Simons Haplomics

Abridged Version

Full Article

Dr. Carol Nottenburg

Patent Analysis

Curriculum Vitae of Dr Simons

Dr Simons' Patents

Master Reference List

REFERENCES EXAMINED - CONTINUING

(MJS < 18 May 2004)

Abbott CM et al 1988 LANCET Apr 2: 1(8588): 763-4

Abu-Hadid MM et al MOL IMMUNOL. Aug: 25(8): 739-49

Ahrens P et al 1987 HUM GENET  Jun: 76(2): 127-8

Akeson AL et al J BIOL CHEM. Nov 5: 263(31): 16291-6

Allen RC et al 1989 BIOTECHNIQUES Jul-Aug: 7(7): 736-44

Amselem S et al 1988 AM J HUM GENET. Jul: 43(1): 95-100

Angelini G et al. 1986 PROC NATL ACAD SCI U.S.A Jun: 83(12): 4489-93

Antonarakis SE et al 1982 PROC NATL ACAD SCI U S A. Jan: 79(1): 137-41

Antonarakis SE et al 1982 J PEDIATR Jun: 100(6): 845-56

Antonarakis SE et al 1982 PROC NATL ACAD SCI U S A Nov: 79(21): 6608-11

Antonarakis SE et al 1985 PROC NATL ACAD SCI U S A May: 82(10): 3360-4

Antonarakis SE et al 1985 LANCET Jun 22: 1(8443): 1407-9

Antonarakis SE et al 1985 N ENGL J MED Oct 3: 313(14): 842-848

Antonarakis SE et al. 1988 HUM GENET. Nov; 80(3); 265-73

Antonarakis SE et al 1988 BR J HAEMATOL Nov: 70(3): 357-61

Arai K et al 1989 PROC NATL ACAD SCI U S A Aug: 86(16): 6092-6

Arnheim N et al 1985 PROC NATL ACAD SCI U S A Oct: 82(20): 6970-74

Arpaia E et al NATURE 1988 May 5: 333(6168): 85-6

Bahnak BR et al 1988 THROMB HAEMOST Oct 31: 60(2): 178-81

Baxter-Lowe LA et al. 1989 J CLIN INVEST Aug: 84(2): 613-8

Beaudet AL et al 1988 N ENGL J MED Jan 7: 318(1): 50-1

Bellis M et al 1987 MOL BIOL EVOL Jul: 4(4): 351-63

Bidwell JL et al. 1988 TRANSPLANTATION Mar: 45(3): 640-6

Boehm CD 1989 CLIN CHEM Sep: 35(9): 1843-8

Boehnke M et al 1989 AM J HUM GENET Jul: 45(1): 21-32

Botstein D et al. 1980 AM J HUM GENET May: 32(3): 314-331

Bouhassira EE et al 1989 J CLIN INVEST Jun: 83(6): 2070-3

Brink PA et al 1987 HUM GENET Sep: 77(1): 32-5

Brinster RL et al 1988 PROC NATL ACAD SCI U S A Feb: 85(3): 836-849

Brocker-Vriends AH et al 1987 THROMB HAEMOST Apr 7: 57(2): 131-6

Buchman VL et al 1988 GENE Oct 30: 70(2): 245-52

Bufton L et al 1986 AM J HUM GENET Apr: 38(4): 447-60

Bugawan TL et al 1988 J IMMUNOL Dec 1: 141(11): 4024-30

Cai SP et al 1989 BLOOD Feb: 73: 372-4

Camerino G et al 1984 PROC NATL ACAD SCI U S A Jan: 81(2): 498-502

Camerino G et al 1985 HUM GENET 71(1): 79-81

Cavalli-Sforza L 1990 AM J HUM GENET Apr: 46(4): 649-51

Chamberlain JS et al 1988 NUCLEIC ACIDS RES Dec 9: 16(23): 11141-56

Chao S et al 1989 THEOR APPL GENET 78(4): 495-504

Chebloune Y et al 1988 PROC NATL ACAD SCI U S A Jun; 85(12): 4431-5

Chehab FF et al 1987 NATURE Oct 22-28: 329(6141): 293-4

Chelly J et al 1989 PROC NATL ACAD SCI U S A Apr: 86(8): 2617-21

Chow CM et al 1989 MOL CELL BIOL Nov: 9(11): 4631-44

Clark AG 1990 MOL BIOL EVOL Mar: 7(2): 111-122

Claustres M et al 1989 J GENET HUM Sep: 37(3): 243-9

Cohen JB, Levinson AD 1988 NATURE Jul 14: 334(6178): 119-24

Coleman RT et al 1986 MOL BIOL MED Jun: 3(3): 213-8

Coleman RT et al 1988 NUCLEIC ACIDS RES Feb 11: 16(3): 1221

Cooper DN et al 1984 HUM GENET 66(1): 1-16

Cooper DN et al 1985 J HUM GENET 69(3): 201-5

Cox DW et al 1987 AM J HUM GENET Nov: 41(5): 891-906

Cremer T et al 1988 HUM GENET Nov: 80(3): 235-246

Davies KE et al 1983 NUCLEIC ACIDS RES Apr 25: 11(8): 2303-2312

Delpech M et al 1986 HUM GENET. Nov: 74(3): 316-7

de Preval C et al. 1987 IMMUNOGENETICS 26(4-5): 249-57

Deng GR NUCLEIC ACIDS RESEARCH Jul 11: 16(13): 6231

Deng TL et al 1989 NUCLEIC ACIDS RES Jan 25: 17(2): 645-58

Denton PH et al 1988 BLOOD Oct: 72(4): 1407-11  

Dennis ES et al 1988 NUCLEIC ACIDS RESEARCH May 11: 16(9): 3815-28

Detera-Wadleigh SD et al 1989 NUCLEIC ACIDS RES Aug 11: 17(15): 6432

Dicker AP et al 1989 BIOTECHNIQUES Sep: 7(8): 830-7

DiLella AG et al 1986 NATURE Aug 28-Sep 3: 322(6082): 799-803

DiLella AG et al 1988 LANCET March 5: 1(8584): 497-499

Di Marzo R et al 1988 BR J HAEMATOL Jul: 69(3): 393-7

Din et al 1985 LANCET Jun 22: 1(8443): 1446-7

Dorsett D et al 1989 GENES DEV Apr: 3(4): 454-68

Drayna D et al 1984 PROC NATL ACAD SCI U S A May: 81(9): 2836-9

Driscoll MC et al 1988 BLOOD Jul: 72(1): 61-5

Duceman BW et al 1986 IMMUNOGENETICS 23(2): 90-9

Duyk GM et al 1990 PROC NATL ACAD SCI U S A Nov: 87(22): 8995-99

Embury SH et al 1987 N ENGL J MED Mar 12: 316(11): 656-61

Emrie PA et al 1988 SOMAT CELL MOL GENET Jan: 14(1): 105-10

Erlich HA et al. 1990 J FORENSIC SCI. Sep; 35(5): 1017-19

Estivill X et al 1987 GENOMICS Nov; 1(3): 257-63

Farrall M et al 1986 LANCET 2: 1402-4

Feener CA et al 1989 NATURE Apr 6: 338(6215): 509-11

Feldman GL et al 1988 LANCET Jun 21: 2(8495): 102

Ferns GA, Galton DJ 1986 HUM GENET July: 73(3): 245-9

Fey MF et al 1990 HUM GENET Apr: 84(5): 471-2

Fojo SS et al J CLIN INVEST. Nov: 82(5): 1489-94

Forrest D et al 1987 VIROLOGY May: 158(1): 194-205

Fournier D et al 1989 J MOL BIOL Nov 5: 210(1): 15-22

Freedenberg DL et al 1987 HUM GENET Jul: 76(3): 262-4

Frossard PM et al 1987 NUCLEIC ACIDS RES Jan 12: 15(1): 381

Fugger L et al. 1989 IMMUNOGENETICS 30(3): 208-13

Fujisaku A et al 1989 J BIOL CHEM Feb 5: 264(4): 2118-25

Funke H et al 1987 J CLIN CHEM CLIN BIOCHEM Mar: 25(3): 131-4

Gaitskhoki VS et al 1993 BIOCHEM MED METAB BIOL Oct: 50(2): 186-9.

Gatti RA et al 1987 AM J HUM GENET Oct: 41(4): 654-67

Geisel J et al 1988 J. CLIN CHEM CLIN BIOCHEM Jul: 26(7): 429‑434

Giannelli F et al 1984 LANCET Feb 4: 1(8371): 239-241

Gibbs RA et al 1989 PROC NATL ACAD SCI U S A Mar: 86(6): 1919-23

Gibson J B, Wilks A V 1989 BIOCHEM GENET Dec: 27(11-12): 679-88

Gitschier J et al 1985 NATURE Apr 25-May 1: 314(6013): 738-40

Gitchhier J et al 1988 BLOOD Sep: 72(3): 1022-8.

Gotoda T et al 1989 BIOCHEM BIOPHYS RES COMMUN Nov 15: 164(3): 1391-6

Graham JB et al 1989 BLOOD Jun; 73(8): 2104-7

Grandchamp B et al 1989 PROC NATL ACAD SCI U S A  Jan: 86(2): 661-4

Greenberg A et al 1989 INT J CANCER Jan 15: 43(1): 87-92

Griffiths LR et al 1988 AM J HUM GENET May: 42(5): 756-771

Gusella JF et al 1982 PROC NATL ACAD SCI U S A Dec: 79(24): 7804-8

Gusella JF et al 1983 NATURE Nov 17-23: 306(5940): 234-8

Gyllensten UB, Erlich HA 1988 PROC NATL ACAD SCI U S A Oct: 85(20) 7652-6

Gyllensten U et al 1989 PROC NATL ACAD SCI U S A  Dec: 86(24): 9986-9990

Haber DA et al 1990 CELL Jun 29: 61(7): 1257-69

Hamada H 1982 PROC NATL ACAD SCI U.S.A. 79(19): 5901-5905

Harper JF, Madges W 1988 MOL GEN GENET Aug: 213(2-3): 315-24

Hastbacka J et al 1992 NAT GENET Nov: 2(3): 204-11

Haugen A et al 1989 MOL CARCINOG 2(2): 68-71

Hay CW et al 1986 BLOOD May: 67(5): 1508-11

Hejtmanick JF et al 1989 PRENAT DIAGNOSIS Mar: 9(3): 177-86

Helentjaris T, Gesteland R 1983 J MOL APPL GENET 2(3): 237-247

Helmuth R et al 1990 AM J HUM GENET Sep: 47(3): 515-523

Herbert CJ et al 1988 MOL GEN GENET Aug: 213(2-3): 297-309.

Higuchi R et al 1988 NATURE Apr 7: 332(6164): 543-6

Hill AV et al 1988 BLOOD Jul: 72(1): 9-14

Hixson JE et al 1988 GENOMICS May: 2(4): 315-­23

Ho CK, Abelson J 1988 J MOL BIOL Aug 5: 202(3): 667-72

Ho CK et al 1990 EMBO J Apr: 9(4): 1245-52

Hodges PE, Rosenberg LE 1989 PROC NATL ACAD SCI U S A Jun: 86(11): 4142-6

Houwen RH et al 1994 NAT GENET Dec: 8(4): 380-6

Hsia YE et al 1989 LANCET May 6: 1(8645): 988-90

Huang LS et al 1989 J BIOL CHEM Jul 5: 264(19): 11394-400

Huang LS et al 1990 J LIPID RESEARCH Jan: 31(1): 71-7

Janco RL et al 1987 BLOOD May: 69(5): 1539-41

Jeffreys AJ 1979 CELL Sep: 18(1): 1-10

Jeffreys AJ et al 1985 NATURE Mar 7-13: 314(6006): 67-73

Jeffreys AJ et al 1988 NUCLEIC ACIDS RES Dec 9: 16(23): 10953-71

Jenkins RN et al 1990 J BIOL CHEM Nov 15: 265(32): 19624-31

Jinks DC et al 1989 HUMAN GENET Mar: 81(4): 363-6

Kagnoff MF et al 1989 PROC NATL ACAD SCI U S A Aug: 86(16): 6274-8

Kan YW, Dozy AM 1978 LANCET Oct 28: 2(8096): 910-2

Kan YW, Dozy AM 1978 PROC NATL ACAD SCI U S A Nov: 75(11): 5631-5

Kan YW et al 1980 N ENGL J MED Jan 24: 302(4): 185-8

Keim P et al 1990 GENETICS Nov: 126(3): 735-742

Kelly DP et al 1990 PROC NATL ACAD SCI U S A Dec: 87(23): 9236-40

Kerem B et al 1989 SCIENCE Sep 8: 245(4922): 1073-80

Knoll BJ et al 1988 J BIOL CHEM Aug 25: 263(24): 12020-7

Kogan SC et al 1987 N ENGL J MED Oct; 317(16): 985-90

Kogan S, Gitschier J 1990 PROC NAT ACAD SCI U S A Mar: 87(6): 2092-6

Krawczak M et al 1988 HUM GENET Sep: 80(1): 78-80

Krawczak M 1988 PROC NATL ACAD SCI U S A Oct: 85(19): 7298-301

Kulozik AE et al 1988 BR J HAEMATOL Dec: 70(4): 455-8

Labouesse M et al 1987 EMBO J Mar: 6(3): 713-21

Lander ES, Botstein D 1987 SCIENCE Jun 19: 236(4808): 1567-70

Landsman D et al 1989 NUCLEIC ACIDS RES Mar 25: 17(6): 2301-14

Lazzeroni LC 2001 STAT METH MED RES Feb: 10(1): 57-76

Leitersdorf E et al 1989 AM J HUM GENET Mar: 44(3): 409-21

Lemaire HG et al 1989 NUCLEIC ACIDS RES. Jan 25: 17(2): 517-22

Lewis RA et al 1990 GENOMICS Jun: 7(2): 250-6

Li HH et al 1988 NATURE Sep 29: 335(6189): 414-417

Lifton RP et al 1990 GENOMICS May: 7(1): 131-5

Limm TM et al 1993 HUM IMMUNOL Sep: 38(1): 57-68

Litt M, Luty JA 1989 AM J HUM GENET Mar: 44(3): 397-401

Little PF et al 1980 NATURE May 15: 285(5761): 144-7

Love JM et al 1990 NUCLEIC ACIDS RES 18: 14, 4123-4130 

Lubahn DB et al 1989 PROC NATL ACAD SCI U S A Dec: 86(23): 9534-8

Luty JA et al 1990 AM J HUM GENET Apr: 46(4): 776‑83

Lyonnet S et al 1989 AM J HUM GENET Apr: 44(4): 511-7

Ma YH et al 1988 ARTERIOSCLEROSIS Sep-Oct: 8(5): 521-4

Macek M et al 1990 ACTA UNI CAROL [MED] (PRAHA) 36(1-4): 108-111

Magdolen V et al 1988 MOL CELL BIOL Dec: 8(12): 5108-15

Mages W et al 1988 MOL GEN GENET Aug: 213(2-3): 449-58

Maggio A et al 1986 HUM GENET Mar: 72(3): 229-30

Mardis ER et al 1989 BIOTECHNIQUES Sep: 7(8): 840-50

Marx J 1990 SCIENCE Mar 30: 247(4950): 1540-42

Martiniuk F et al 1990 DNA CELL BIOL Mar: 9(2): 85-94

Masson P et al 1989 CELL Aug 25: 58)4): 755-65

Mathison L et al 1989 MOL CELL BIOL Oct: 9(10): 4220-8

Matoskova B et al 1989 MOL CELL BIOL. Jul: 9(7): 3148-50

Mattick JS. 1994 CURR OPIN GENET DEV. Dec: 4(6): 823-31

McGee TL et al 1989 GENE Aug 1: 80(1): 119-28

McIntosh I et al 1989 AM J MED GENET Feb: 32(2): 274-6

Metherall JE et al 1986 EMBO J Oct: 5(10): 2551-7

Miura O et al 1989 BIOCHEM Jun 13: 28(12): 4934-8

Moller DE et al 1989 MOL ENDOCRINOL. Aug: 3(8): 1263-9

Monteiro MJ, Cox RA 1987 J MOL BIOL Feb 5: 193(3): 427-38

Moschonas et al 1982 NUCLEIC ACIDS RES Mar 25: 10(6): 2109-20

Murray JC et al 1987 AM J HUM GENET Apr: 40(4): 338-50

Nafa K et al 1990 HUM GENET Apr: 84(5): 401-5

Nakamura Y et al 1987 SCIENCE Mar 27: 235(4796): 1616-1622

Nakamura Y et al 1988 GENOMICS May: 2(4): 302-9

Nakamura Y et al 1988 AM J HUM GENET Dec: 43(6): 854-859

Nakamura Y et al 1989 AM J HEMATOL Sep: 32(1): 24-9

Nakano T, Suzuki K 1989 J BIOL CHEM Mar 25: 264(9): 5155-8

Nam HG et al 1989 PLANT CELL Jul: 1(7): 699-705

Newgard CB et al 1987 AM J HUM GENET Apr: 40(4): 351-64

Newton CR et al 1989 LANCET Dec 23-30: 2(8678-9): 1481-3

Nottenburg C et al 1987 J IMMUNOL Sep 1: 139(5): 1718-26.

Nozari G et al 1988 ANAL BIOCHEM Jul: 172(1): 180-4

Ochman H et al 1988 GENETICS Nov: 120(3): 621-623

O'Hara PJ, Grant FJ 1988 GENE Jun 15: 66(1): 147-58

Ohno K, Suzuki K 1988 BIOCHEM BIOPHYS RES COMM May 31: 153(1): 463-9

Old JM et al 1986 J MED GENET Feb: 23(1): 14-18

Olson M et al 1989 SCIENCE Sep 29: 245(4925): 1434-1435

Orkin SH et al 1982 NATURE Apr 15: 296(5858): 627-31

Orkin SH et al 1982 NATURE Dec 23: 300(5894): 768-9

Orkin SH et al 1985 EMBO J Feb: 4(2): 453-6

Palsdottir A et al 1987 IMMUNOGENETICS 25(5): 299-304

Paolella G et al 1987 HUM GENET Oct: 77(2): 115-7

Parker R et al 1987 CELL Apr 24: 49(2): 229-39

Patterson M et al 1989 AM J HUM GENET May: 44(5): 679-85

Paul H et al 1987 HUMAN GENET Mar: 75(3): 264-8

Peake IR et al 1990 BLOOD Aug 1: 76(3): 555-61

Petersen MB et al 1990 GENOMICS May: 7(1): 136-8

Philipsen JN et al 1989 J MOL EVOL Mar: 28(3): 185-90

Phillips JA 3^rd et al 1980 PROC NATL ACAD SCI U S A May: 77(5): 2853-6

Pietu G et al 1988 THROMB HAEMOST Aug 30: 60(1): 102-6

Poncz M et al 1983 J BIOL CHEM Oct 19: 258(19): 11599-11609

Potter H, Dressler D 1986 GENE 48(2-3): 229-39

Quirk SM et al 1989 CELL Feb 10: 56(3): 455-65

Quirk SM et al 1989 NUCLEIC ACIDS RES Jan 11: 17(1): 301-15

Ragusa A et al 1989 AM J HUM GENET Jul: 45(1): 106-111

Rathbun GA et al 1988 IMMUNOGENETICS 27(2): 121-6

Raulf F et al 1989 J NEUROSCI RES. Sep: 24(1): 81-8

Rees A et al 1986 HUM GENET Feb: 72(2): 168-71

Riess O et al 1990 IMMUNOGENETICS 32(2): 110-6

Riordan JR et al 1989 SCIENCE Sep 29: 245(4925): 1066-73

Rommens JM et al 1989 SCIENCE Sep 8: 245(4922): 1059-65

Rouabhi F et al 1988 HUM GENET Aug: 79(4): 373-6

Ruano G, Kidd KK 1989 NUCLEIC ACID RES Oct 25: 17(20): 8392

Saha BK et al 1986 J IMMUNOL Dec 15: 137(12): 4004-9

Saiki RK et al 1985 SCIENCE Dec: 230: 1350-4

Saiki RK et al 1986 NATURE Nov 13-19: 324(6093): 163-6

Saiki RK et al 1988 N ENGL J MED Sep 1: 319(9): 537-541

Saiki RK et al 1989 PROC NATL ACAD SCI U S A Aug: 86(16): 6230-6234

Sattaur O 1988 NEW SCIENTIST Dec 3: 120(1641): S1-S4

Scharf SJ et al 1988 HUM IMMUNOL May: 22(1): 61-9

Scharf SJ et al 1988 PROC NATL ACAD SCI U S A May: 85(10): 3504-8

Scharf SJ et al 1989 PROC NATL ACAD SCI U S A Aug: 86(16): 6215-9

Scambler PJ et al 1987 NUCLEIC ACIDS RES May 11: 15(9): 3639-52

Searles LL et al 1990 MOL CELL BIOL Apr: 10(4): 1423-31

Seino S, Bell GI 1989 BIOCHEM BIOPHYS RES COMMUN. Feb 28: 159(1): 312

Semenza GL et al 1989 NUCLEIC ACIDS RES Mar 25: 17(6): 2376

Servenius B et al 1987 J BIOL CHEM Jun 25: 262(18): 8759-66

Sheehy MJ et al 1989 J CLIN INVEST Mar: 83(3): 830-835

Shtivelman E, Bishop JM 1989 MOL CELL BIOL Mar: 9(3): 1148-54

Simons MJ et al 1993 HUM IMMUNOL Sep; 38(1): 69-74

Sinha AA et al 1988 SCIENCE Feb 26: 239(4843): 1026-9

Sinnett D et al 1990 GENOMICS Jul: 7(3): 331-4

Skolnick MH, Wallace RB 1988 GENOMICS May; 2(4): 273-9.

Smeaton I et al 1987 IMMUNOGENETICS 25(3): 179-83

Snyder LC et al 1988 J Biol Chem. Nov 15: 263(32): 17150-8

Stephens JC et al 1990 AM J HUM GENET Jun: 46(6): 1149-55

Stevanovic M et al 1989 GENE Jun 30: 79(1): 139-50

Strobel MC, Abelson J 1986 MOL CELL BIOL Jul: 6(7): 2663-73

Strobel MC, Abelson J 1986 MOL CELL BIOL Jul: 6(7): 2674-83

Sutton M et al 1989 AM J HEMATOL  Sep: 32: 66-69

Symons DB et al 1987 J IMMUNOGENET. Dec: 14(6): 273-83

Takahashi H et al 1988 J BIOL CHEM Oct 25: 263(30): 15528-34

Tanksley SD et al 1989 BIO/TECHNOLOGY Mar: 7(3): 257-264

Tautz D 1989 NUCLEIC ACIDS RES Aug 25: 17(16): 6463-6471

Tautz D, Renz M 1984 NUCLEIC ACIDS RES May 25: 12(10): 4127-4138

Taylor R et al 1989 J MED GENET Aug: 26(8): 494-8

Thein SL et al 1988 BR J HAEMATOL Oct: 70(2): 225-31

Theophilus B et al 1989 AM J HUM GENET Aug: 45(2): 212-25

Tiercy JM et al 1988 PROC NATL ACAD SCI U S A Jan: 85(1): 198-202

Todd JA et al 1987 NATURE Oct 15-21: 329(6140): 599-604

Traver CN et al 1989 PROC NATL ACAD SCI U S A Aug: 86(15): 5898-5902

Tsang TC et al 1989 THROMB HAEMOST Jun 30: 61(3): 343-7

Tsavaler L et al 1988 PROC NATL ACAD SCI U S A Oct: 85(20): 7680-4

Tsui LC et al 1986 AM J HUM GENET Dec: 39(6): 720-8

Tuan D et al 1979 NUCLEIC ACIDS RES Jun 11: 6(7): 2519-44

Udey JA, Blomberg BB 1988 NUCLEIC ACIDS RES Apr 11: 16(7): 2959-69

Vance JM 1989 EXP NEUROL May: 104(2): 186-189

van Kuppevelt TH et al 1989 PROC NATL ACAD SCI U S A Jul: 86(14): 5415-8

Vidaud M et al 1989 PROC NATL ACAD SCI U S A Feb: 86(3): 1041-5

Vijayraghavan U et al 1989 GENES DEVEL Aug: 3(8): 1206-16

Vrieling H et al 1988 MUTAT RES. Mar: 198(1): 107-13

Wainscoat et al 1986 NATURE Feb 6-12: 319(6053): 491-3

Weber JL, May PE 1989 AM J MED GENET Mar: 44(3): 388-396

Weber JL 1990 GENOMICS Aug: 7(4): 524-530 (corresponding to US Patent 5,075,217)

Weber JL 1990 CURR OPIN BIOTECHNOL Dec: 1(2) 166-47

Wehnert M et al 1989 DISEASE MARKERS Apr-Jun: 7(2): 113-7

White R et al 1985 NATURE Jan 10-18: 313(5998): 101-105

Williams C et al 1988 LANCET Jul 9: 2(8602): 102-3

Winey M et al 1989 GENE Mar 15: 76(1): 89-97

Winship PR et al 1984 NUCLEIC ACIDS RES Dec 11: 12(23): 8861-8872

Winship PR et al 1989 LANCET Mar 25: 1(8639): 631-634

Wion KL et al 1986 NUCLEIC ACIDS RES Jun 11: 14(11): 4535-42

Wong C et al 1987 NATURE Nov 26–Dec 2: 330(6146): 384-6

Wong WW et al 1989  J EXP MED Mar 1: 169(3): 847-63

Wu DY et al 1989 PROC NATL ACAD SCI U S A Apr: 86(8): 2757-60

Wyman AR, White R 1980 PROC NATL ACAD SCI U S A Nov: 77(11): 6754-8

Ye RD et al 1989 J BIOL CHEM Apr 5: 264(10): 5495-502

Young LJ et al 1988 HUM GENET Jun: 79(2): 137-41

Yu CY, Campbell RD 1987 IMMUNOGENETICS 25(6): 383-90

Zhang K et al 1987 GENE 57(1): 27-36

Zhu H et al 1989 MOL CELL BIOL Apr: 9(4): 1507-12

Zimmer M et al 1987 CURRENT GENETICS 12(5): 329-36

 Master Reference Abstracts

Abbott CM, McMahon CJ, Whitehouse DB, Povey S.
Prenatal diagnosis of alpha-1-antitrypsin deficiency using polymerase chain reaction.
Lancet 1988 Apr 2: 1(8588): 763-4.

------------------------------------------------------------------------------------------------------------------------------------

Abu-Hadid MM, Fuji H, Sood AK.  Department of Molecular Immunology, Roswell Park Memorial Institute, Buffalo, NY 14263.

Identification of an alternatively spliced Kd and the Qa-6d mRNAs by using amplified cDNA.
Mol Immunol. 1988 Aug: 25(8): 739-49.
 
We have employed the primer chain reaction method for direct sequencing of H-2 mRNAs. This approach is highly sensitive and permits quantitation and sequencing of the canonical as well as alternatively spliced mRNAs that may be expressed at 5-10% level in comparison to the major H-2 species. Using this technique, we have identified a novel species of alternatively spliced Kd mRNA expressed in L1210 lymphoma and in the spleen and liver of DBA/2 mice. Similarly, we found a previously described alternatively spliced species of H-2Dd mRNA to be expressed in L1210 lymphoma and have determined the sequence of the cytoplasmic domain of Ld mRNA. In addition, we have identified a Class I MHC transcript presumably encoded by a gene allelic to Q6 gene of BALB/c mice.

------------------------------------------------------------------------------------------------------------------------------------------------

Ahrens P, Kruse TA, Schwartz M, Rasmussen PB, Din N.
A new HindIII restriction fragment length polymorphism in the hemophilia A locus.
Hum Genet. 1987 Jun: 76(2): 127-8.
 
Using a fragment of the cDNA for human coagulation factor VIII as a hybridization probe, we have detected a new polymorphic HindIII site in intron 19 of the factor VIII gene. The frequency of the minor allele is 0.30. This polymorphism shows strong linkage disequilibrium with a previously described BclI polymorphism in intron 18.

------------------------------------------------------------------------------------------------------------------------------------

Akeson AL, Wiginton DA, Dusing MR, States JC, Hutton JJ. Children's Hospital Research Foundation, Cincinnati, Ohio.

Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts.
J Biol Chem. 1988 Nov 5: 263(31): 16291-6.
 
Adenosine deaminase (ADA) deficiency in humans is one cause of severe combined immunodeficiency disease. Single base mutations affecting the ADA protein have been identified for both alleles of the ADA-deficient cell line GM2606 and for one allele of the ADA-deficient cell line GM2825A. One allele of GM2606 has a mutation altering amino acid 101 from Arg to Trp, and the other allele has a mutation altering amino acid 211 from Arg to His. As previously reported, one ADA allele of GM2825A has a single base mutation changing Ala-329 to Val-329, and the other allele has a mutation which eliminates exon 4 from the mature mRNA. Sequence analysis of polymerase chain reaction-amplified GM2825A DNA showed a single base change of A to G within the invariant bases of the 3' splice site of intron 3 that can account for the mis-splicing of exon 4. To test the effect on ADA catalytic activity of these mutations and the mutations previously found in the ADA-deficient line GM2756, expression vectors containing normal and mutant ADA-coding sequences under transcriptional regulation of the Rous sarcoma virus long terminal repeat were constructed and transfected into human fibroblasts. All transfected cells had levels of ADA mRNA 15-25 times higher than the endogenous ADA message. Yet, cells transfected with the normal ADA-coding sequences had ADA enzymatic levels 40 times higher than cells transfected with any of the mutant ADA sequences. This analysis demonstrates that while the mutant ADA-coding sequences are transcribed, they do not encode a functional ADA protein.

------------------------------------------------------------------------------------------------------------------------------------------------

Allen RC, Graves G, Budowle B.  Dept. of Pathology and Laboratory Medicine, Medical University of South Carolina, Children's Hospital, Charleston 29425.
Polymerase chain reaction amplification products separated on rehydratable polyacrylamide gels and stained with silver.
Biotechniques. 1989 Jul-Aug: 7(7): 736-44.
 
Separation of polymerase chain reaction (PCR) amplification of specific fragment length polymorphisms was carried out on rehydratable polyacrylamide gels on a horizontal flat slab system. A discontinuous sulfate-borate buffer system was employed on 5-8% T gels crosslinked with 3.5% C. Samples were diluted in leading sulfate ion buffer at 1/10 the ionic strength of the separating gel buffer and placed directly onto the surface of the rehydrated gels in 0.5-10 microliters volumes. The trailing ion and counterion were contained in a gel plug and placed directly onto the anodal and cathodal ends of the gel, and the electrodes placed directly onto the surface of the gel plugs. Filter paper wicks, soaked in diluted leading ion buffer, were placed along each side to lower the ionic strength of the edges, thereby increasing mobility at the edge and thus preventing smile effects. The gel-gel contact of the plug and separating gel prevent the production of a junction potential which occurs between dissimilar materials such as a paper wick and the gel. Ten- to 20-cm separations were carried out from 2-5 h, respectively, and resolution in the 20 cm system was 1.6-4 bp (base pairs) between 100 and 500 bp, 4-7 bp between 500 and 1000 bp, 12-20 bp between 1000 and 2000 bp and about 50 bp between 2000 and 3000 bp. Between 3000 and 4000 bp, resolution fell off to +/- 100 bp. Sensitivity, using a silver stain, indicated that one could readily distinguish less than 10 pg of DNA per mm width on the gels.

------------------------------------------------------------------------------------------------------------------------------------------------

Amselem S, Nunes V, Vidaud M, Estivill X, Wong C, d'Auriol L, Vidaud D, Galibert F, Baiget M, Goossens M. INSERM U.91 Hopital Henri Mondor, Creteil, France.
Determination of the spectrum of beta-thalassemia genes in Spain by use of dot-blot analysis of amplified beta-globin DNA.
Am J Hum Genet. 1988 Jul: 43(1): 95-100.
 
We have delineated the molecular lesions causing beta-thalassemia in Spain, a country that has witnessed the passage of different Mediterranean populations over the centuries, in order to evaluate the extent of heterogeneity of these mutations and to make possible simplified prenatal diagnosis of the disorder in that country. The use of the polymerase chain-reaction (PCR) technique to preferentially amplify beta-globin DNA sequences that contain the most frequent beta-thalassemia mutations in Mediterraneans enabled us to rapidly analyze 58 beta-thalassemia alleles in a dot-blot format either by hybridization with allele-specific radiolabeled oligonucleotide probes or by direct sequence analysis of the amplification product. The Spanish population carries seven different beta-thalassemia mutations; the nonsense codon 39 is predominant (64%), whereas the IVS1 position 110 mutation, the most common cause of beta-thalassemia in the eastern part of the Mediterranean basin, is underrepresented (8.5%). The IVS1 mutation at position 6 accounts for 15% of the defects and leads to a more severe form of beta+-thalassemia than originally described in most of the patients we studied. In this study, we demonstrate further the usefulness of the dot-blot hybridization of PCR-amplified genomic DNA in both rapid population surveys and prenatal diagnosis of beta-thalassemia.

------------------------------------------------------------------------------------------------------------------------------------------------

Angelini G, de Preval C, Gorski J, Mach B.
High-resolution analysis of the human HLA-DR polymorphism by hybridization with sequence-specific oligonucleotide probes.
Proc Natl Acad Sci U S A. 1986 Jun: 83(12): 4489-93.  Erratum in: Proc Natl Acad Sci U S A 1986 Sep: 83(17): 6664.
 
The human major histocompatibility complex class II antigens of the HLA-D are highly polymorphic, surface proteins essential in the cellular interactions necessary for an immune response. The analysis of this polymorphism is crucial for (i) histocompatibility matching for transplantation and (ii) understanding the association between HLA-D and certain important diseases. The polymorphism of certain HLA-D haplotypes may escape detection by current methodologies. Analysis at the genomic level of the polymorphism of one of the HLA-D subregions HLA-DR, using oligonucleotide probes specific for the polymorphic regions, is capable of distinguishing single nucleotide differences. The DRw6 haplotype was analyzed in view of the lack of DRw6 specific sera. On the basis of nucleotide sequence analysis, the DRw6 haplotype consists of at least two subtypes. When analyzed with oligonucleotide probes, this split identifies new polymorphic groups that differ from the DRw6 serological subgroups.

------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Boehm CD, Giardina PJ, Kazazian HH Jr.
Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster.
Proc Natl Acad Sci U S A. 1982 Jan: 79(1): 137-41.

By using probes for -, Yβ₁-, and β-globin genes, we found four additional polymorphic restriction sites that have frequencies >0.1 in persons of Mediterranean area origin, Asian Indians, and American Blacks. Three of these (HincII sites) and the two previously described polymorphic HindIII sites [one in intervening sequence (IVS) II of each γ-globin gene] are distributed over 32 kilobases (kb) of DNA located 5′ to the δ-globin gene. This region of DNA comprises two-thirds of the β-globin gene cluster. Since each of these five polymorphic sites can be present (+) or absent (-), in theory there exist 32 possible combinations of sites (haplotypes). However, in Italians, Greeks, Indians, and Turks, 3 of the 32 haplotypes, (+----), (-+-++), and (-++-+), account for 92% of 89 β^A chromosomes examined. The observed frequencies for these haplotypes are 0.64, 0.15, and 0.13 in the populations studied, in contrast to expected frequencies (based on the observed gene frequencies at each of the five sites) of 0.20, 0.006, and 0.005, respectively. In American Blacks, a fourth haplotype, (----+), which is rare in non-Black populations, has a frequency of 0.37 in contrast to its expected frequency of 0.05. These results suggest a nonrandom association of DNA sequences over 32 kb 5′ to the δ-globin gene in all populations studied. Two other polymorphic sites 3′ to the δ gene (the newly discovered Ava II site in IVS II of the β-globin gene and the BamHI site 3′ to it) are nonrandomly associated with each other but randomly distributed with respect to the above haplotypes. This suggests that randomization of sequences has occurred within 12 kb of DNA between these two nonrandomly associated sequence clusters. Nonrandom association of polymorphic restriction sites has practical consequences in that it limits the usefulness of these additional HincII sites for prenatal diagnosis of hemoglobinopathies by linkage analysis. These sites provide little additional information for detection of β-thalassemia, while the polymorphic Ava II site, which lies outside the nonrandomly associated sequences 5′ to the δ gene, improves the test applicability from 52% to 70% of couples at risk.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Phillips JA 3rd, Kazazian HH Jr.
Genetic diseases: diagnosis by restriction endonuclease analysis.
J Pediatr. 1982 Jun: 100(6): 845-56.
 
We have summarized a number of different genetic disorders which can be diagnosed at the DNA level using restriction endonuclease fragment analysis. A whole spectrum of defects can be recognized: point mutations, deletions, additions, and crossing-over products or hybrid genes. These same restriction endonuclease techniques can enable different genes to be marked by polymorphism patterns. Thus, abnormal genes can be identified even if their exact DNA lesion is unknown or cannot be directly detected. The progress that has been made with the hemoglobinopathies and the experience from this group of single gene disorders should find application to other diseases as soon as specific probes become available.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Orkin SH, Kazazian HH Jr, Goff SC, Boehm CD, Waber PG, Sexton JP, Ostrer H, Fairbanks VF, Chakravarti A.

Evidence for multiple origins of the beta E-globin gene in Southeast Asia.
Proc Natl Acad Sci U S A. 1982 Nov: 79(21): 6608-11.
 
To investigate whether recurrent mutation has contributed to the high frequency of the beta E-globin gene in Southeast Asia, we used the haplotypes at three polymorphic restriction sites within and to the 3' side of the beta-globin gene to predict the framework of 23 beta E-globin genes. These haplotypes suggested that beta E-globin genes are present in two different beta-globin gene frameworks. DNA sequence determination of one gene representing each framework demonstrated that the same mutation (GAG leads to AAG at codon 26) was present in both frameworks. Moreover, the frameworks differed at three nucleotide positions known to be polymorphic in Mediterraneans. These polymorphic sites are located 70 nucleotides to the 5' side of the beta E mutation and 382 and 1032 nucleotides to the 3' side of it. The existence of the beta E mutation in these two beta-globin gene frameworks can be explained by (i) recurrent mutation giving rise to beta E-globin, (ii) a double crossing-over event, or (iii) two single crossing-over events. Mathematical analysis suggests that the first alternative, recurrent mutation of G leads to A at the first nucleotide of codon 26, is most likely.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Kittur SD, Metaxotou C, Watkins PC, Patel AS.

Analysis of DNA haplotypes suggests a genetic predisposition to trisomy 21 associated with DNA sequences on chromosome 21.
Proc Natl Acad Sci U S A. 1985 May: 82(10): 3360-4.
 
To test the hypothesis that there is a genetic predisposition to nondisjunction and trisomy 21 associated with DNA sequences on chromosome 21, we used DNA polymorphism haplotypes for chromosomes 21 to examine the distribution of different chromosomes 21 in Down syndrome and control families from the same ethnic group. The chromosomes 21 from 20 Greek families with a Down syndrome child and 27 control Greek families have been examined for DNA polymorphism haplotypes by using four common polymorphic sites adjacent to two closely linked single-copy DNA sequences (namely pW228C and pW236B), which map somewhere near the proximal long arm of chromosome 21. Three haplotypes, +, +---, and - with respective frequencies of 43/108, 24/108, and 23/108, account for the majority of chromosomes 21 in the control families. However, haplotype - was found to be much more commonly associated with chromosomes 21 that underwent nondisjunction in the Down syndrome families (frequency of 21/50; X2 for the two distributions is 9.550; P = 0.023; degrees of freedom, 3). The two populations (control and trisomic families) did not differ in the distribution of haplotypes for two DNA polymorphisms on chromosome 17. The data from this initial study suggest that the chromosome 21, which is marked in Greeks with haplotype - for the four above described polymorphic sites, is found more commonly in chromosomes that participate in nondisjunction than in controls. We propose an increased tendency for nondisjunction due to DNA sequences associated with a subset of chromosomes 21 bearing this haplotype.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Copeland KL, Carpenter RJ Jr, Carta CA, Hoyer LW, Caskey CT, Toole JJ, Kazazian HH Jr.

Prenatal diagnosis of haemophilia A by factor VIII gene analysis.
Lancet. 1985 Jun 22: 1(8443): 1407-9.
 
Cloned factor VIII deoxyribose nucleic acid (DNA) sequences were used as probes in the prenatal diagnosis of haemophilia A. Fetal DNA from cultured amniotic fluid cells was examined for a DNA polymorphism within the factor VIII gene which marked the haemophilia A gene in the pregnant obligate carrier. The fetus was predicted to be an affected male, and the diagnosis of haemophilia A was confirmed both in utero and after termination of the pregnancy.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Waber PG, Kittur SD, Patel AS, Kazazian HH Jr, Mellis MA, Counts RB, Stamatoyannopoulos G, Bowie EJ, Fass DN, et al.

Hemophilia A. Detection of molecular defects and of carriers by DNA analysis.
N Engl J Med. 1985 Oct 3: 313(14): 842-8.
 
To understand the molecular basis of hemophilia A and to provide heterozygote detection and prenatal diagnosis by DNA analysis, we used cloned factor VIII:C DNA fragments to study 10 affected families. In four of these families, inhibitors of factor VIII:C had developed in affected persons. In one such family a deletion of approximately 80 kb within the factor VIII:C gene was identified. Carriers of the deletion were identified through detection of an abnormal DNA fragment located at the deletion end points. In another family a single nucleotide change in the coding region of the factor VIII:C gene produced a nonsense codon leading to premature termination of factor VIII:C synthesis. Carrier detection was performed in eight female members of this four-generation family. In a third family a small change in the size of a restriction-endonuclease fragment correlated with the presence of the mutant gene, and in the other seven families the molecular defect has not yet been identified. In addition, we used two common polymorphic sites in the factor VIII:C gene to differentiate the normal from the defective gene in four of six obligate female carriers from families with patients in whom inhibitors did not develop. Carrier detection was possible in other members of these families. These data suggest that DNA analysis of the factor VIII:C gene provides an accurate method of carrier detection and, potentially, of prenatal diagnosis in at least 50 per cent of the pedigrees affected by hemophilia A.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Oettgen P, Chakravarti A, Halloran SL, Hudson RR, Feisee L, Karathanasis SK.
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

DNA polymorphism haplotypes of the human apolipoprotein APOA1-APOC3-APOA4 gene cluster.
Hum Genet. 1988 Nov: 80(3): 265-73.
 
The genes coding for apolipoproteins A1, C3, and A4 (APOA1, APOC3, APOA4) are closely linked and tandemly organized within a 15-kilobase (kb) DNA segment on the long arm of human chromosome 11. The nucleotide variability of a 61-kb DNA segment containing these genes and their flanking sequences was studied by restriction analysis of a sample of 18 unrelated Northern Europeans using seven different genomic DNA probes. Eleven restriction site polymorphisms located within this DNA segment were used for haplotype analysis of 129 Mediterranean and 67 American black chromosomes. Estimation of the extent of nonrandom association between these polymorphisms indicated considerable linkage disequilibrium within the APOA1-APOC3-APOA4 gene cluster. Several haplotypes arose by recombination, and the rate of recombination within this gene cluster was estimated to be at least 4 times greater than that expected based on uniform recombination. The polymorphism information content of each of these polymorphisms, taken individually, ranges between 0.053 and 0.375, while that of their haplotypes ranges between 0.858 and 0.862. Therefore, DNA polymorphism haplotypes in the APOA1-APOC3-APOA4 gene cluster constitute a highly informative genetic marker on the long arm of human chromosome 11.

------------------------------------------------------------------------------------------------------------------------------------------------

Antonarakis SE, Kang J, Lam VM, Tam JW, Li AM.
Department of Paediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Molecular characterization of beta-globin gene mutations in patients with beta-thalassaemia intermedia in south China.
Br J Haematol. 1988 Nov: 70(3): 357-61.

We have studied the spectrum of mutations producting beta-thalassaemia intermedia in South China. The methods of mutation detection include oligonucleotide analysis, polymerase chain reaction amplification of the beta-globin gene and direct genomic sequencing. The mutations have been identified in 22 beta-globin genes from the patients in 11 unrelated families. Seven different mutations have been identified and the A to G substitution in the TATA box of the beta-globin gene accounts for 42% of these mutant beta-globin genes. Most patients have a beta(+) thalassaemia and one copy of the TATA box mutation. In two patients with beta(0) thalassaemia intermedia the mild phenotype may be explained in one by the presence of the - + - + + 5' beta-globin gene cluster haplotype which contains the Xmn I site -158 nt to the G gamma-globin gene or in the other by the number of alpha-globin genes present.

------------------------------------------------------------------------------------------------------------------------------------

Arai K, Madison J, Huss K, Ishioka N, Satoh C, Fujita M, Neel JV, Sakurabayashi I, Putnam FW.   Department of Biology, Indiana University, Bloomington 47405.

Arnheim N, Strange C, Erlich H

Use of pooled DNA samples to detect linkage disequilibrium of polymorphic restriction fragments and human disease: studies of the HLA class II loci.
Proc Natl Acad Sci U S A. 1985 Oct: 82(20): 6970-4.
 
A rapid method has been developed and used to search for restriction fragment length polymorphisms (RFLPs) that are in linkage disequilibrium with disease-associated loci. By using genomic blot-hybridization analysis with DQ beta-chain and DR beta-chain cDNA probes, we examined DNA polymorphisms within the HLA class II loci associated with susceptibility to insulin-dependent mellitus (IDDM). To facilitate the search for informative RFLPs, we compared pooled DNA samples from IDDM patients with pooled DNA samples from randomly selected control individuals, instead of using the conventional approach of examining DNA samples from individuals in two groups. (The conditions under which this approach is useful are treated theoretically in the Appendix.) Several specific polymorphic restriction fragments associated with IDDM were revealed by using this economical and rapid approach. The restriction enzymes and probes identified as informative in this screening were then used to analyze HLA-DR-typed IDDM families, homozygous typing cells, and unrelated individuals to determine the association of the specific restriction fragments with HLA-DR serological type and the frequency in control and IDDM populations. Some individual polymorphic fragments for which the IDDM population was enriched correlated strongly with HLA-DR3, whereas others correlated strongly with HLA-DR4. Some fragments (e.g., a 10-kilobase Taq I fragment detected with the DR beta probe) that were more prevalent in the IDDM population subdivided the serologically defined HLA-DR type and may be informative markers for IDDM susceptibility.

------------------------------------------------------------------------------------------------------------------------------------

Arpaia E, Dumbrille-Ross A, Maler T, Neote K, Tropak M, Troxel C, Stirling JL, Pitts JS, Bapat B, Lamhonwah AM, et al.  Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

Identification of an altered splice site in Ashkenazi Tay-Sachs disease.
Nature. 1988 May 5: 333(6168): 85-6.

Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (ref. 1). A relatively high frequency of carriers (1/27) of a lethal, infantile form of the disease is found in the Ashkenazi Jewish population, but it is not yet evident whether this has resulted from a founder effect and random genetic drift or from a selective advantage of heterozygotes. We have identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient. This change, the substitution of a C for G in the first nucleotide of intron 12 is expected to result in defective splicing of the messenger RNA. A test for the mutant allele based on amplification of DNA by the 'polymerase chain rection and cleavage of a DdeI restriction site generated by the mutation revealed that this case and two other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for two different mutations. The occurrence of multiple mutant alleles warrants further examination of the selective advantage hypothesis.

------------------------------------------------------------------------------------------------------------------------------------

Bahnak BR, Lavergne JM, Verweij CL, Rothschild C, Pannekoek H, Larrieu MJ, Meyer D.   INSERM U.143, Hopital de Bicetre, Paris, France.

Carrier detection in severe (type III) von Willebrand disease using two intragenic restriction fragment length polymorphisms.

Thromb Haemost. 1988 Oct 31: 60(2): 178-81.

 
DNA from a family with a female member affected with severe (type III) vWD was analysed using three restriction enzymes and a partial vWF cDNA probe. Two restriction fragment length polymorphisms (RFLPs) detected with the enzymes Bgl II and Xba I proved to be informative in this family. A 36.0 Kb allele demonstrated with the enzyme Xba I was rare in the general population but very important in this family for segregation analysis of the alleles and their association with the putative defective chromosome. The propositus was homozygous for the 36.0 Kb Xba I polymorphic band and heterozygous for the Bgl II polymorphism. She was the only member of the family showing this allelic pattern. The linkage of the alleles could be determined because her mother was homozygous for the 9.0 Kb Bgl II polymorphism but heterozygous for the Xba I polymorphism. The segregation of the alleles could be traced to the proband's son and a niece. The genotypic analysis revealed that her niece could be considered as carrying a defective gene for severe vWD.

------------------------------------------------------------------------------------------------------------------------------------------------

Baxter-Lowe LA, Hunter JB, Casper JT, Gorski J.   Blood Center of Southeastern Wisconsin, Inc., Milwaukee 53233.

HLA gene amplification and hybridization analysis of polymorphism. HLA matching for bone marrow transplantation of a patient with HLA-deficient severe combined immunodeficiency syndrome.
J Clin Invest. 1989 Aug: 84(2): 613-8.
 
The treatment of choice for certain immunodeficiency syndromes and hematological disorders is bone marrow transplantation (BMT). The success of BMT is influenced by the degree of HLA compatibility between recipient and donor. However, aberrant expression of HLA sometimes makes it difficult, if not impossible, to determine the patient's HLA type by standard serological and cellular techniques. We describe here the application of new molecular biological techniques to perform high resolution HLA typing independent of HLA expression. A patient with HLA-deficient severe combined deficiency was HLA typed using in vitro amplification of the HLA genes and sequence-specific oligonucleotide probe hybridization (SSOPH). Two major advances provided by this technology are:detection of HLA polymorphism at the level of single amino acid differences; and elimination of a requirement for HLA expression. Although the patient's lymphocytes lacked class II HLA proteins, polymorphism associated with DR7,w53;DQw2;DRw11a (a split of DR5), w52b (a split of DRw52);DQw7 were identified. The patient's class I expression was partially defective, and typing was accomplished by a combination of serological (HLA-A and -C) and SSOPH analysis (HLA-B). Complete patient haplotypes were predicted after typing of family members [A2;B35(w6); Cw4; DRw11a(w52b);DQw7 and A2;B13(w4); Cw6;DR7(w53); DQw2]. Potential unrelated donors were typed and a donor was selected for BMT.

------------------------------------------------------------------------------------------------------------------------------------------------

Beaudet AL, Spence JE, Montes M, O'Brien WE, Estivill X, Farrall M, Williamson R.

Experience with new DNA markers for the diagnosis of cystic fibrosis.
N Engl J Med. 1988 Jan 7: 318(1): 50-1.

------------------------------------------------------------------------------------------------------------------------------------------------

Bellis M, Jubier-Maurin V, Dod B, Vanlerberghe F, Laurent AM, Senglat C, Bonhomme F, Roizes G.  Centre National de la Recherche Scientifique, Institut de Biologie, Montpellier, France.

Distributions of two recently inserted long interspersed elements of the L1 repetitive family at the Alb and beta h3 loci in wild mice populations.
Mol Biol Evol. 1987 Jul;4(4):351-63.
 
The presence of the L1 sequences, L1Md4 next to the pseudogene beta h3 and I12 found in the twelfth intron of the albumin gene, in certain strains of laboratory mice but not of others has led to the suggestion that these sequences were recent insertions into the Mus mus domesticus genome. To be sure that they are really recent insertions and not relics of an ancestral chromosome, we investigated the presence or absence of these sequences in populations of wild mice belonging to the semispecies M. m. domesticus and M. m. musculus as well as in other species of the genus Mus and in related murids. The sequence I12 in the albumin gene was found in 34% of the chromosomes of the wild mice belonging to M. m. domesticus and to a lesser extent (6%) in M. m. musculus. Of 114 M. m. domesticus chromosomes, L1Md4 was found in only nine, seven of which came from the same locality. Its presence was associated with the haplotype Hbbp, which is relatively rare in European populations of M. musculus. Since there was no evidence for the presence of these two L1 sequences in more distantly related species, we conclude that they are recent insertions in the M. musculus genome.

------------------------------------------------------------------------------------------------------------------------------------------------

Bidwell JL, Bidwell EA, Savage DA, Middleton D, Klouda PT, Bradley BA. Molecular Genetics Laboratory, United Kingdom Transplant Service, Bristol, England.

A DNA-RFLP typing system that positively identifies serologically well-defined and ill-defined HLA-DR and DQ alleles, including DRw10.
Transplantation. 1988 Mar;45(3):640-6.
 
A single enzyme/multiple probe system of HLA-DR and DQ typing using restriction fragment-length polymorphism (RFLP) analysis is presented. TaqI-digested genomic DNAs are hybridized sequentially with short DR beta, DQ beta, and DQ alpha cDNA probes. The DR beta probe discriminates between the DR allelic specificities DR1 to DRw14, with the two exceptions of some DR3/DRw13 and some DR7/DRw9 combinations. We describe the positive identification of a DRw10-specific RFLP and demonstrate its segregation in families. The DQ beta probe defines an allelic system that identifies the alleles DQw1, DQw2, and DQw3. This permits the resolution of DR3/DRw13 and DR7/DRw9 alleles by defining the DR/DQ association caused by linkage disequilibrium. The DQ alpha probe defines another allelic series interrelated with, but independent from, the DQ beta series. Specific DQ beta/DQ alpha RFLP combinations correlate with known Dw splits of DR2, DRw6, and DR7. Combined use of the three probes permits the identification of HLA-DR, DQ, and certain Dw specificities and provides an effective and easily interpretable system for major histocompatibility complex class II allogenotyping.

------------------------------------------------------------------------------------------------------------------------------------------------

Boehm CD.  Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, MD 21205.

Use of polymerase chain reaction for diagnosis of inherited disorders.
Clin Chem. 1989 Sep: 35(9): 1843-8.
 
The polymerase chain reaction (PCR) is a rapid method for generating a 10(6)- to 10(7)-fold increase in the number of copies of a discrete DNA or RNA sequence. The technique is being used for rapid prenatal diagnosis and carrier testing of several inherited disorders. After PCR, mutations producing single-gene disorders can be detected by several different methods, including endonuclease digestion and gel electrophoresis (applicable when a mutation affects an endonuclease recognition site), gel electrophoresis (used for detection of deletions), and hybridization to an oligonucleotide probe specific for a mutation. Less often, gene sequencing of a PCR product is used to rapidly identify a mutation. In addition, the PCR technique can be applied to polymorphism analysis to provide diagnosis by linkage analysis. In other areas, PCR is being used to detect and characterize microbial pathogens and to characterize mutations associated with carcinogenesis. The PCR method is useful in situations in which the amount of DNA sample is limited, such as in forensics and prenatal testing, or in which the quality of the DNA sample is poor.

------------------------------------------------------------------------------------------------------------------------------------------------

Boehnke M, Arnheim N, Li H, Collins FS.  Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor 48109.

Fine-structure genetic mapping of human chromosomes using the polymerase chain reaction on single sperm: experimental design considerations.

Am J Hum Genet. 1989 Jul;45(1):21-32.

The polymerase chain reaction (PCR) makes it possible to rapidly generate a very large number of copies of a specific region of DNA. Application of PCR to individual human sperm cells permits the typing of a large number of independent male meiotic events. If the donor male is heterozygous at three loci, sperm typing using PCR will permit ordering of loci in a manner analogous to classical methods of experimental genetics. Sequential analysis of trios of loci by sperm typing will provide a very accurate means of ordering any number of tightly linked loci. Here, we describe experimental design and sample-size issues raised by the application of sperm typing by PCR for mapping human chromosomes, and we demonstrate that sperm typing will be an efficient method for generating fine-structure human genetic maps.

------------------------------------------------------------------------------------------------------------------------------------------------

Botstein D, White RL, Skolnick M, Davis RW.

Construction of a genetic linkage map in man using restriction fragm