MLC test (Bach and Hirschhorn, Bain and Lowenstein) Microlymphotoxicity test (Terasaki and McClelland) Selective cell culture medium HAT (Littlefield) Spontaneous chromosomal instability (German, Schroeder) Cell fusion with Sendai virus (Harris and Watkins) Cell culture from amniotic fluid cells (H. P. Klinger) Hereditary diseases studied in cell cul- tures (Danes, Bearn, Krooth, Mellman) Population cytogenetics (Court Brown) Fetal chromosomal aberrations in spon- taneous abortions (Carr, Benirschke) 1965 Limited life span of cultured fibroblasts (Hayflick, Moorehead) 1966 Catalog of Mendelian phenotypes in man (McKusick) 1968 HLA-D the strongest histocompatibility system (Ceppellini, Amos) Repetitive DNA (Britten and Kohne) Biochemical basis of the AB0 blood group substances (Watkins) DNA excision repair defect in xeroderma pigmentosum (Cleaver) Restriction endonucleases (H. O. Smith, Linn and Arber, Meselson and Yuan) First assignment of an autosomal gene locus in man (Donahue, McKusick) Synthesis of a gene in vitro (Khorana) 1970 Reverse transcriptase (D. Baltimore, H. Temin, independently) Synteny, a new term to refer to all gene loci on the same chromosome (Renwick) Enzyme defects in lysosomal storage diseases (Neufeld, Dorfman) Individual chromosomal identification by specific banding stains (Zech, Casper- son, Lubs, Drets and Shaw, Schnedl, Evans) Y-chromatin (Pearson, Bobrow, Vosa) Thymus transplantation for immune deficiency (van Bekkum) 1971 Two-hit theory in retinoblastoma (A. G. Knudson) 1972 High average heterozygosity (Harris and Hopkinson, Lewontin) Association of HLA antigens and dis- eases 1973 Receptor defects in the etiology of genetic defects, genetic hyperlipidemia (Brown, Goldstein, Motulsky) Demonstration of sister chromatid ex- changes with BrdU (S. A. Latt) Philadelphia chromosome as transloca- tion (J. D. Rowley) 1974 Chromatin structure, nucleosome (Kornberg, Olins and Olins) Dual recognition of foreign antigen and HLA antigen by T lymphocytes (P. C. Doherty and R. M. Zinkernagel) Clone of a eukaryotic DNA segment mapped to a specific chromosomal location (D. S. Hogness) 1975 Asilomar conference First protein-signal sequence identified (G. Blobel) Southern blot hybridization (E. Southern) Monoclonal antibodies (Köhler and Milstein) 1976 Overlapping genes in phage \u3c6 X174 (Barell, Air, Hutchinson) First transgenic mouse (R. Jaenisch) Loci for structural genes on each human chromosome known (Baltimore Confer- ence on Human Gene Mapping) 1977 Genes contain coding and noncoding DNA segments (\u201csplit genes\u201d) (exon/in- tron structure) (R. J. Roberts, P. A. Sharp, independently) First recombinant DNA molecule that contains mammalian DNA Methods to sequence DNA (F. Sanger; Maxam and Gilbert) X-ray diffraction analysis of nucleo- somes (Finch et al.) 1978 "-Globulin gene structure (Leder, Weissmann, Tilghman and others) Mechanisms of transposition in bacteria Production of somatostatin with recom- binant DNA Introduction of \u201cchromosome walking\u201d to find genes Advances that Contributed to the Development of Genetics Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 16 1979 First genetic diagnosis using DNA tech- nology (Y. H. Kan) 1980 Genes for embryonic development in Drosophila studied by mutational screen (C. Nüsslein-Volhard and others) 1981 Sequencing of a mitochondrial genome (S. Anderson, S. G. Barrell, A. T. Bankier) 1982 Tumor suppressor genes (H. P. Klinger) Prions (proteinaceous infectious parti- cles) proposed as cause of some chronic progressive central nervous system dis- eases (kuru, scrapie, Creutzfeldt-Jakob disease) (S. B. Prusiner) 1983 Cellular oncogenes (H. E. Varmus and others) HIV virus (L. Montagnier, R. Gallo) 1984 Localization of the gene for Huntington disease (Gusella) Identification of the T-cell receptor (Tonegawa) Variable DNA sequences as \u201cgenetic fin- gerprints\u201d (A. Jeffreys) Helicobacter pylori (B. Marshall) 1985 Polymerase chain reaction (Mullis, Saiki) Characterization of the gene for clotting factor VIII (Gitschier) Sequencing of the AIDS virus Localization of the gene for cystic fibro- sis Hypervariable DNA segments Genomic imprinting in the mouse (B. Cattanach) 1986 First cloning of human genes. First iden- tification of a human gene based on its chromosomal location (positional cloning) (Royer-Pokora et al.) RNA as catalytic enzyme (T. Cech) 1987 Fine structure of an HLA molecule (Björkman, Strominger et al.) Cloning of the gene for Duchenne muscular dystrophy (Kunkel) Knockout mouse (M. Capecchi) A genetic map of the human genome (H. Donis-Keller et al.) Mitochondrial DNA and human evolu- tion (R. L. Cann, M. Stoneking, A. C. Wilson) 1988 Start of the Human Genome Project Successful gene therapy in vitro Molecular structure of telomeres at the ends of chromosomes (E. Blackburn and others) 1989 Cloning of a defined region of a human chromosome obtained by microdissec- tion (Lüdecke, Senger, Claussen, Horsthemke) 1990 Evidence for a defective gene causing inherited breast cancer (Mary-Claire King) 1991 Cloning of the gene for cystic fibrosis and for Duchenne muscular dystrophy Odorant receptor multigene family (Buck and Axel) Complete sequence of a yeast chromo- some Increasing use of microsatellites as polymorphic DNA markers 1992 Trinucleotide repeat expansion as a new class of human pathogenic mutations High density map of DNA markers on human chromosomes X chromosome inactivation center iden- tified p53 knockout mouse (O. Smithies) 1993 Gene for Huntington disease cloned 1994 Physical map of the human genome in high resolution Mutations in fibroblast growth factor receptor genes as cause of achondro- plasia and other human diseases Identification of genes for breast cancer 1995 Master gene of the vertebrate eye, sey (small-eye) (W. J. Gehring) STS-band map of the human genome (T. J. Hudson et al.) 1996 Yeast genome sequenced Mouse genome map with more than 7000 markers (E. S. Lander) 1997 Sequence of E. coli (F. R. Blattner et al.), Helicobacter pylori (J. F. Tomb) Mammal cloned by transfer of an adult cell nucleus into an enucleated oocyte (Wilmut) Embryonic stem cells Chronology Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 17 1998 Nematode C. elegans genome sequenced 1999 First human chromosome (22) sequenced Ribosome crystal structure 2000 Drosophila genome sequenced First draft of the complete sequence of the human genome First complete plant pathogen (Xylella fastidiosa) genome sequence Arabidopsis thaliana, the first plant genome sequenced (For more complete information, see references and http://www.britannica.com and click on the science channel, Lander and Weinberg, 2000.) Advances that Contributed to the Development of Genetics Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. Fundamentals Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 20 Molecular Basis of Genetics The Cell and Its Components Cells are the smallest organized structural units able to maintain an individual, albeit limited, life span while carrying out a wide variety of functions. Cells have evolved on earth during the past 3.5 billion years, presumably orginat- ing from suitable early molecular aggregations. Each cell originates from another living cell as postulated by R. Virchow in 1855 (\u201comnis cellula e cellula\u201d).