Journal of Thrombosis and Haemostasis, 13: 695

DOI: 10.1111/jth.12931


Mutation goes global F . R . R O S E N D A A L * † and P . H . R E I T S M A * ‡ *Department of Thrombosis and Hemostasis, Leiden University Medical Center; †Department of Clinical Epidemiology, Leiden University Medical Center; and ‡Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

To cite this article: Rosendaal FR, Reitsma PH. Mutation goes global. J Thromb Haemost 2015; 13: 695.

‘Mutation is random; natural selection is the very opposite of random’ Richard Dawkins, The Blind Watchmaker (1986) Whereas nowadays newspapers are full of views on immigration into Europe, similar events happened on a much grander scale in both the distant and the not so distant past. The Roman Empire suffered damage from Germanic tribes pushed south by invading nomads, and was eventually overrun by Goths, Visigoths and Vandals. Long before, some 10 000 years ago, people migrated into Europe from the Middle-East, and populated the land, bringing new languages and diseases. Most European languages belong to the Indo-European stem, with Sanskrit as their linguistic ancestor. Factor V Leiden originated approximately 30 000 years ago in the Middle East, and was imported into Europe. Whereas some of the other European language groups, such as the Uralic languages spoken in Finland and Hungary, are considered to be younger, one language, which is spoken by the Basque people living around the western part of the Pyrenees Mountains, may precede the introduction of Indo-European languages. In a ‘Forum’ article in this issue of the Journal of Thrombosis and Haemostasis, Bauduer discusses hemostatic particularities of this population, notably the absence of factor V Leiden. The Basque had populated the area before the immigrants bearing factor V Leiden arrived, and therefore today it is nearly absent in this group. Differences in the prevalence of genetic traits between populations are interesting because they give us a glimpse of their history, as well as of the natural history of diseases. Some differences may be simply explained by the presence or absence of a common ancestor, as with the Basque. Likewise, factor V Leiden is absent in people of African and Asian descent. Sometimes, the opposite has occurred, and a high prevalence of a trait may have resulted from a limited number of ancestors and absence of immigration. A prime example is Quebec, where French immigration was restricted after the defeat of de Montcalm in 1759. Protein C deficiency, due to a specific single mutation, is © 2015 International Society on Thrombosis and Haemostasis

much more frequent in Quebec than in France, even though the mutation has been traced to a single 17th century immigrant from Poitiers who moved to the New World. Because he, or his immediate descendants, was a bit more prolific than others, and small differences in the number of progeny had a large effect on the isolated population, this protein C mutation became highly prevalent. Such founder effects are only possible for variants with little or no effect on mortality; when mutations are lethal, their prevalence is completely dictated by the mutation frequency (i.e. the frequency with which new mutations arise). This is why, for instance, hemophilia, which is a disease that until only 60 years ago led to infant mortality, has the same prevalence throughout the world. Still, even between geographic areas of Europe, there are differences in the prevalence of factor V Leiden: in Sweden it is over five times more common than in Italy. A simple and likely explanation is a founder effect: although not fully isolated, populations in a certain area will not have mated randomly with neighboring populations, and again, a limited number of carrier ancestors with an accidentally high number of offspring may have done the trick. The alternative is that it was not all accidental. Even factor V Leiden may influence fitness, and as for some other traits, ethnic or regional differences may depend on selective advantage of carriership. Wellknown examples are the sickle cell trait, which protected against malaria, and carriership of cystic fibrosis, which protected against cholera, thereby ensuring positive selection of the mutation. Are these observations of differences in the prevalence of genetic traits and disorders only historic oddities, or are they relevant to modern medicine? Obviously, knowledge of these variations may assist in the diagnosis of a hemostatic or thrombotic disorder: a Chinese lady with thrombosis is unlikely to have factor V Leiden, while a Jewish girl who suffers from mucosal bleeding may well have factor XI deficiency. In a world where travel used to take decades in the Stone Age, months in Roman times, weeks a century ago and a matter of hours in the present day, populations are now mixing, and genetic diseases previously uncommon in an area, may appear. Prior probabilities of disease are shifting, and diagnoses become more challenging.

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