The Frequency of "rare" Protein Variants in Marshall Islanders and Other Micronesians

Page 1

BEST COPY AVAILABLE 1. Research supported by the Atomic Energy Commission Genetics; University of? Michigan, Laboratory, Associated Uni.verstties, Inc., Upton, T,. 1.,

Page 2

R:’t’et~r.Ly,in connection with an ollgoiqg medical study of certain ;[\I-Sl~.\ll).slanclersprompted by the Vikini incident (1) , w’e have had the Ol)I)OL-tI.LIIi,tyLo examine il s(’ries of blood samples from these Islandecs sup,gestls lower Creq”uency of rare variants in this group than in s~lch p,roups ,as Jdpanese, C,~\lcasians, or South American Indians. There are s<’me bothersoine problems in comparisons across gro~lps sampled in cliffer~nt \.7:lys,however,~ihich make the usual statistical contrasts impossible; some of these problems are aired. The sLudy population is composed of persons now refliding on Ebeye, I{ongelap, aLIC~ Majuro Islands, for the most part related to one another as members of nuclear families. The number of independent genomes in the sample is thus considerably less than the number of persons. App~oximately IIalf of ~he children Ln the sample were born to parents inadvertently radiated as a result of fall-out from a nuclear explosion at the time 01 ~h~t Ei!cini test, in 1954. However, as will be Apparent under RESULTS, tl~c cluestion of a rddiation effect will not arise in any substantial

Page 3

sllipmeL\L LO Ann Arbor. I/t{shedred blood cells and pl~sma were stored ‘rl~econditions for e~ectrophoresis and typing of systems 1, 2, 8, 9, 10, 12, 13, 15, 16> 18 and 20-24 in Table 1 were carried out as described pl-c?vj.ously (2) . lllectrophoresis of systems 14 and 19 and st’aining of for system 19 employed the positive staining method as reported by I’eters, t!,~pkitlsonand Harris (4). System 3 W*IS determined by the method of Ch.~rlesworth (5), system 4 by the method of Tashi.an (6), system 5 by ll;lcI,leL-llo,lof Cllen, Anderson and Giblett (7), system 6 by the method of {Jeitl<:lmp(8) , SYS tern II I)y the method of Edwards , Hopktnson and Harris (9) , and system 20 also by the methods of Weitlarnp et al (10) and l’ani.s 1. The pol.ymorpl~i.sms.--Genetic polymorphisms were observed in six..— acid pl]osphatase, 6-pllosphoglucose dehydrogenase, and Group specific comporlent. l’henoEype ancl allele frequencies are given in Table 2.

Page 4

Ti\ese three individuals were relate’d as siblings, one of whose parents I~as tested and normal, the other untested. 2. Earc variants. --One rare variant was observed in a total of——- one of tile three screening systems in use for albumins, namely, t’ne pH 5.0 sodi~lm acetate buffer system of Weitkarnp et al (10) . ‘i’hevariant is illu:;trdted in Fig. 1. Its electrophoretic behavior appears simLlac LO that of all)umin l[ed~n as reported by IJeitkamp et al (10) . It o,.cllrred in a girl, aged 5, whose mother was normal (and not exposed R) fall-out) and father not available for study. The fact that the vari.snt has been demonstriited in only a single person with only one technique lea~~es its ictentification somewhat unsatisfactory, but the situation cannot be improved upon at present. sms .--Gene frequencies for the 6 polymorphisms thin the ratl~er considerable range rrported in

Page 5

a l]o’lymorplli.sm) . By this definition of rare variant, we exclude from system reported by Bla!ce et al (12) i’n the Western Caroline Islands, and tite polyllorphism for the type 2 of phosphoglycerate kinase reported by Lhese sams authors. Tl~is same convention will require us to eliminate v:!riant oi all]umin, a variant thus fa’r encountered in a single tribe, b~[t th~cc with a Gene frequency of 0.08. In sampling populations where r:~tl)t:rclo:+e biological. relationships between individuals can scarcely bc n-,~oicled,it 1s well to remember that even in samples of 1000, a variant lillite,ito lnembers of a single extended kindred may assume the proportions of a pOlyino~p!lism as here defined. In the case of the variants excluded from the Mi.f:ronesia count, a variant with the elcctrophorctic mobility of type 7 P(;~llhas bc:c’ncncountcrecl at several localities in tile Far East, ,a~)(lit seems likely this is u “widespread” polymorphism. However, the same c:lnno[.be said for Lltevariant with the mobility of PGM1-3 or nmrl)hisms. If furtlter studies in P!icronesiu revealed these, alleles

Page 6

Some. of the Iiicronesian Islands have had extensive con~act with in 1~.indthat a rare variank may have been introduced from the outside, as pointed out by Blalce et al (12) i.n connection with the ]JIIIvariant We note in this connection that the CA I encountered in the Chamorros of Guam and similar to a v~riant encountered in oi t~jo variants is not synonymous with biochwical identity. of r:lr(.var.it~ntsLll o variety of pop~ll.ations. We mentioned earlier Lhe

Page 7

ti:(~s~~ries w}~ich origioatc in this laboratory and involve essentially urlweighted average, based on as many of the systems listed in Table 2 ;):;arc cover.~d in the. references cited, By this convention, tl~e variant Lreq(t?ncy for So(lth Amarican Indians, based on systems 1, 2, 8-10, lnwer frr(;{lencytl~an ill our last publication on this subject (2) is ‘riILJ.fL-equ?ncy in [Jest European Caucasians, based on systc~ns 1., 2, 8-16, As llOt.C!d,there are ol~vioLlsdifficulties in statistical cornpartsuns bet~~een tilese series. O~(r own ;licro[~esian clata, and we sllspect to some e.xtcnt tltat of others, contains closely related individuals, as does (Jtlrclata on Amerindians, By contr~st, tl]edata on Caucasians and Japanese

Page 8

(~), andwe maintain that position Ilere. The logic i:; that a rather con,%ider31jle sIIuEf{~u: Of tribal pop~;l-ations, such as occurred in the Ilot Qlter tile total nllmh~r C)f variants present. However, conven(.ional s~em inappropriate. In particular, e~timates of frequencies from studies Of pop~ll.ati(jnssuch as ilicronesiarrs or Amerindians ark quite susceptible to 3 “.j:l[’l;pot” Cff(>ct--~ne island with a high frequency variant could Imrlceclly alter the pict{lr~:. I{owever, some 27 Lslands have been stimpled t!~.t,f~d:~tlei~cy of r.irc variants as defined, these varl.ants occurting in riiffcrence ltln~es, ix~ part, on the definition of rare variant, which in t(lrn is intimately related to the size and nature of the sample. ‘L’llus,if as t.llestildy o17}licronesians is extended it becomes clear that vil~iant crlcolll~teredin 39 persons (12) are sharply localized and no or fcw ncicliti.oll,l.l.exalnplcs of the variant are encountered, then either or both of llle.cPmight drop bel.ow tile arbitrary 2 percent frequency level

Page 9

he l“~~lde.i-cdmore compar~ble to those of Caucasians and Japan&se by elimi.ilfiting,the old and the young from the formez two samples, b[lt tile l~asic is:;~lewould ”still remain: the individuals in the former two s,ampl’eswill he more re lated than those i.n the latter two. The most prnct.ical way to meat tl~is issue seems an extension of the sample, frequenci~s which a l:~r~er sample will permit must consider a variety ‘rh~~]Jzublsm is nut a trivial one. The frequency of such variamts ill natura-l populations is malntai.ned by a complex balance between scler.tion, mlltation, and population structure. Basic p~rameters though Lhey be, hotll the manner of action of selection and the rate and type? is nl~lc}]Plore l.nborLous than the latter, and it is tempting to p[lisll(~

Page 10

l-,~ofi.t,l?)l;~pl~:~~uedhy t!l(.indirect approach, sample size must be sample necessary to a trustvariants in populations like Blood specimens from .1 sample of 187 Marshall islanders were st~rdieclwith refer,~nce to variants of 22 serum proteins and erythroin 4,047 determinations. These resul~s on rare variants Iiave been

Page 12

GclleLi.&Structure of a Tribal Population, the Y.anomama Indi:lns. TX Cene Frequencies for 18 Serum Protrin anti Erychrocyte Enzyme Systems in the Yanonarua and Five gelwse, fructoaldolase, glyoxylase 11, and sorhital dehydro~en~ge”, 1{~’manErythrocytes”) in Biochemical Methods in Red cell Genetics , J. J. Yunis, Ed., Academic Press, p 307.

Page 13

“V:lriation ii~Red Cell Enzyme Groups anong Populations of Transfcrrins of TWO Tropical Populations”, Nature, 189, 897.

Page 14

Variant of ~;rythrocyte Carbonic Anhydrase in Micronesians Islancls and in other ~~arts of Micronesia, vith a 5t~pplement

Page 15

“O!]servations sur la Repartition des Groupes Senques De S cas De Dis Albuminerni.e Observes En France, Rev. Europ.

Page 16

(‘lb) Neel, .T. V. 1974 Developments in monitoring human population fo’r mutation rates, Mutation Res., ~, 319.

Page 18

Croup specific component 116 50 2 1. TIIC }ip” type 17dS observe d in 4 individuals

Page 19

6.9. ~\lbu,:li.nsalnples shown are normal serum 1, 5, 7, 8 and 11 ; Wap.LshaLl.i-1,6, 12; Naslcapi, 10. Normal samples include reference serum from our own laboratory and serum from normal Marshall Island samples. All variants, except the presently reported ~[arshalL [sland variant, have been previously compured by Tanis