Construction of a General Human Chromosome Jumping Library with Application to Cystic Fibrosis Author s Francis S Collins Mitchell L Drumm Jeffery L Cole Wendy K Lockwood George F Vande Woude Michael C Iannuzzi Source Science New Series Vol 235 No 4792 Feb 27 1987 pp 1046 1049 Published by American Association for the Advancement of Science Stable URL http www jstor org stable 1698770 Accessed 28 07 2009 14 36 Your use of the JSTOR archive indicates your acceptance of JSTOR s Terms and Conditions of Use available at http www jstor org page info about policies terms jsp JSTOR s Terms and Conditions of Use provides in part that unless you have obtained prior permission you may not download an entire issue of a journal or multiple copies of articles and you may use content in the JSTOR archive only for your personal non commercial use Please contact the publisher regarding any further use of this work Publisher contact information may be obtained at http www jstor org action showPublisher publisherCode aaas Each copy of any part of a JSTOR transmission must contain the same copyright notice that appears on the screen or printed page of such transmission JSTOR is a not for profit organization founded in 1995 to build trusted digital archives for scholarship We work with the scholarly community to preserve their work and the materials they rely upon and to build a common research platform that promotes the discovery and use of these resources For more information about JSTOR please contact support jstor org American Association for the Advancement of Science is collaborating with JSTOR to digitize preserve and extend access to Science http www jstor org 11 S Matsushita F Ibuki A Aoki Arch Biochem 102 446 1963 Biophys 12 C E Wright H H Tallan Y Y Lin Annu Rev Biochem 55 427 1986 13 K P M HeirweghandS B Brown Eds Bilirubin CRCPress BocaRaton FL 1982 vols 1 and2 R Schmidand A F McDonagh in TheMetabolic Basis of InheritedDisease J B Stanbury J B Wyngaarden D S Fredrickson Eds McGrawHill New York 1978 pp 1221 1257 14 M Sarnat in Topicsin NeonatalNeurology H B Sarnat Ed Grune Stratton New York 1984 pp 109 136 G B Odell and H S Schutta in andMetabolicEncephaCerebral EnergyMetabolism lopathy D W McCandless Ed Plenum New York 1985 pp 229 261 15 K Bernhard G Ritzel K U Steiner Helv Chim Acta 37 306 1954 H Beer and K Bernhard Chimia13 291 1959 16 Y Yamamoto E Niki Y Kamiya Bull Chem Soc Jpn 55 1548 1982 17 Differentsolventswere used since biliverdinis not solublein chloroformand bilirubinis insolublein methanol The solubilityof oxygenin chloroformis only 20 greaterthanthat in methanol 25 18 F R Mayo Act Chem Res 1 193 1968 19 A F McDonagh L A Palma F R Trull D A Lightner J Am Chem Soc 104 6865 1982 A 28 J A T P Meuwissenand K P M Heirwegh in byProteins G Blauerand H Sund Eds Transport D A Lightnerand A F McDonagh Ace Chem de Gruyter Berlin 1978 pp 387 401 Res 17 417 1984 A F McDonaghand D A 29 Y Yamamoto M H Brodsky J C Baker B N in press Ames Anal Biochem 75 443 1985 Lightner Pediatrics 30 A F McDonaghandF Assisi Biochem A F McDonagh N Engl J Med 314 121 1986 J 129 797 G W BurtonandK U Ingold J Am Chem Soc 1972 in 1D is to 31 The observed 103 6472 1981 lag Fig thought reflectthe of the nitrogenatmospherein N A Porteret al J Am Chem Soc 102 5597 gradualequilibration the reactiontubes with air over the courseof the 1980 L R C Barclayand K U Ingold ibid 103 6478 1981 Y Yamamotoet al Biochim experiment Acta 795 332 1984 32 The impetusforthisstudywas to providea test of a Biophys The phase transitiontemperatureof soybeanPC general hypothesis put forward by one of us metabol A N G thatend productsof degradative bilayeris below0 C J De Gier J G Mandersloot ic pathwaysmay playimportantrolesas protective L L M Van Deenen Biochim Biophys Acta 150 in is that this bilirubin a likely 666 1968 Therefore we believethat thereis no context agents and candidatefor sucha role This workwas supported significantdifferencein the liposomestructurebetween37 and 50 C by NationalCancerInstituteOutstandingInvestigator grantCA 39910 B N A NIEHS National ChemicalSociety of Japan Ed KagakuBinran HealthSciences Center Instituteof Environmental Maruzen Tokyo 1975 p 769 S Srivastava R S Phadke G Govil C N R Rao grantES 01896 B N A NIH grantsAM 26307 MD 20551 and GM 28994 A N G Biochim Acta 734 353 1983 A N Erin A F M Biophys NSF grantDMB 85 18066 A N G andUniversiet al ibid 774 96 1984 A N Erin V K ty of CaliforniaToxic SubstancesResearchand Skrypin V E Kagan ibid 815 209 1985 E ColleranandP O Carra in Chemistry andPhysiolTeachingProgram Y Y We alsothankH Hurd for helpon earlieraspectsof this study ogyofBilePigments P D BerkandN I Berlin Eds GovernmentPrinting Office Washington DC 22 September1986 accepted6 January1987 1977 pp 69 80 F McDonagh L A Palma D A Lightner ibid p 6867 20 21 22 23 24 25 26 27 Construction of a General Human Chromosome Jumping Library with Application to Cystic Fibrosis FRANCIS S COLLINS MITCHELL L DRUMM JEFFERY L COLE WENDY K LOCKWOOD GEORGE F VANDE WOUDE MICHAEL C LANNUZZI In many genetic disorders the responsible gene and its protein product are unknown The technique known as reverse genetics in which chromosomal map positions and genetically linked DNA markers are used to identify and clone such genes is complicated by the fact that the molecular distances from the closest DNA markers to the gene itself are often too large to traverse by standard cloning techniques To address this situation a general human chromosome jumping library was constructed that allows the cloning of DNA sequences approximately 100 kilobases away from any starting point in genomic DNA As an illustration of its usefulness this library was searched for a jumping clone starting at the met oncogene which is a marker tightly linked to the cystic fibrosis gene that is located on human chromosome 7 Mapping of the new genomic fragment by pulsed field gel electrophoresis confirmed that it resides on chromosome 7 within 240 kilobases downstream of the met gene The use of chromosome jumping should now be applicable to any genetic locus for which a closely linked DNA marker is available HE USE OF LINKAGE ANALYSIS 1 and high resolutioncytogeneticshas allowedchromosomalmappingin an increasingnumber of disordersof single humangenes even in situationswheregene function is unknown Recent examplesincludeHuntingtondisease 2 adultpolycystic kidneydisease 3 cysticfibrosis 4 7 chronic granulomatousdisease 8 Duchennemusculardystrophy 9