HYPEIIGLTCAEMIA AS A MENDELIAN P~ECESSIVE CHAI~ACTEP~ IN MICE.

Transcription

1 HYPEGLTCAEMA AS A MENDELAN P~ECESSVE CHA~ACTEP~ N MCE. BY P. J. CAM~CDGE, M.D. (LEND.), 32 Nottngham Place, Ma~'y~ebone, London, W, 1, AND H. A. H. {OWAZD, B.So. (Lol, m.). h'~ the course of an nvestgaton nto the factors controllng the sugar content of the blood n mammals, commenced some years ago, we found that f the effects of frght and shock were guarded aganst by usng only anmals accustomed to beng handled, the percentage after a twelve to twenty-four hot~rs fast rarely vared more than about 5 mg. from a mean average of 85 rag. per 100 c.c. when self-cotoured or pebald anmals were consdered, but that albnos and anmals whch were unformly black frequently gave results dfferng by 25 rag. or more from ths average, the former showng hgh and the latter low fgures. These exceptonm levels for the fastng blood sugar were so regularly encountered that t was evdent they were not merely the result of accdent, and t seemed probable there was some htherto unrecognsed relaton between the factors determnng colour and those controllng the sugar content of the blood. As our records showed that albnos dd not nvarably possess hgh fastng blood sugars, and that n black anmals the percentage of sugar n the fastng blood was not always below the average, t was 91ear that the colour factors and the sugar factors were not dentcal, although the frequent assocaton of abnormaltes of colour wth pronounced devatons from the mean average of sugar n the blood suggested some connecton. n order to dscover, f possble, the law underlyng ths apparent relaton we commenced a seres of breedng experments, usng mce for the purpose. These anmals were selected because they multply rapdly, occupy lttle space, and a large volume of work has already been publshed concernng eolour transmsson n them. They present the dsadvantage, however, that, owng to ther small sze, t s necessary to kll the anmal to obtan suffcent materal for a retable determnaton of the percentage of sugar n the blood, so that ff death occurs naturally or by accdent before a breedng experment s completed a seres of observatons may be nullfed. Ths happened n several of our seres, bttt a su~cent

2 388 Hyperglycaeqna n Mce number of completed observatons have been made to warrant conclusons beng drawn regardng the relaton between albnsm and hyperglycaema, and[ for the present we shall confne ourselves to that aspect of the questom As wll presently appear, the experments showed no genetcm connecton between albnsm and hgh sugar percentage, and the assocaton frst observed must consequently be regarded as fortutous. n all cases the blood requked for the sugar estmatons was obtaned by decaptatng the anmal and the determnatons were Carred out by a modfcaton of the Foln and Wu process, employng 0.2 c.c. of blood, whch we have descrbed elsewhere t. Frst Generaton. Famly A. A matng between two albno mce, both possessng hgh fastng blood sugars of 116 rag. and t20 rag. respectvely, yelded a famly of seven, all albnos wth hgh blood sugars rangng from ll,l to 124 rag. per 100 c.c. A.-. xa.h3 A.H. 7 Fa'mfy B. By matng 3 Mbno havng a hgh blood sugar, 120 rag., wth 8 black and whte pebald havng a low blood sugar, 80 nag., we obtaned a second famly consstng of fve albnos showng low blood sugars, 76 to 8~ rag., and sx black and whte pebalds also showng low blood sugars, 76 to 80 rag. A.-. x C,L. A.L. C.L. 5 6 _Famly C. A thrd famly consstng of seven chocolate coloured anmals, all wth low blood sugars rangng from 78 to 86 rag., resulted from the crossng of # albno havng a hgh blood sugar, 118 rag., wth chocolate havng a low blood sugar, 76 rag. A.H. x C.L. [ t C.L. 7 t New Vews on Dabetes, O:cford ~ed. Publcatons, p, 5, "~ A., albno; C., coloured; H., hgh; L., low.

3 P. J. C~MM~DOE ~ND H. A. H. HOWARD 389 lva'mly D. By crossng? albno havng a hgh blood sugar, 118 rag., wth 8.pebald chocolate and whte havng a low blood sugar, & nag., we obtaned a fourth famly of nne, all.pebalds, showng low blood sugars rangng from 76 to 84 nag. C.L. x A.H., C.L. 9 J These ntal results ndcated that a hgh blood sugar behaves as a recessve to a normal blood sugar n the same way as albnsm behaves to colour. n the famles A, U and D both parents were obvously honaozygous for colour and fo~" sugar, but n famly B the coloured.partner was apparently heterozygous for colour, although homozygous for sugar, thus explanng the appearance n. ther.progeny of ap.proxmately equal numbers of albnos and coloured anmals, all wth low blood sugars. Second Generaton. Favdly E. On matng 3 albno havng a hgh blood sugar, 120 nag., from famly A, wth 2 albno havng a low blood sugar, 80 nag., from famly B, we obtaned 35 ndvduals, t8 of whch were albnos wth hgh blood sugars, 114 to 12~ nag., and 17 were albnos wth low blood sugars, 76 to 84 nag. A.K. x A.H. A.H. x C.L. 1 E A.~[. A.L F Expectaton : Equalty, Fa~dly F. A cross between one of the 3 hgh blood sugar albnos, 116 nag., of famly A wth a? low blood sugar pebald, 80 rag., from famly B, gave 23 mce consstng of 8 albnos wth hgh blood sugars, 116 to 122 nag., 8 albnos wth low blood sugars, 76 to 85 nag., 7.pebalds wth hgh blood sugars, 116 to 120 rag., and 8 pebalds wth low blood sugars, 80 to 84 nag. A.H. xa.h. A.H. 0.L. A.tt. ~ GL.? 1 A.H. A.L. C.H. 0.L Expectaton : Equalty.....t~

4 390 Typerglycaema n Mce Famly G. A hgh blood sugar albno, 114: rag., from famly A on beng mated wth a low blood sugar black and whte pebald, 78 mg., from famly B gave a famly of 23, 5 albnos havng hgh blood sugars, 114:- to 120 rag., 6 albnos havng low blood sugars, 76 to B4: rag., 6 pebalds havng hgh blood sugars, 118 to 122 rag., and 6 pebalds havng low blood sugars, 80 to 84: rag. A.H. x A,tL A.H, C.L. A.}L3 x C.L.?... F~ 1 A.H. A.L. (J.-. C.L Fe Expec~,~ton : Equalty. Famly H. The crossng of a chocolate coloured mouse possessng a low blood sugar, 7B rag., from famly C wth a pebald chocolate and whte, also havng a low blood sugar, 80 mg., from famly D gave a second generaton of 4:7, consttuted of 3 albnos wth hgh blood sugars, 118 ~o 120 rag., 9 albnos wth ow blood sugars, 78 to 84: rag., 9 coloured anmals wth hgh blood sugars, 116 to 120 rag., and 26 coloured wth low bloodsugars, 74: to 88 rag. A.H. O.L. O.L. A.H. 1 J f t A,H, A.L. C.H. 0,L F~ Famly J. The matng of ~;wo other mce from the same famles, C and D, one a chocolate havng a low blood sugar, 82 mg., and the other a chocolate and brown pebald also wth a ow blood sugar, 80 rag., resulted n a famly of 32. Classfed accordng to colour and' the sugar content of the fastng blood, these showed 2 albnos wth hgh blood sugars, 116 to 120 rag., 6 albnos wth ow blood sugars, 78 to 84: rag., 8 coloured wth hgh blood sugars, 113 to 120 rag., and 18 colourecl wth low blood sugars, 76 to 84: rag. A.H. C.L, O.L. x A.H. O.L. ~ C.L. [ ; t A.H.A.L, O.H. C.L &

5 P. J. CA~MDaE A~D H. A. H. HOWARD 391 Famly K. n a thrd experment wth members of famles C and D, a chocolate coloured mouse possessng a low fastng blood sugar, 80 rag., was crossed wth a pebald chocolate and whte, also showng a low fastng blood sugar, 82 rag., and a second generaton of 30 resulted. Two of these were albnos wth hgh blood sugars, 118 to 120 nag.; 6 were albnos wth low blood sugars, 78 to 8~ rag., 6 were colonred and had hgh blood sugars, 116 to 120 rag., whle 16 were coloured but showed low blood sugars, 78 to 88 rag. A.H, x C.L, Famles H, J, K added together gve: A.-L x C.L. l t c.l. d' x C.L F~ 1 A.H. A.L. G.H. O.L F A.t. A.L. C.H. O.L where d 61.2 s the expectaton. The fndngs obtaned wth the second generaton confrmed the con~ cluson that hyperglycaeml"a, lke albnsm, s a recessve character, for examnaton of the fgures showed that they were n close accord wth those requred for such a condton by the l~endelan theory~ They further demonstrated qute dstnctly that, although both hyperglycaema and albnsm are recessve characters, they are genetcally ndependent, as the one s not necessarly assocated wth the other. t would therefore seem that the factors gvng rse to albnsm do not nclude those leadng to an abnormally hgh blood sugar as our orgnal observatons suggested mght possbly be the case. The numbers moreover dspose of any dea of lnkage between the two factors. The assocaton orgnally notced must therefore have been an accdental feature of the strans used. t s clearly a matter of consderable nterest and mportance, however, that a defnte chemcal abnormalty, such as hyperglycaema, should have been proved expermentally to be transmtted n accordance wth Mendel's theory of heredty. Evdence suggestng that certan other abuormates of metabolsm may be transmtted accordng to l%{endel's laws has been collected and publshed by several observers, bat as ther nvestgatons have been confned to a study of the famly hstores of cases presentng such chemcal defects the da~a have necessarly been ncomplete.

6 392 Tlyperglycaema n Mce Ba~eson 1 and Punne~t ~ have ponted out ~ha~ ~he ncdence of alcaptonura n human bengs suggesgs ~ha~ t s a recessve character n the Mendelan sense, and Gaffed a has collected hs gores of cases ndcatng ghat congental s~ea'gorrhoea, congental haema~oporphya'a, pengosura and cystn~tra may be of a smlar gype. We wsh ~o acknowledge our ndebtedness ~o Sr F: W. Andrewes for permsson to carry oug the expermental par~ of ths work n the Paghologeal Depargment of St Bargholomew's {osptal, and also to ghank Professor Ba~eson for very kndly revsng ghe proofs of ths paper. ReTort of the Evoluton Gommttee of the Royal Socety, 1902, No. 1, p. 133 no~e. "- Proe. of the RoyM So~. of Med. 1908,. Epdem. Sect~., p a nbor~ Errors of Metabolsm, O.~ord ~ed. Publc&~ons, GA~B%~DGE : PXlaTED ]3Y W, LEWS~ ~%.A.~ AT TE UNVE%STY P%ESS