Non-identicality of monozygous twins.

ML Kothari, LA Mehta 
 

Correspondence Address:
M L Kothari

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Twinning (from twine = a double thread) is a universal human feature. The constancy of its incidence in an ethnic group makes it, like cancer or cleft-lip, a herd feature, a part of heredity. Its frequency varies from 1 in 30 births in Nigeria to 1 in 150 births in Japan. Roughly 1 out of 3 twin births are monozygous (MZ), arising from a single fertilized ovum and thus having "identical genotypes,"[23] as opposed to dizygous (DZ) twins that are "genetically quite distinct"[14] like "siblings of separate birth."[14]

That MZ twins are genetically identical is an idee fixe, a cliche enshrined in biology,[1],[14] genetics,[12] and immunology.[11] The identicality, however, becomes questionable when MZ twins exhibit "frequent discordance" vis-a-vis various physiologic and pathologic features[15],[16],[19],[21] e.g., "concordant cancer in identical twins is exceptional."[25]

To explain away many a discordance between the supposedly genetically identical twins, recourse has been taken to environmental differences, cytoplasmic differences, equations of heritability versus variability, non-penetrance of the heritable mutant gene, gonadal mutation, and premutation.[19] The cul-de-sac nature of the above explanations compels flagrant violations of Occam's razor. To wit, the discordance exhibited by 58 per cent of MZ twins vis-a-vis congenital club-foot necessitates presupposing "special prenatal circumstances" involving "variations in the outer or the inner environment of the embryo" complicated by "a special genotype or genotypes necessary for the formation of club-foot".[21]

The over 100 centres for twin studies, in Europe, Japan, and the USA[4] nurse the common illusion that they are investigating "genetically identical human" pairs, with the further assumption that whatever the differences that are noted among such pairs are due to "environmental" factors. That the registry,[4] in a single country, of the health data of 50,000 pairs of MZ twins between 1870 and 1930, and, in another country of the medical histories of 23,000 living MZ pairs born between 1886 and 1973, and many such registries elsewhere have merely piled statistics upon statistics and theories upon theories, without throwing light on any single problem, bears testimony to the fundamental point that has been missed: MZ twins are highly similar, but not identical.

The recognition of the monozygotic or dizygotic origin of a given pair of twins - the most debated problem in twin studies[16]- is made by the means of similarity diagnosis using detailed comparison of the phenotypes: Great similarity is taken as evidence of monozygosity.[16],[21] But to dub great similarity as identicality, and genetic one at that, is to miss the many ways in which MZ twins differ--"the within-pair differences of monozygotic twins are frequently found to have a wide and continuous range from near identity to great dissimilarity."[16] The nine-banded armadillo always delivers MZ quadruplets, without denying to each member of the quartet the right to assert its individuality, its urge to differ from its fellow fetuses in particular and from other armadilloes in general. Siamese twins, bound in flesh and blood and indisputably MZ, are frequently less similar than twin pairs known to be dizygotic.[16]

Dubos[7] has glorified each individual as unprecedented, unparalleled and unrepeatable, an exaltation not denied to the members of MZ twin pairs. They form no exception to the generalization[26] that the only invariable law of nature is variation. GOD, the Generator Of Diversity,[11] does not fail even when it comes to two beings spawned off the same zygote. An analysis of the trump concordance-viz., the acid test[6],[21] of intrapair tissue transplantability-allows us to settle the matter in favour of the concept advanced above.

The universal assumption that intrapair histocompatibility of MZ twins is a function of the identicality of genotypes calls for a sea change in view of the fact that such a phenomenon of easy tissue-exchangeability also occurs in freemartin binovular, genetically different twin calves "which share a common placenta in utero and are consequently bathed in each other's blood before birth; they sometimes prove to be chimeras."[11] Starting with the observations made by Owen,[17] the foregoing was confirmed by Medawar and colleagues in cattle twins[3] and in man,[8] and such tolerance was induced in mice 2 by injecting into the embryo, in utero, living cell suspensions from an animal of an antigenically different strain. Swappability of tissues between members of a pair is a function not of the identicality of genotypes but of the transplantation tolerance through clonal elimination[20] induced by natural or artificial exposure to each other's cells at an appropriate time. The celebrated histocompatibility between MZ twins, whereby one twin can readily receive graft from the other and vice versa, is entirely dependent on their mutual chimerism consequent upon the placental connection, a chance occurrence not denied to binovular twins with patently distinct genotypes, yet a chance occurrence definitely denied to monozygous twins should they be dichorial in nature.

Of 3 sets of MZ twins in human beings 2 tend to be monochorial (monoplacental), and one dichorial (biplacental),[5],[9] the former mediating chimerism, the latter denying it. Dichorial MZ twins treat each other as mutually histoincompatible, and graft rejection is as natural and rapid as between unrelated individuals. The time at which the monozygote splits to spawn twins determines the nature of their placentation. If the split occurs from the time of conception to the third day when trophoblast has not yet differentiated, the placenta tends to be dichorial and diamniotic. Between 3rd and 8th day (blastocyst stage), the placenta becomes monochorial but diamniotic. From 8th day to 13th day, the placenta remains monochorial and amnion also tends to be one. After 13th day, the monochorial and monoamniotic placenta may be associated with Siamese twins.

MZ twins, by their rather frequent monoplacentality, achieve the transplantation tolerance with ease to become chimeras that exhibit histocompatibility. The chimerism of MZ twins must be so subtle as to have escaped detection so far. Such chimerism, called point chimerism (of point mutation), is only waiting to be discovered by modern cytogenetics. It is a poorly emphasized fact[16],[21] that DZ twins may share a placenta and MZ may fail to share one, a set of circumstances that may make DZ twins more histocompatible than MZ twins. Grafts between MZ twins do not always succeed,[11],[16] and rather startlingly enough,[22] an acute graft-versus-host disease can occur following marrow transplant between "genetically identical" twins even when the recipient had been prepared with irradiation and cytotoxic drugs.[10],[18] (Why should the recipient be prepared if the donor is genetically identical?) To hold[6],[21] intrapair tissue transplantability as a sine qua non as also the cardinal test of monozygosity is to miss the role played by the placental connection.

Medawar[13] has described highly inbred animals as "pure line" organisms in whom the "genetic variation has been extinguished" to the point of their resembling each other "as closely as if they were identical twins." The implications here are clear-inbred animals with a single genetic strain are many animals with a single genetic soul, and so are the members of a pair of MZ twins. Both assumptions are wrong: Intrastrain grafts in highly inbred strains of animals are not exempt from rejection;[24] the same may happen in MZ twins.[11],[16] The most we can say of inbred animals/MZ twins is that grossly they tend to be so similar that the finer points of variation-both phenotypic and genotypic-are not easily detectable and therefore tend to be glossed over.

The logic advanced herein to explain MZ twins' mutual histocompatibility or so-called identicality also accounts for the failure of transplantation between MZ twins as also its success among DZ twins. Such an approach divests MZ twins of their specialized identical status, allows them to be widely discordant, and reaffirms the infallibility of the force of variation or individuation. In due humility, all that we-medical men, biologists, geneticists-need to do is to accept individuality as Nature's unfailing gift, no matter what types of twins, triplets or quadruplets, or how they are derived.

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