How can identical twins have different phenotypes

He adds that the study was unique because the scientists were able to find 11 pairs of suitable twins — a challenging task for a relatively uncommon disease. A handful of such twin-based studies have been conducted in autism, multiple sclerosis, and other diseases, but most of them focused on fewer pairs.

Holoshitz is also planning further experiments. He wants to figure out, among other things, whether blocking the culprit genes can help to slow the pain and inflammation of arthritis.

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Your mind is in fact an ongoing construction of your brain, your body, and the surrounding world. Discover special offers, top stories, upcoming events, and more. Thank you for submitting your email! It looks like something went wrong. Try refreshing this page and updating them one more time. If you continue to get this message, reach out to us at customer-service technologyreview. Skip to Content. Gene expression studies of identical twins could help explain why, in some cases, only one of them gets a disease.

Create a personalised content profile. Measure ad performance. Select basic ads. Create a personalised ads profile. Select personalised ads. Apply market research to generate audience insights. Measure content performance. Develop and improve products. List of Partners vendors. How do you explain identical twins that don't look alike? The stereotype of identical twins is that they are exactly the same: they look alike, they dress in matching outfits, they share the same likes and dislikes.

Parents of identical twins know differently, however. Despite their shared genetic component, identical multiples are unique individuals. Though they do share similarities, they also have many differences.

For example, my own children have always exhibited about a twenty-five percent difference in their weight. When they were newborns, weighing four and five pounds, it was quite obvious.

At other times as they've grown up, it's not noticeable. We have confirmed that they are indeed identical twins, yet people are often skeptical because they don't "look" alike. They don't act like either. One likes to dance; the other likes to play basketball. Certainly, we encourage them to pursue their individual interests, but the initial inclination towards these activities was all their own.

Albert H. Wong, Irving I. Human monozygotic twins and other genetically identical organisms are almost always strikingly similar in appearance, yet they are often discordant for important phenotypes including complex diseases.

Such variation among organisms with virtually identical chromosomal DNA sequences has largely been attributed to the effects of environment. Environmental factors can have a strong effect on some phenotypes, but evidence from both animal and human experiments suggests that the impact of environment has been overstated and that our views on the causes of phenotypic differences in genetically identical organisms require revision.

New theoretical and experimental opportunities arise if epigenetic factors are considered as part of the molecular control of phenotype. Epigenetic mechanisms may explain paradoxical findings in twin and inbred animal studies when phenotypic differences occur in the absence of observable environmental differences and also when environmental differences do not significantly increase the degree of phenotypic variation.

For biologists and psychologists, twins have been an important resource for exploring the etiology of disease and for understanding the role of genetic and environmental factors in determining phenotype, and this fundamental question was first enunciated in its alliterated form by Galton in the 19th century 2. The relative contribution of nature versus nurture can be estimated by comparing the degree of phenotypic similarities in monozygotic MZ versus dizygotic DZ twins.

MZ twins arise from the same zygote, whereas dizygotic twins arise from a pair of separate eggs, fertilized by two different sperm. As a result, MZ twins have the same chromosomal DNA sequence, except for very small errors of DNA replication after the four to eight cell zygote stage. Therefore, the degree of genetic contribution to a given phenotype can be estimated from the comparison of MZ to DZ concordance rates or intra-class correlation coefficients.

Traits that show higher MZ versus DZ similarity are assumed to have a genetic component because the degree of genetic sharing and the degree of phenotypic similarity are correlated. Most if not all common human diseases show a significant heritability by this definition; however, while MZ twins appear virtually identical, they are often discordant for disease.

For example, the heritability of schizophrenia is variously reported to be in the range of 0. A heritability figure of 0. Yet, half of MZ twin pairs, in the case of schizophrenia, do not share the disease.

The situation is similar for virtually all complex non-Mendelian diseases in which there is clearly some appreciable degree of heritable risk, yet a significant proportion of MZ twin pairs is discordant for the disease. Figure 1 shows the MZ and DZ concordance rates for some common behavioral and medical disorders.

Although heredity clearly influences disease risk, the substantial discordance between MZ twins indicates that chromosomal DNA sequence alone cannot completely determine susceptibility 8. The imperfect disease concordance in MZ twins is an example of a more general phenomenon: i.

It is not easy to measure empirically the amount of non-genetic variation that is due to environmental factors. There are examples of significant environmental effects on disease risk, such as smoking and lung cancer 10 , but direct evidence of other measured environmental effects on phenotype is rare.

In addition, there is an increasing body of experimental evidence suggesting that the generally accepted assumption—variation not attributable to genetic factors must therefore be environmental—may require revision.

This article will review human twin and animal data that highlight paradoxical findings regarding the contribution of heredity and environment to phenotype, followed by a reinterpretation of these experiments that incorporates epigenetic factors. One of the landmark studies in human twin research that challenges the received importance of environment is the Minnesota Study of Twins Reared Apart, in which detailed physical and psychological assessments were conducted longitudinally in over MZ and DZ pairs of twins who had been reared apart since early childhood 11 , This study design allows comparisons between genetically identical MZ twin pairs who have been raised in a shared environment, at least as similar as for any two siblings, and those who have been raised in different homes, cities and states.

Thus, the degree of dissimilarity between the MZT and the MZA pairs can be assumed to be the result of different environments A series of tests were administered simultaneously to each pair of MZA and MZT twins, and the correlations of their scores on each scale were calculated and compared with test—retest correlations as a measure of the reliability of each scale.

In addition to the traits mentioned previously, these included: electroencephalographic patterns; systolic blood pressure; heart rate; electrodermal response EDR amplitude in males and number of EDR trials to reach habituation; the performance scale on the WAIS-IQ; the Raven Mill-Hill IQ test; the California Psychological Inventory; social attitudes on religious and non-religious scales and various scales of MPQ 11 , The findings of the Minnesota study are generally consistent with other studies of MZA twins.

For example, a recent effort to look at the etiology of migraine headaches gathered data from the Swedish Twin Registry and found that susceptibility to migraine was mostly inherited and that the twins separated earlier had even greater similarity in migraine status.

Smoking rates in women in the early s the oldest cohort in this sample were very low and social factors inhibiting smoking in women could result in there being strong local environmental effects, whereas more modern cohorts, with less restrictions on acceptable female behavior, were free to smoke for the same reasons genetic as men Peptic ulcer, a disease that contains an evident environmental component i. The results are another example of paradoxical findings in which the contribution of environmental and genetic factors is unclear.

So, the question that remains after analyzing these data is: what can account for the discordance in MZ twin pairs? However, different environments in MZA do not result in a higher degree of phenotypic discordance when compared with MZT.

Similar inconsistencies regarding the impact of environmental effects have also been detected in the studies of experimental animals. Some of the questions raised by human twin studies can be re-examined by experimental manipulations of laboratory animals. Animal strains that have been inbred for many generations have almost identical genomes, that is, they are virtually isogenic. True MZ twins can also be generated through in vitro embryo manipulations that provide an opportunity to directly separate the effects of genes from pre-natal environment.

At the very least, the effects of constrained versus diverse environments can be quantified to determine the relative contribution of specific environmental factors to phenotypic variation. In an elegant series of experiments designed to explore the relative contributions of genes, environment and other factors to laboratory animal phenotype, Gartner 17 was able to demonstrate that the majority of random non-genetic variability was not due to the environment.

Genetic sources of variation were minimized by using inbred animals, but reduction of genetic variation did not substantially reduce the amount of observed variation in phenotypes such as body weight or kidney size. Strict standardization of the environment within a laboratory did not have a major effect on inter-individual variability when compared with tremendous environmental variability in a natural setting.

To directly segregate genetic from pre- and post-natal effects, in vitro embryo manipulations in isogenic animals can be performed.

In two mouse strains and in Friesian cattle, Gartner artificially created MZ and DZ twins by transplanting divided and non-divided eight-cell embryos into pseudopregnant surrogates. The effect of different uterine environments was tested by transplanting pairs of MZ or DZ embryos into the same or into two different surrogate dams. Pre-natal and post-natal environments were tightly controlled and, most importantly, were equally variable between the isogenic DZ and MZ twin pairs.

The variance s 2 of mean body weights and time to reach certain developmental milestones like eye opening, between twin pairs s b 2 and within twin pairs s w 2 was calculated for both MZ and DZ groups. The F -test comparisons for variation between the MZ and DZ groups overall were not significantly different.

Therefore, despite the fact that all mice were isogenic, and developed in identical pre- and post-natal environments, the MZ twin pairs showed a greater degree of phenotypic similarity among co-twins than did the DZ twin pairs, thus implicating non-DNA sequence—and non-environment—based influences on the zygote at or before the eight-cell stage as the main source of phenotypic variation. The cloning of mammals has recently been accomplished in a variety of species, and these experiments, technical feats in themselves, also present an opportunity to differentiate the effects of chromosomal DNA sequence from other factors that can influence phenotype.

Although the offspring of these cloning experiments have the same genome as the donor animals, they exhibit a variety of phenotypic abnormalities that obviously cannot be attributed to genetic causes In some cases, the phenotypes are pathological and represent disease states, whereas other abnormalities are more subtle, suggesting that these observations are relevant to understanding both susceptibility to human complex diseases and variation within a normal functional spectrum The most famous of these cloning experiments was performed with sheep, but along with seemingly healthy lambs, many clone siblings died perinatally as a result of overgrowth, pulmonary hypertension and renal, hepatobiliary and body-wall defects Some cloned mice are susceptible to obesity In addition to higher overall weight, the cloned mice have the same inter-individual variability in weight as non-cloned control mice of the same genetic background Clones in other species also show considerable variation in lifespan and disease phenotypes between genetically identical clones and non-cloned members of that species.

This has been reported in pigs 24 and in cattle, where the main post-natal abnormality is musculoskeletal in origin This list is far from comprehensive and is meant to illustrate our point that significant phenotypic variation, including crossing a threshold to fatal disease, can emerge from animals that have an identical, cloned genetic background, and frequently-occurring differences in mitochondrial DNA cannot be a universal mechanism for a wide spectrum of phenotypic differences.

These early examples of cloned animals were subjected to intense scrutiny in highly supervised and controlled environments, yet they still exhibit disease in an inconsistent fashion. If environment were the source of this phenotypic variation, then one would expect the same emergence of disease among non-cloned members of this species, in an even greater extent, because their environment is not usually so tightly constrained.

More likely, there are other potential explanations for this variation. The general conclusion drawn from the previously described experiments is that substantial phenotypic variation may occur in the absence of either genetic background differences or identifiable environmental variation. When genetic sources of variation are excluded, environmental factors are usually considered to be the source of the remaining variation. However, the previously described data do not support this hypothesis.

It is easy to see how the environment is often blamed for this non-genetic variation in phenotype. It is difficult to prove that environmental factors are not affecting phenotype.

Environmental sources of phenotypic variation can only be excluded by showing that variation persists in a zero-variation environment. Obviously it is difficult to design such an experiment in which environmental variation can be shown to be near-zero, but the studies described previously circumvent this problem. They did so by either directly controlling the degree of environmental variation as in Gartner's experiments or by using naturally occurring human twins or artificially induced through in vitro embryo manipulations controls as comparison groups.

In all of these examples, there exists a component of phenotypic variation whose source remains unexplained. Epigenetics refers to DNA and chromatin modifications that play a critical role in regulation of various genomic functions. Although the genotype of most cells of a given organism is the same with the exception of gametes and the cells of the immune system , cellular phenotypes and functions differ radically, and this can be at least to some extent controlled by differential epigenetic regulation that is set up during cell differentiation and embryonic morphogenesis 26 — Even after the epigenomic profiles are established, a substantial degree of epigenetic variation can be generated during the mitotic divisions of a cell in the absence of any specific environmental factors.

Such variation is most likely to be the outcome of stochastic events in the somatic inheritance of epigenetic profiles. One example of stochastic epigenetic event is a failure of DNA methyltransferase to identify a post-replicative hemimethylated DNA sequence, which would result in loss of methylation signal in the next round of DNA replication reviewed in In tissue culture experiments, the fidelity of maintenance DNA methylation in mammalian cells was detected to be between 97 and Thus, the epigenetic status of genes and genomes varies quite dynamically when compared with the relatively static DNA sequence.

This partial epigenetic stability and the role of epigenetic regulation in orchestrating various genomic activities make epigenetics an attractive candidate molecular mechanism for phenotypic variation in genetically identical organisms.

From the epigenetic point of view, phenotypic differences in MZ twins could result, in part, from their epigenetic differences. Because of the partial stability of epigenetic regulation, a substantial degree of epigenetic dissimilarity can be accumulated over millions of mitotic divisions of cells in genetically identical organisms. The epigenetic defect is thought to arise from the unequal splitting of the inner cell mass containing the DNA methylation enzymes during twinning, which results in differential maintenance of imprinting at KCNQ1OT1.

In another twin study, the bisulfite DNA modification-based mapping of methylated cytosines revealed numerous subtle inter-individual epigenetic differences, which are likely to be a genome-wide phenomenon The finding that differences in MZT are similar to MZA, for a large number of traits, suggests that in such twins stochastic events may be a more important cause of phenotypic differences than specific environmental effects.

If the emphasis is shifted from environment to stochasticity, it may become clear why MZ twins reared apart are not more different from each other than MZ twins reared together.

It is possible that MZ twins are different for some traits, not because they are exposed to different environments but because those traits are determined by meta-stable epigenetic regulation on which environmental factors have only a modest impact. It is not our intention to argue that environment has no effect in generating phenotypic differences in genetically identical organisms.

Rather, we are suggesting that epigenetic studies of disease may help to understand the pathophysiology of, and susceptibility to, etiologically complex, common illnesses. The current method of studying most diseases includes molecular genetic approaches to identify gene-sequence variants that affect susceptibility and epidemiological efforts to identify environmental factors affecting either susceptibility or outcomes.

However, epidemiological studies in humans are limited by a number of methodological issues. Obviously, it is unethical to deliberately expose people to putative disease-causing agents in a prospective randomized controlled trial and it is impossible to control human environments in a way that eliminates most sources of bias in epidemiological studies