THE BIOLOGICAL CENTURY FIUIMY EVENING TALKS AT THE MAIUNI~ BIOLOGICAL LAROKATORY __-- Editctl by Rob-t B. Barlow, Jr., John E. Dowling, and Gcrdd Wcissmann `I'hc Mxinc Hiologicnl Laboratory Wootls I lolc, Massochusctts Distrihutcd by tl;rrvard University Press Cambridge, Massachusclls L011d011, EnglmJ .lo';llll : I ,I l)l~l:lll~l:(~ I'111 going to discuss gcnctic II1;Ipx. L 3i:d I ;i:;zui11c 111:lt tllc re;lckr 11;\\; :I gcllcl-;ll lm~\vlctlgc of goncs :llltl cIlI-oIllosoIllcs, hll tlocs nol hnow 50 mrcll 01` the clct;1ils 01. DNA cbcmistry tl~at 111~ sinqdil`ica- [ions in that realn1 will bc irritating. Just relax, ;llld rend :I story Ol genetic imps, ;inti how our untlerst;mliug of the n1:lps has developed. This essay is bnseci on an evenin, 0 Iccturc, not 3 scnicstcr course in molecular biology (XC bibliographic note). Thomas Hunt Morgan cam to ;I chair in Zoology at Columbia University in 1904 at the bchcst of tbc rcnowncd cytologist, B. I3. Wilson. Shortly thereafter I1c began brcetling D~~so~d~ila wit11 the intention to mnkc it tbc cxcmplar ofgcnctic investigation. And he set up the fnn:ous Ily room, shown in Figure 1. This picture was purportedly taken (according to Curt Stern's notes) secretly, witllout Morgan's k~wwlcdgc. I-k was supl~oscd to hnvc lwen somcwbat 27 26 J. Lmmneac; ~-~- ._______- phobic about the matter. The picture was taken with ;t camera that was concealed in one of the fly incubators. As you cm see, Morgan is almost concealed by the cream bottles that wcrc used for growing flies at that time. It is ;L small cxcrcise in personal nostalgia to recall where the fly room was. It was on the sixth floor of Schcrmcrhorn Hall, Room 613, close to where I started my own research as a collcgc student in 194 1. Bctwecn 190s and 1928, this room was the creche of the chromosome theory of heredity. I've stnrtcd ;1 campaign at Columbia that there should be some commemo- ration of this rcmarkablc place-the Thomas Hunt Morgm fly room. In I91 l-30 years bcforc my nrrivnI--Alfred Sturtcvant was nlso an rmtlcrgraduate at Columbia. He had joined Morgan's laborn- tory togcthcr with Calvin Bridges and Herman Mullcr. These four people wcrc really the slcanl engine for the origination of our modcrn theory or gcnctics. IIcre is AlCrcd's own statcmcnt of how he came upon the gcnelic map: TI IE "FLY ROOM" In 1 WI Cnsllc published diagrnms to show the interrelations of germ nffccfing Ihe color-of rabbits. It seems possible now t11at thcsc diagrams wcrc intcntlcd IO rcprcsent dcvclopmcntnl interactions, but they wcrc t:~ken (nt Columbia) as an ;lttempt to show the spatial relations in the nucleus. In the latter part of I!, I I, in convcrsnlion with Morgan about this attcmpl-which wc agreed had nothing in its favor-l sucltlcnly rcalizcd Ihat lhc variations in strength of linkage, alrcndy rrttributetl by Morgan to tliffercnces in the spatial separation of the genes, offered the possibility of determining sequences in the linear dimension of ;L chromosome. I wait home mid spent most of the night (to lllc ncglcct of my uiidcrgradu;itc Ilomcwork) in producing tllc fil-21 chron~oson~~ mnp, which included the sex-linked genes y, w, v, rn, and r, in the order and approximately the rclntivc spacing that they still nppe:~r on lhc stmitlnrd maps (Sturtcvunt, I9 13). -Quoted from Sturtcvant (1365) Linkage is the CO~SC~~C~C~ of gcncs being located on the same chromosome no1 far from one another. Such genes will co-segregntc in crosses unless some other event hnppc~~s. That othcrcvcnt is called "crossing-over," ;intl the frcclucncy of crossing over is n function 0T IIIC distance bctwccn gcncs on the chromosome, ;mrl th;~t is Ir;lnsl;ltctl to distance on a gcnctic map. As Sturtcvant notes ;tbove, his l`irst maps show n number d gents located in the order and ;ipproxim~~lcly the rclativc spacing lhnt lllcy still qqxir on ;I st;ulchrtl ~wp (Figs. 2, 3). ,319 GCNETIC MAPS - No crossovers 6,972 flies Crossovers bctwccn Crossovers between Double w and 118 y and H crossovers 3.454 flies GO flies 9 flies Figures 2 and 3. E.wII~~I~~.s ($ gcuetic rnc~ps. (Reproduced with pennissiorf from Am. Zool. 26: 57%581, 1986.) A Y " ----)2.Z .._- Now III can be either to the right or to the left of y, 3s shown here: El C Y' w Y m r 0.0 1.0 30.7 JJ.7 57.6 i i i 29 GENkTlC MAPS If markers are perfectly linked they will appear at the same point on tltc clnanosomc. Ifthcy scpamtc from one another 1 o/o of the time, wc say they are one linkage unit, one centimorgan, apart. To verify the linear order of markers, one has to take markers not just by twos, but at least by threes to resolve ambiguities as to the specific sequence. When they do all fit together rensonrtbly well by a series of three point tests and highcr, wc have n corroboration of the linear map. AI that time Dtmnp/dcr was known to have four pairs of c!tromosomcs. A pcculinrly looking chromosome called the Y WAS present in the malt and not the female, and a few sex-linked markers, tha( is 10 say gcncs, were located on the X chromosome. E. B. Wilson had first hy!>othcsizccl that the inllcritancc of colorblindness could bc cxphtinctl by the !>osition of that marker in the sex chrotnosotne of the human. `I'hc sex-linket! markers, bcsidcs bolstering the chromosome theory, arc tcchnic;tlly much easier 10 study; results can be obtained in one gcncralion rather than two gcncrations of breeding. By I9 15, wc had the listing of the linkage groups ofI)r.ost,l,lrila, 3s shown in Figure &I. The chromosome picture hatltt't changed, but uow [hcrc arc X5 genes. The gcncs fell into four linkage grou!>s, ;t r;ttion:tl finding bccausc foLtrc!lrontosotltc pairs were available. Only ;I cou!~lc of gcncs could bc idcntificd with the tiny chromosome nutilbcr-l. One llling th;rt is cvitlcn( itnmct!i;t~cly is Lhat lhc locations ol`thc gctlcs for l`aclors involving cliffcrcnt dcvelo!X~letl~a! oulcomcs m:Ac no particular scnsc wh;ttsoevcr. Many ol`thc chromosomes had (~cucs f'or color; cvcry one of them had gctics for wing sha!X, and so En. Ag:iiti thcrc sccins to be no dcvclo!~nlctll;~I sense lo the map. WC know today 11121 if you compare diffcrcnt s!)ccics ofDw,s0philn you will I`itttl that llrc gcnctic locations of homologotts gcncs arc terribly acr;u~~blccl. You can look li)r corrcspottdcncc bc(wccn any one oi'll~c chromosomes in one species and anolher. You will J`ind tltat, ty!)i- ally, the moht obvious gcnctic tliffcrcncc between species is the structural chaigc in the chromosomes whcrc picccs ofc!~roniosomcs have !~cn moved around to many diffcrcnt places. So for many years the iden that the comprehensive gcnelic map could enhance our insight into the dcvcloptnenta! role of the genes wns substantially frustrated. Fine slructurc studies have been more informntivc. As I larlyn H:tlvorson mcntionccl in his introduction, gcnc ma!`- ping continuctl well through the `Ns, having been fitcilitaled by `I'ticophilits Pninlcr's serendipitous tliscovcry, in 1933, of the @ml cliromosotiics 01` lhc salivary gl:tnils or f~ro.vt~p/ri/rr (I?& 5). Abnormal rlar Ultid IIOW Cherry Chrome Cleft Club DKprCSSell Dolled Eosin FWCI Forked Furrow4 Fused GfWll Jaunty Lemon Lelhals, 13 hlinialure Notch Reduplicxlcd Ruby Rudirwnlxy Sable Shilled Short Skcc spoon Yip01 Tan Truncalc Vermilion While Yrllow GROUP I Region ANecled Abdomen Eye Venarion Wing Eye color Body color Vennlion Wing Wing Thorax Eye color Ommalidin Spines Eye Venalion nody color Wing Body color Die Wing VenalIon Eye color IX@ Wings llody color Vcna11on \Ving \Vhg Wing Uody color Alllellna \Ving Eye color Eye color I)ody color GROUP IV Narnc Region ,\Irccl