a transposon in a gene encoding an enzyme that controls the starch content

of pea embryos.
S. J. Baker and four colleagues show that the introduction of wild-type p53
genes suppress the proliferation of human cancer cells.
R. Bookstein and four colleagues show that cells from some human prostate
cancers contain mutated retinoblastoma genes and that the uncontrolled
growth of these cells is suppressed when wild-type RB alleles are introduced
into them.
B. Blum, N. Bakalara, and L. Simpson propose that RNA editing is performed
by guide RNA molecules.
R. N. Van Gelder and five colleagues devise a method for amplifying RNA
utilizing an RNA polymerase from bacteriophage T7.
B. G. Herrmann and four colleagues clone the T complex, which is required
for the formation of mesoderm in the mouse.
F. Yamamoto and four colleagues work out the molecular basis of the ABO
blood group system.
J. Malicki, K. Schughart, and W. McGinnis introduce a homeobox gene from
the mouse into Drosophila embryos and observe that it can induce homeotic
transformations similar to those produced by the Antennapedia gene. There-
546 APPENDIX C: CHRONOLOGY
fore, genes from animals that have been evolving independently for hundreds
of millions of years generate products that function interchangeably.
D. Malkin and 10 colleagues show that the defects underlying the Li-Fraumeni
syndrome are mutations in the p53 gene. Subsequent studies reveal that p53
mutations are present in about half of all human cancers.
F. Barany invents the ligase chain reaction. This provides a rapid screening pro-
cedure for identifying mutations in selected DNA sequences.
X. Fang and three colleagues clone the gene in Plasmodium vivax that encodes
its Duffy receptor.
H. Biessmann and six colleagues show that a specific retrotransposon can trans-
pose to the broken ends of Drosophila chromosomes and “heal” them.

M. A. Oettinger and three colleagues identify RAG-1 and RAG-2, genes whose
products catalyze V(D)J recombination.
P. M. Kane and five colleagues discover protein splicing in yeast.
1991 S. M. Simon and G. Blobel demonstrate that translocons in the endoplasmic
reticulum contain aqueous pores through which proteins manufactured on ri-
bosomes pass from the cytoplasm to the ER lumen.
G. M. Preston and P. Agre isolate the cDNA for aquaporin-1.
B. G. Baldwin and three colleagues compare the chloroplast DNAs of Hawaiian
silverswords with those of North American tarweeds and conclude that species
from two genera of California tarweeds are the closest living relatives of the
Hawaiian silverswords.
L. Buck and R. Axel report the cloning and characterization of 18 different
genes from a multigene family of about a thousand genes which encode odorant
receptors in the rat. This is the first report in which odorant receptors are de-
scribed and molecularly characterized in any species.
M. L. Sogin proposes that the ancestor of eukaryotes was a chimera formed by
the fusion of prokaryotes with complementing metabolic capabilities.
M. A. Houck and three colleagues suggest that mites may transfer P elements
between Drosophila species.
D. A. Wheeler, J. C. Hall, and five colleagues succeed in introducing cloned
Drosophila simulans period genes into the genomes of D. melanogaster carrying
inactive per alleles. Transduced males “sing” the simulans’ song.
J. W. Ijdo and four colleagues identify specific nucleotide sequences in band
q13 of human chromosome 2, which mark the site of telomere-telomere fu-
sions that converted two rod-shaped ancestral chromosomes into the V-shaped
chromosome 2 of modern humans. This resulted in a reduction in the number
of chromosome pairs to 23 from the 24 pairs characteristic of chimpanzees,
gorillas, and orangutans.
A. J. M. H. Verkerk and 20 colleagues identify the FMR-1 gene at the fragile
site of the human X chromosome and demonstrate that the gene contains an

expanded CGG triplet in patients suffering from fragile X–associated mental
retardation.
D. R. Knighton and six colleagues determine the three-dimensional structure
of the catalytic core shared by all known eukaryotic protein kinases.
APPENDIX C: CHRONOLOGY 547
R. R. Ernst is awarded the Nobel Prize in Chemistry for his contributions to
the development of high-resolution nuclear magnetic resonance (NMR) spec-
troscopy.
1992 G. G. Oliver and 146 colleagues from a consortium of 35 European labora-
tories publish the first complete nucleotide sequence for a eukaryotic chromo-
some. Chromosome III of Saccharomyces cerevisiae is the third smallest. It is
315,357 bp long and contains 182 ORFs, of which 117 (80%) show no signifi-
cant homology to any previously sequenced yeast genes.
R. M. Story, I. T. Weber, and T. A. Steitz determine the three-dimensional
structure of RecA, a protein playing a central role in crossing over and DNA
repair of E. coli.
M. C. Rivera and J. A. Lake make phylogenetic studies of the translation elon-
gation factors isolated from various prokaryotes and eukaryotes. Comparisons
of amino acid sequences identify a subgroup of archaeons as the immediate
relatives of eukaryotes and therefore the source of the nucleus.
D. Haig proposes the theory of parent–offspring conflict to explain the evolu-
tion of parental imprinting.
E. G. Krebs and E. H. Fischer receive the Nobel Prize for discovering protein
kinases and elucidating their roles in signal transduction.
1993 M. C. Mullins and C. Nu
¨
sslein-Volhard generate hundreds of developmental
mutants in the zebra fish, opening a new era in study of the genetic control of
vertebrate development.
D. R. Rosen, T. Siddique, and 32 colleagues identify 11 different ALS muta-

tions in 13 families. The mutations are all in the gene that encodes the SOD
enzyme.
R. Hallick and seven colleagues determine the complete nucleotide sequence
for the DNA of chloroplasts from Euglena gracilis. Some chloroplast genes con-
tain twintrons.
A. Chaudhuri and five colleagues clone the gene for the Duffy blood group
factor. It encodes a 338 amino acid protein that is attached to the erythrocyte
plasma membrane and is required for the invasion of certain malaria parasites.
S. L. Baldauf and J. D. Palmer conclude from a phylogenetic study of combined
sequence data from certain ubiquitous proteins that animals and fungi are each
other’s closest relatives. Therefore both animals and fungi have been placed in
a monophyletic supergroup, the Opisthokonta.
G. Maroni publishes the first atlas of the comparative morphology of the genes
of a specific eukaryote. The monograph illustrates 90 Drosophila genes that
transcribe mRNAs ranging in size from 319 to 4,749 base pairs.
C. Pisano, S. Bonaccorsi, and M. Gatti report that a protein which is not en-
coded by Y-linked genes binds to a specific, giant, lampbrush loop on the Y
chromosome in Drosophila spermatocytes. This protein is a component of the
sperm tail. They suggest that the Y loops in spermatocytes bind exogenous
specific proteins and facilitate their assembly into axonemes.
L. Pereira and six colleagues determine the organization of the FBNI gene. This
encodes fibrillin, and mutations in it cause Marfan syndrome.
M. E. MacDonald and 56 colleagues belonging to the Huntington’s Disease
Research Group clone and sequence the Huntington disease gene and show
that an unstable trinucleotide repeat is expanded in victims of the disease.
548 APPENDIX C: CHRONOLOGY
J. A. Tabcharani and six colleagues demonstrate that the cystic fibrosis trans-
membrane conductance regulator functions as a channel capable of conducting
multiple anions. They show that positively charged amino acids in the sixth
membrane helix of the transmembrane domains of the CFTR protein are re-

quired for halide transport.
R. J. Roberts and P. A. Sharp receive the Nobel Prize in Medicine for discover-
ing split genes.
M. Smith and K. B. Mullis receive the Nobel Prize in Chemistry for inventing
the site-directed mutagenesis technique and the polymerase chain reaction, re-
spectively.
1994 N. Morral and 30 colleagues from 19 European laboratories study the microsat-
ellites associated with the ∆F508 mutation in the cystic fibrosis genes of CF
families from various parts of Europe. They conclude that the mutation origi-
nated in southwestern Europe at least 50,000 years ago.
D. E. Nilsson and S. Pelger show from a computer simulation that an organ
similar in complexity to a fish eye can evolve from a patch of skin containing
photosensitive cells in a relatively short time (ϳ400,000 generations).
M. Chalfie and three colleagues demonstrate that green fluorescent proteins
can be used to visualize sites in cells where specific genes are being expressed.
P. Gill and eight colleagues identify the remains of the Romanov family by
DNA analysis.
S. E. Gabriel and four colleagues find a positive correlation between the
amount of cystic fibrosis conductance regulator protein in intestinal cells and
the amount of fluid secretion induced by cholera toxin. They propose that cys-
tic fibrosis heterozygotes are resistant to cholera, and this selective advantage
is responsible for the high frequency of the gene in human populations.
W. C. Orr and R. S. Sohal construct transgenic lines of Drosophila bearing extra
copies of catalase and superoxide dismutase genes. The aging process is slowed
in these flies.
N. W. Kim and nine colleagues develop a sensitive assay for telomerase activity.
Using it they show that human somatic cells from differentiated tissues lack
telomerase activity, whereas cells from a variety of cancers contain active telo-
merases. Normal ovaries and testes also were positive for telomerase activity.
Y. Chikashige and six colleagues observe the movement of chromosomes dur-

ing meiotic prophase in Schizosaccharomyces pombe by fluorescence micros-
copy. They report that the telomeres group together and assume a leading posi-
tion during movement of the chromosomes.
T. Tully and eight colleagues isolate genes that control the formation of mem-
ory in Drosophila.
Y. Zhang and five colleagues clone the obese gene of the mouse and determine
its structure. The product appears to be a secretory protein that controls the
size of the body fat depot.
R. J. Bollag and five colleagues demonstrate that the T genes of the mouse
encode a protein motif (the T box), which binds to DNA. This T box also
occurs in genes with critical roles in the development of amphibians, fishes,
and insects.
S. Whitham and five colleagues use the maize Activator transposable element
to tag and clone a disease-resistance gene in tobacco.
APPENDIX C: CHRONOLOGY 549
Y. Miki and 44 colleagues identify BRCA1, a human anti-oncogene that, when
mutated, confers susceptibility to breast and ovarian cancer.
D. Arendt and K. Nu
¨
bler-Jung provide support for the Saint-Hilaire hypothesis
of 1822. Their comparative studies of the expression of homologous genes that
control the dorsoventral patterning of embryonic cells show that in flies and
mice these genes have opposite effects. Dorsalization genes in Drosophila cause
ventralization in Mus, whereas genes that cause ventralization in flies specify
dorsal patterns in mice.
J. B. Clark, W. P. Maddison, and M. G. Kidwell report phylogenetic studies
that show horizontal transfer of P elements has occurred at least twice in the
genus Drosophila.
M. Rodbell and A. G. Gilman receive a Nobel Prize for discovering G proteins
and elucidating their role in cellular signal transduction.

1995 G. Halder, P. Callaerts, and W. J. Gehring demonstrate in Drosophila melano-
gaster that the gene eyeless is a master control gene for eye morphogenesis.
M. Schena and three colleagues used DNA microarray technology to simulta-
neously monitor the expression of 45 different genes in Arabidopsis. The micro-
arrays were prepared by high-speed robotic printing of cDNAs on glass.
C. Wilson and J. W. Szostak report in vitro evolution experiments which gener-
ate RNAs that can catalyze self-alkylation reactions.
J. Hughes and seven colleagues publish the sequence of the 4,320 amino acids
in polycystin, the product of the PKD1 gene. Mutations in this gene cause
polycystic kidney disease in humans.
J. Feng and 15 colleagues induce senescence in HeLa cells by adding an anti-
sense RNA that contains a message opposite to the templating domain of hu-
man telomerase.
S. Baxendale and 10 colleagues compare human and puffer fish Huntington
disease genes and show that the human gene is over seven times larger because
its introns are larger, not its exons.
R. Wooster and 40 colleagues identify BRCA2.
R. D. Fleischmann, J. C. Venter, and 38 colleagues publish the first complete
nucleotide sequence of a free-living organism (Haemophilus influenzae). A few
months later, C. M. Fraser, J. C. Venter, and 27 colleagues publish the com-
plete nucleotide sequence of Mycoplasma genitalium.
R. Sherrington, P. H. St. George-Hyslop, and 31 colleagues isolate and charac-
terize a gene on chromosome 14 which is responsible for 80% of the cases of
early-onset, familial Alzheimer’s disease. Two months later, G. D. Shellenberg
and 21 colleagues report locating a gene on chromosome 1 that encodes a pro-
tein showing great similarities in amino acid sequence to the product of the
AD gene on chromosome 14. Mutations in the AD gene on chromosome 1 are
responsible for the other 20% of the cases of early-onset, familial AD. The
products of these genes are called presenilin 1 and 2.
S. Labeit and B. Kolmer clone the cDNA for cardiac titin. This is the largest

protein known, some 50 times the size of average proteins.
K. Zhao, C. M. Hart, and U. K. Laemmli purify a protein from Drosophila that
binds to insulator DNAs and demonstrate by immunostaining that this protein
attaches to hundreds of interbands and many puff boundaries on polytene chro-
mosomes.
550 APPENDIX C: CHRONOLOGY
S. Horai and four colleagues compare the nucleotide sequences for the entire
mitochondrial genomes of three individual women (Japanese, European, and
African) and females belonging to four species of apes. The analysis supports
the theory that all human mtDNA molecules are derived from a woman who
lived in Africa about 140,000 years ago.
L. A. Tartaglia and 18 colleagues identify a gene, OB-R, that encodes a leptin
receptor and show that the mRNA for this membrane-bound protein is tran-
scribed in the hypothalamus.
M. Moritz, Y. Zheng, B. Alberts, and five colleagues identify gamma-tubulin-
containing ring complexes in centrosomes and show that they function as mi-
crotubule nucleating sites.
E. B. Lewis, E. Wieschaus, and C. Nu
¨
sslein-Volhard receive the Nobel Prize in
Medicine for their analyses of the genetic mechanisms that control cell differen-
tiation during embryogenesis and metamorphosis in Drosophila.
1996 G. D. Penny and four colleagues use gene targeting to demonstrate that in
order for an X chromosome to undergo inactivation, the Xist gene on that X
must be transcriptionally active.
B. Lemaitre and four colleagues elucidate the genetic control in Drosophila of
the synthesis of different antimicrobial peptides in response to bacterial or fun-
gal infections.
C. Bult and 39 colleagues show that most of the genes making up the genome
of the archaeon Methancoccus jannaschii have no equivalent in other organisms.

J. Dubnau and G. Struhl, as well as R. Rivera-Pomar and four colleagues, show
that a homeobox protein can control translation by binding to discrete target
sequences on specific mRNAs.
J. G. Lawrence and J. R. Roth propose the selfish operon model to explain the
evolution of gene clusters in bacteria.
M. Lewis and seven colleagues determine the crystalline structure of lactose
operon repressor proteins complexed with operator DNA or inducer.
A. Goffeau and 15 colleagues publish “Life with 6,000 Genes,” a review of the
structure of the yeast genome. The complete nucleotide sequences for all 16
chromosomes of Saccharomyces cerevisiae took the combined labors of 600 sci-
entists in North America, Europe, and Japan and is the first genome available
for a eukaryote.
E. Spanopoulou and five colleagues show that the protein encoded by the
RAG-1 gene contains a homeobox through which it binds to lymphocyte DNA
during V(D)J recombination. They point out that RAG-1/RAG-2 complexes
behave like the transposases of nematodes.
G. Burger and three colleagues conclude from a study of the comparative struc-
ture of mitochondrial ribosomal proteins that the mitochondria in all eukary-
otes have a monophyletic origin.
T. Kaneko and 23 colleagues completely sequence the genome of the cyano-
bacterium Synechocystis and determine the position of over 3,000 ORFs. Many
of these genes are later identified in the chloroplasts of photosynthetic protoc-
tists and land plants.
B. A. Krizek and E. M. Meyerowitz present a model that explains the transfor-
mations brought about by homeotic mutations during the development of the
Arabidopsis flower.
APPENDIX C: CHRONOLOGY 551
1997 F. R. Blattner and 16 colleagues sequence the genome of Escherichia coli and
begin to assign functions to its genetic elements.
F. Kunst and 150 collaborators publish the complete nucleotide sequence for

the genome of Bacillus subtilis and describe its genetic organization.
H-P. Klenk and 50 colleagues determine the genome structure of Archaeoglobus
fulgidus and compare it to Methanococcus jannashii, the other archaeon for
which sequence data are available. There are surprising qualitative differences.
Abundant genes that allow protein splicing occur in Methanococcus, but none
occur in Archaeoglobus.
I. Wilmut and four colleagues report the successful cloning of a mammal. The
sheep Dolly has chromosomes derived from a cell of the udder of a pregnant
female. Once mature, Dolly gave birth to a healthy lamb. This offspring, how-
ever, was the result of a normal mating and gestation.
M. Krings and five colleagues are able to isolate and sequence segments of mt-
DNA from bones of Neandertal fossils and compare them to homologous seg-
ments from modern humans. They conclude that Neandertals constitute a spe-
cies distinct from Homo sapiens.
J. Summerton and D. Weller describe the design, preparation, properties, and
potential uses of Morpholinos, synthetic polymers with antisense characteris-
tics.
C. F. Fraser and 34 colleagues determine the genomic sequence of the Lyme
disease spirochaete, Borrelia burgdorferi. It has a main chromosome that is lin-
ear, as are some of its plasmids.
F. Yang and three colleagues use chromosome-specific paint probes to demon-
strate that the Indian muntjak (2N = 6) has a reduced chromosome number
because of the end-to-end fusion of different chromosomes. For example, its
chromosome 3 is an assemblage of seven chromosomes present in the Chinese
muntjak (2N = 46).
S. Keeney, C. N. Giroux, and N. Kleckner show Spo11 to be a DNA double-
strand-break-producing topoisomerase that is responsible for meiotic crossing-
over in yeast.
J. C. Lawrence and H. Ochman suggest that most bacteria contain mosaic ge-
nomes and show that in a species like E. coli, 15–30% of the genome is made

up of DNA sequences contributed from other species by horizontal mobile
elements.
J. A. Yoder, C. P. Walsh, and T. H. Bestor suggest that DNA methylation is a
mechanism that evolved to suppress the effects of selfish DNA.
D. H. Skuse and nine colleagues present evidence from girls with Turner syn-
drome that the X chromosome contains imprinted genes that affect their social
behaviors.
P. D. Boyer and J. E. Walker share the Nobel Prize in Chemistry for their
contributions to the enzymology of ATP synthase.
S. B. Prusiner is awarded the Nobel Prize in medicine for his elucidation of the
molecular structure of prions.
1998 S. T. Cole and 41 coworkers sequence the DNA of Mycobacterium tuberculosis
and work out its genetic structure.
552 APPENDIX C: CHRONOLOGY
S. G. Anderson and nine colleagues determine the nucleotide sequence of the
Rickettsia prowazeki genome and conclude that this parasitic bacterium has un-
dergone reductive evolution. They also stress the similarities between the 16S
RNAs of mitochondria and these bacteria.
The C. elegans Sequencing Consortium, made up of 407 scientists associated
with the Sanger Centre in Cambridge, England, and the Washington University
of Medicine in St. Louis, Missouri, USA, determine the nucleotide sequence
and gene organization for the first multicellular species, the nematode Caenor-
habiditis.
R. W. Frenck, E. H. Blackburn, and K. M. Shannon show for peripheral leuko-
cytes that telomeres shorten as humans age. However, the rate of loss of telo-
meric repeats is most rapid during the first four years of life and more gradual
during the period from 25 to 80.
Y. J. Lin, L. Serounde, and S. Benzer isolate methuselah, a gene that extends
the life span of Drosophila, and they subsequently determine the properties of
the protein it encodes.

M. Lyon proposes that DNA sequences on mammalian X chromosomes, called
LINE-1 elements, may interact with XIST RNA to facilitate gene silencing by
helping this RNA spread along the chromosome.
A. Fire and five colleagues show that the injection of double-stranded RNA
into Caenorhabditis silences specific genes. They call this phenomenon “RNA
interference.”
R. S. Stephens and 11 colleagues sequence the genome of Chlamydia trachoma-
tis and investigate its genetic structure. They conclude that the species contains
many genes with phylogenetic origins from eukaryotes.
E. S. Belyaeva and five colleagues discover a gene that controls the underrepli-
cation of heterochromatin in polytene chromosomes of Drosophila.
J. G. Gall and C. Murphy show that demembranated Xenopus sperm heads,
when injected into oocyte nuclei from Xenopus or Notophthalmus, swell and
liberate their chromosomes, which then take on a transcriptionally active lamp-
brush morphology.
W. B. Whitman, D. C. Coleman, and W. J. Wiebe estimate the total number
of prokaryotes on earth to be 4–6 × 10
30
cells. Their calculations show that
prokaryotes are the largest living reservoir of C, N, and P.
1999 K. Petren, B. R. Grant, and P. R. Grant work out the phylogeny of Darwin’s
finches based on microsatellite DNA length variations among the related Gala-
pagos species.
T. Galitski and four colleagues demonstrate that most genes in Saccharomyces
cerevisae continue to be expressed at the same relative levels in yeast strains of
different ploidies (1N, 2N, 3N, 4N). However, a small subset of genes exists
whose transcription rates are dramatically induced or repressed as ploidy levels
rise.
J. D. Evans and D. E. Wheeler demonstrate that, during the larval differentia-
tion of genetically identical female honeybees into worker or queen castes, dif-

ferent sets of specific genes are switched on or off.
K. E. Nelson and 28 colleagues determine the genome sequence of Thermotoga
maritima. They conclude that although this hyperthermophile belongs to the
bacteria, it has acquired a significant portion of its genome by horizontal trans-
mission of genes from archaeons.
APPENDIX C: CHRONOLOGY 553
R. M. Andrews and five colleagues resequence human mtDNAs. They analyze
the original DNA sample used by Anderson et al. (1981) and also mtDNA
from HeLa cells. They uncover several errors and suggest some simple revisions
to correct the Cambridge reference sequence and clarify its position in mtDNA
lineages.
G. P. Copenhaver and 13 colleagues analyze the centromeres of Arabidopsis
thaliana at the nucleotide level and show that they contain genes capable of
transcription.
M. J. Beaton and T. Cavalier-Smith show for a group of cryptomonad species
that differ in cell volumes by a 10-fold factor that nuclear and nucleomorph
genome sizes obey different scaling laws. Nuclei in larger cells have more DNA,
but nucleomorphs do not. This finding supports the hypothesis that noncoding
DNA has a skeletal function in eukaryotic nuclei.
O. White and 31 colleagues determine the genome sequence and the genetic
organization of the radioresistant bacterium Deinococcus radiodurans R1.
I. Dunham and 216 colleagues are the first to sequence a human chromosome.
They show that the smallest chromosome (number 22) contains 545 genes
spread along a 33.4 mb molecule of DNA.
The MHC Sequencing Consortium (consisting of 28 contributors from eight
international centers) publishes a map of the gene loci in the human major
histocompatibility complex.
J. G. Gall and three colleagues demonstrate that many proteins and RNAs that
function in the synthesis and posttranscriptional processing of RNAs are assem-
bled in Cajal bodies.

G. Blobel receives the Nobel Prize for deciphering the method used by cells
to target newly synthesized proteins to the endoplasmic reticulum or other
organelles.
2000 P. Underhill and an international group of 20 colleagues publish a study of
paternal lines of evolutionary descent that they traced by following markers in
the DNA of Y chromosomes from humans belonging to ethnic groups from
different parts of the world.
W. V. Ng and 42 colleagues determine the genome sequence and genetic orga-
nization of the archaeon Halobacterium species NRC1.
A collaborative, international group of 152 scientists that called itself the Arabi-
dopsis Genome Initiative publishes a genome sequence for the first plant, Arabi-
dopsis thaliana. They conclude that about 70% of its 25,500 genes are dupli-
cated and that the actual number of different genes is less than 15,000.
C. Lemieux, C. Otis, and M. Turmel sequence the genome of the chloroplast
of the green alga Mesostigma viride. They conclude that this chDNA shows an
organization that predates the split between chlorophytes and green plants
about 800 million years ago.
A. C. Bell and G. Felsenfeld show that CTCF, a DNA-binding protein, serves
to insulate an imprintable gene (Igf2) from its enhancer.
M. Hattori and 63 colleagues determine the nucleotide sequence of human
chromosome 21 and show that it contains only 40% as many genes as chromo-
some 22, which is similar in size.
F. Catteruccia and six colleagues develop a method for introducing foreign
genes into malaria mosquitoes that utilizes the Minos transposon.
554 APPENDIX C: CHRONOLOGY
D. R. Davies and three colleagues report the three-dimensional structure of
Tn5 transposase complexed with the recognition sequences that terminate the
transposon, and they propose a mechanism for transposition that involves a
synaptic complex, transposition intermediate that is hairpin shaped.
M. D. Adams and 189 colleagues publish the genome sequence of Drosophila

melanogaster euchromatin. They estimate that this genome contains 13,600
structural genes.
G. M. Rubin and 54 colleagues publish an analysis of the comparative genomics
of yeast, worm, fly, and human that is encyclopedic in scope. They find, for
example, that at least 30% of the structural genes of Drosophila have orthologs
in Caenorhabiditis. Of 289 genes associated with human diseases, 61% have an
ortholog in Drosophila.
N. G. Jablonski and G. Chaplin propose a comprehensive theory to explain the
variation in human skin color.
A. G. Fraser and five colleagues use RNA interference to assign phenotypes to
90% of the genes on chromosome 1 of Caenorhabditis elegans. This technique
enables them to increase the number of sequenced genes with known pheno-
types from 70 to 378.
J. F. Heidelberg and 31 colleagues determine the DNA sequences and the orga-
nization of genes within the two chromosomes of the cholera bacterium, Vibrio
cholerae.
M. F. Hammer and eleven colleagues show that Jewish and Middle Eastern
non-Jewish populations share a common pool of Y-chromosome markers.
B. Korber and nine colleagues present evidence that HIV-1 emerged from
chimpanzees about 70 years ago.
R. S. Singh and R. J. Kulathinal propose a sex gene pool theory of speciation
applicable to all higher sexual organisms. R. S. Singh then links it to a specia-
tion model that also includes asexual organisms and plants.
E. Kandel receives the Nobel Prize for his contributions to the molecular defi-
nition of long-term memory.
2001 M. M. Yusupov and six colleagues determine the three dimensional structure
of the bacterial 70S ribosome at 5.5A
˚
resolution. The ribosomes are from a
species of thermophilic bacteria.

J. J. Ferretti and 22 colleagues sequence the genome of Streptococcus pyogenes
and illustrate its genetic structure. They determine the location of the 40 differ-
ent genes associated with virulence.
H. Tettelin and 38 colleagues sequence the genome of Streptococcus pneumoniae
and assign functions to many of the coding sequences contained in its DNA
molecule.
R. Pawliuk and 13 colleagues use a genetically engineered lentivirus as an RNA
vector to integrate a normal human beta hemoglobin gene into the chromo-
some of a host. This is a mouse genetically engineered to have defects in beta-
chain synthesis. Normal genes are integrated into hematopoetic stem cell chro-
mosomes, and the transgenic mouse synthesizes normal levels of hemoglobin.
D. W. Wood, E. W. Nester, and 49 colleagues describe the organization of the
genome of Agrobacterium tumefaciens C58.
C. S. L. Lai and four colleagues isolate and characterize FOXP2, a gene re-
quired for the development of language in children.
APPENDIX C: CHRONOLOGY 555
M. Ridanpaa and twelve colleagues show that a hereditary disease of humans
cartilage-hair hypoplasia (CHH) is caused by mutations in the RMRP gene. This
is the first untranslated nuclear gene that upon mutation is found to cause a
human disease.
V. V. Kapitonov and J. Jura use an in silico analysis to identify rolling-circle
transposons.
O. Masden and nine colleagues and W. J. Murphy and five colleagues use gene
sequence data to construct phylogenies for placental mammals. The resulting
phylogenetic trees differ substantially from the traditional ones developed from
comparative anatomy and fossil data.
The International Human Genome Sequencing Consortium, led by F. S. Col-
lins and consisting of hundreds of scientists from around the world and J. C.
Venter and colleagues at Celera Genomics independently determine the draft
sequence of the euchromatic portion of the human genome. Annotated maps

of the human genome are published in Nature vol. 409 (Feb. 15 issue) and
Science vol. 291 (Feb. 16 issue).
L. H. Hartwell, R. T. Hunt, and P. M. Nurse receive the Nobel Prize in Physiol-
ogy or Medicine for their discoveries of key chemicals that regulate the cell
division cycle.
2002 M. J. Gardner and 44 other members of an international consortium success-
fully sequence the genome of Plasmodium falciparum, the protozoan causing
subtertian malaria, the most dangerous form of the disease.
R. H. Holt and 122 other members of an international consortium successfully
sequence the genome of Anopheles gambiae, a principal vector of malaria, and
analyze the functions of many of the genes uncovered.
K. Kondo and four colleagues document the first case of horizontal gene trans-
fer between a specific prokaryote (the bacterium Wolbachia) and a specific
eukaryote (the beetle Callosobruchus).
P. Dehal and 86 colleagues generate a draft sequence of the genome of the
ascidian Ciona intestinalis. This was the first Urochordate to have its genome
sequenced.
X. Huang and three colleagues develop a technique for identifying amplified
and overexpressed genes in the chromosomes of cultured human cancer cells.
The first gene identified by this technique is TAOS.
Y. Matsuoka and five colleagues identify the oldest surviving teosinte ancestor
of corn and conclude that highland farmers started its domestication in south-
ern Mexico about 9,000 years ago.
S. Aparicio and 40 colleagues present the draft sequence and initial analysis of
the genome of Takifugu rubripes.
The Nobel Prize in Medicine is awarded jointly to Sydney Brenner, H. Robert
Horvitz, and John E. Sulston for their work concerning genetic regulation of
organ development and programmed cell death.
K. Wu
¨

thrich shares the Nobel Prize in Chemistry with J. B. Fenn and K. Ta-
naka for his contributions to the development of nuclear magnetic resonance
spectroscopy as a tool for determining the three-dimensional structure of bio-
logical molecules.
556 APPENDIX C: CHRONOLOGY
2003 H. T. Skaletsky and 39 colleagues sequence the male-specific region of the
human Y chromosome and describe the organization of its heterochromatic
and euchromatic elements.
K. Si, S. Lindquist, and E. R. Kandel discover that a neuronal CPEB protein
from Aplysia, which regulates protein synthesis at activated synapses, alters its
form and behaves like a prion in its biologically active state. They propose that
conversion to the prion-like state plays a role in the maintenance of synaptic
changes that allow long-term memory storage.
M. W. Nachman, H. E. Hoekstra, and S. L. D’Agostino elucidate the molecular
genetic mechanisms for adaptive melanism in a desert mouse Chaetodipus inter-
medius. Mutations in a gene that controls the syntheses of yellow or black mela-
nins produce coat colors that have been selected to provide camouflage for the
mice that live in dark- vs light-colored natural environments.
J. E. Galagan and 76 colleagues publish a draft sequence for the genome of
Neurospora and analyze the structure and functioning of the genetic system
revealed.
T. Anzai and 21 colleagues compare the nucleotide sequences in homologous
1.75 mbp stretches of DNA from humans and chimpanzees. The segments
contain the major histocompatibility complexes. Unexpectedly, the majority of
the evolutionary sequence divergence between the two primates is found to be
due not to single base substitutions, but to insertions and deletions (indels).
The International Human Genome Sequencing Consortium announces the suc-
cessful completion of the Human Genome Project, nearly 2 years ahead of
schedule. The euchromatic portion of the human genome is completely se-
quenced with an error rate of less than 1 per 10,000 bases.

P. Agre receives the Nobel Prize in chemistry for discovering aquaporins, the
channels that facilitate the movement of water molecules through cell mem-
branes.
2004 G. W. Tyson and nine colleagues use community genome sequencing to deter-
mine the genomes and metabolic interrelations of archaean species flourishing
in a toxic acid pool at the bottom of a mine shaft.
J. C. Venter and 22 colleagues use community genome sequencing on the pro-
karyotes filtered out of a 1,500 liter sample of surface water from the Sargasso
Sea. They sequence 1.05 billion base pairs of DNA representing 1.2 million
genes from an unknown number of marine species. Approximately 800 of the
genes encode light sensitive proteins.
M. Matsuzaki and 41 colleagues sequence the genome of Cyanidioschyzon mero-
lae and determine its functional morphology. This red alga has the smallest
genome of all photosynthetic eukaryotes.
G. Rice and eight colleagues study the tertiary and quaternary structures of the
coat proteins of certain dsDNA viruses that attack species of Archaea, Bacteria
and Eukaryotes. They demonstrate conformational similarities in these proteins
and conclude that these viruses evolved from a common ancestor that lived
prior to the formation of the three domains of cellular life.
E. Birney, M. Clamp, and R. Durbin publish the algorithms GeneWise and
Genomewise which are widely used in studies of comparative evolutionary ge-
nomics.