The Biology of Mirror-Image Twins by Charles Boklage, East Carolina University

The idea of "mirror-image" twins always gets me excited, but maybe not quite like most folks. This idea goes back to a biologist named Spemann who published most of his work in German in the 1920's. He worked with newt embryos. Newts are small amphibians with legs, a kind of salamander. In some parts of this country they are called 'lizards' and used as fish bait. Lizards are reptiles, with dry scaly skin. Newts and other salamanders are amphibians, with smooth moist skin, who lay their eggs in water and are tadpoles before they grow legs. They are an attractive subject organism for developmental biology research, because the fertilized eggs can quite readily be watched closely while developing in an ordinary dish of water on an ordinary lab bench.

Spemann experimented by tying fine hairs around some newt embryos. If he pinched an embryo all the way in two, with only very rare exception it died. If, however, he stopped tightening the hair while the two halves were still held together by a bridge of cells, and put it back in the water, some of those didn't die. Some of the ones that lived developed into twins. In some of those twin pairs, the normal asymmetries of the internal organs were reversed in one of the animals; heart right- instead of left-of-center, stomach to the right and the larger lobe of the liver to the left, and so on. So he had produced monozygotic twin embryos, by a process which caused a reversal of normal developmental asymmetries in one member of each pair. This is where the whole idea of "mirror-image twins" comes from. There is no reason to think natural human twinning has anything to do with any process at all like that. The cells of one embryo have to separate to become two separate people, but there is every reason to believe that is a consequence of twinning and not a cause. It happens after the cellular event that decides twinning, not before.

Newman and some other researchers who were contemporaries of Spemann took the newt results to represent a mechanism of twinning which could be substituted for our frighteningly complete ignorance of the mechanisms of human twinning. So, from that time forward, "everybody knows" that monozygotic twins are produced by the "splitting" of an embryo, presumably mechanically, in some process that must somehow closely resemble tying it in half with a child's hair. And, if it happens late enough in development, it should result in mirror-image reversal of normal developmental asymmetries. That's what "everybody knows", and it's nonsense.

In all of the records of medicine and science, the entire number of twins (or any other humans) ever found to have inverted positions of the internal organs like Spemann's twin salamanders had is very small. On the other hand, a great many pairs of twins do differ in motor hand preference - handedness. That includes many pairs who otherwise resemble each other very closely. So, drawing from Spemann's results, the logic goes, sometimes the "identical" twinning process must occur late enough to result in "mirror-image" handedness. It got even crazier from there. When I got into this business in the mid-1970s, the literature said that twins were more often lefthanded than singletons, and that this was primarily due to the monozygotics, because of their mirror-imaging when their "split" was late. After a fair amount of careful work, it turns out that every paper which claimed a statistically significant excess of monozygotic twins among lefthanders had included data gathered in the 1920s and 1930s. The special thing about those data was that any twin pair who differed in handedness was assumed to be - not just monozygotic, but "late-splitting" - monozygotic. If such twins had different- colored hair and eyes, clearly different heights or weights or body types, even different sexes, these oddities were considered to be the obvious consequences of the embryonic disruption caused by the late splitting. Blood typing was just barely becoming understood and was not available for use in the zygosity typing of twins. If we count every dizygotic pair which includes only one lefthander as monozygotic instead of dizygotic, then yes indeed we compute a huge excess of lefthanders among the monozygotic .... and a shortage among dizygotics!, compared to the general population.

What My Studies Showed...

As a matter of clear and simple fact, dizygotic twins are much more likely to differ in handedness than monozygotic. So, if a difference in handedness means an embryonic "splitting" that may have happened fairly late in embryonic development, then we simply must conclude that dizygotic twins are more like to have experienced such events than the monozygotics! Another thing about it - no one, ever, no twin, no singleton, no one, ever, has been found with the normal asymmetries of brain structure or function completely reversed. Not one. Not ever. The normal left-right differences in brain structure and function are very basic and important facts of normal development.

I collected handedness data from over 800 three-generation twin families. I was able to use the results from 773 families, over 10,000 people. The results are straightforward: Twins do have a higher frequency of lefthandedness than the general population, which is mostly single-born. Monozygotic twins and dizygotic twins have the same higher frequency. Monozygotic twins do not have a higher frequency than dizygotic twins. There is no difference in frequency of lefthandedness between monozygotic and dizygotic twins. No difference. The monozygotic twinning process, whatever it may turn out to be, is not in any demonstrable way related at all to what Spemann did to the newts. The monozygotic twinning process does not differ from the dizygotic process in any of the causes of lefthandedness.

The twins do not have a significantly higher frequency of lefthandedness than their single-born siblings. So, nothing about being twins causes lefthandness. Twin embryogenesis does not increase the frequency of lefthandedness over that of the singleborn siblings of twins. Nothing about twin pregnancy causes lefthandedness. Nothing about who spent more time on top or on whichever side of the womb. Nothing about the events of twinning causes lefthandedness. So where does the excess of lefthandedness among twins come from?

The single-born siblings of the twins also showed a substantially higher frequency of lefthandedness than the general population. There was no difference between the siblings of monozygotic twins and the siblings of the dizygotic twins. The twins do have very slightly more lefthandedness than their singleton siblings do. The difference is not statistically significant - which means it could be due entirely to chance in selecting that particular sample from a population in which there was truly zero difference.

That means we really have no good reason to believe there is any real difference between twins and their siblings in frequency of lefthandedness. But there is something interesting about it.

The excess in second-born twins was more than enough to explain the difference between twins and their single-born siblings. When those twin-family handedness data were collected in 1975-78, more than half of all twin pregnancies were discovered to be twins only after one baby had been delivered and somebody realized that Mama was still pregnant. There was very commonly a delay between the delivery of the first twin and the delivery of the second, often a delay of several minutes. During that delay, the second twin was subject to a greatly reduced flow of maternal blood - reduced supplies of food and oxygen, reduced waste removal - suffocation in a word. The right side of the baby's brain normally has a substantially larger blood flow. The left hemisphere is more vulnerable to the effects of the temporary asphyxiation. So, a small excess of lefthandedness in twins relative to their single-born twins, although not statistically significant, may be a biologically real consequence of slightly-reduced left-hemisphere functionality due to temporary asphyxiation of second-born twins. Now that ultrasound examination is routine in North American and Western European obstetric practice, that difference should be eliminated. Twins born since the early- to mid-1980s might not show such a difference, but I don't think anybody has tested it properly.

Why Are So Many Twins Lefthanded?

So, where does the excess frequency of lefthandedness in twins-and-the-siblings-of-twins come from? The best answer seems to be that they inherit it from their parents with about 70% heritability. That means about 70% of the variation in handedness in this population can be explained by genetic relationships. In those 773 twin families, each lefthanded parent increased the probability of lefthandedness in the children by about 50%. With one lefthanded parent, we see about half-again the frequency of lefthandedness seen when both parents are righthanded. With both parents lefthanded, about double the frequency. Again, no difference between the families of monozygotic twins and the families of dizygotics. Mothers of twins are almost twice as often lefthanded as their own sisters. Fathers of twins are almost twice as often lefthanded as their brothers.

Twins and their siblings have an excess of lefhandedness compared to the general population. They inherit this from their parents, who are much more often lefthanded than the aunts and uncles of twins who are not themselves parents of twins. The mechanism of this apparent inheritance is not simple. There are families in this sample whose handedness distribution fits the expectations of a single recessive genotype which is expressed about half the time. There are other families where the distribution fits that of a simple dominant genotype, again with about 50% penetrance. That sort of dominant genotype pattern is almost impossible to distinguish from a multifactorial model. Over the sample as a whole, the best fit is a multifactorial model with about 70% heritability. That's technical, and it's jargon, and it is not simple to understand or to teach it in detail. I believe, however, that I can give you a useful idea without too much trouble.

Multifactorial means 'involving many factors'. Not one gene. Many genes. Plus nongenetic 'environmental' factors. How many is many genes? Maybe quite many; maybe only three or four. We just barely know how to make predictions for two interacting genes. We cannot usually analyze even a two-gene situation effectively because that requires that we should somehow realize and measure a separate component of the growth or behavior representing each of the two genes.

In all the world of living things, we know of only a handful of situations where the behavior of a genetic system yields a clear and simple fit to a multifactorial or polygenic model. But we more or less insist on using it as an approximate fit for all the situations in human development where we know the process is genetically controlled, but we can not make sense of any single gene model. Some of that is about certain features of growth, a great deal of it about features of behavioral development such as handedness.

Twinning and nonrighthandedness are somehow genetically related. The exact mechanisms involved are not clear. But it is a good example of something very important that most people don't understand about human developmental genetics. Many of the most important genes do not show up every time they are present.

Most twin conceptions result in no births at all, and for every twin pair born, about 10-12 people who grew from twin embryos are born single. It is actually possible that every lefthander in the world is a twin. I'm not saying I believe that, but it is not impossible and there is no evidence against it.

There's probably more here than you ever wanted to know or think about. Simplicity is great. It really helps to understand and to explain things. But false simplicity is, well, ... false ! Most of the simple stores about the biology of twinning are false.

Mirror-imaging is real. It does happen. Handedness is very much the wrong place to look for it. There are other asymmetries which are sometimes mirrored - a wrinkle in the right ear of one and the left ear of the other, the order in which the various teeth appear, a difference in size of the palpebral fissures (the opening of the eye). Play with those. Look at your twin in a mirror - that reverses any asymmetry and a difference you are accustomed to and never saw before can really show up when it is reversed.

For more information, please email: Charles Boklage, East Carolina University