The Viking genetic marker

[Youenn]

Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings


N Milman a and P Pedersen b

Hereditary hemochromatosis has been recognized as a clinical disorder for more than 100 years. The common form of the disorder is caused by the Cys282Tyr mutation (C282Y) of the HFE gene. Hereditary hemochromatosis affects predominantly people of Northern European origin. The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and the founder effect. It has been estimated that the C282Y mutation appeared 60-70 generations ago. It was initially suggested that the ancestral C282Y mutation occurred within the Celtic group of peoples. However, we hypothesize that the distribution of the C282Y mutation in Europe is more consistent with an origin among the Germanic Iron Age population in Southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. The aim of the present study was to evaluate the validity of these two hypotheses. Several arguments are in favor of the 'Viking hypothesis': first, the highest frequencies (5.1-9.7%) of the C282Y mutation are observed in populations in the Northern part of Europe, i.e. Denmark, Norway, Sweden, Faeroe Islands, Iceland, Eastern part of England (Danelaw) and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from Northern to Southern Europe. Intermediate allele frequencies (3.1-4.8%) are seen in the populations in Central Europe, which is the original Celtic homeland. Low allele frequencies (0-3.1%) are recognized in populations in Southern Europe and the Mediterranean.

Hereditary hemochromatosis has been recognized as a disease or disorder for more than 100 years (1). The hereditary nature of the disorder was substantiated by the discovery in 1975 that the gene associated with the common form of hemochromatosis mapped close to the HLA-A region on chromosome 6 (2). Recently, the causative Cys282Tyr mutation of the HFE gene (C282Y mutation) located on chromosome 6p has been discovered (3). Hereditary hemochromatosis was initially described exclusively in people of North Western European origin (4). This finding has subsequently been confirmed by genetic studies in other parts of the World including the Caucasian populations in Canada, USA, South Africa, Australia and New Zealand (5). It is a common concept that the C282Y mutation occurred on a single chromosome carrying the ancestral haplotype (4) and most of hemochromatosis chromosomes 6 carry characteristic microsatellite marker alleles (6). This single C282Y mutation was subsequently spread both by emigration and consanguineous marriage.

Because C282Y hemochromatosis is rarely associated with disability and death during the reproductive years, it seems unlikely that the disorder would confer a selective disadvantage. In contrast, the high prevalence of the C282Y mutation suggests a positive selective effect of the phenotypic characteristics. An increased intestinal absorption of food iron in both homozygous as well as in heterozygous persons yields relative protection against iron deficiency (5, 7). This was an advantage for women during childbearing age due to blood losses at menstruation and pregnancy, and for men subjected to bloodletting in warfare by sword, axe, or spear. Furthermore, the C282Y mutation appears to offer a relative protection against type 1 insulin-dependent diabetes mellitus (7), which in the past caused premature death and a reduced reproductive potential. However, so far there is no established pertinence to the presumed evolutionary advantage of inheriting the C282Y mutation. In the future, as the effects of the HFE molecule are clarified, additional evolutionary advantages may be disclosed.
Due to the distribution pattern of hereditary hemochromatosis, it was hypothesized by Simon et al. (4) that the initial mutation had occurred in the Celtic people and subsequently was spread with the migration of the Celts. Subsequent papers by Smith et al. (8) and Lucotte (9) were also in favor of a Celtic origin of the C282Y mutation. Later it was hypothesized by Olsson and Ritter (10) and Milman and Sørensen (11) that in Europe, the distribution of the disorder was more consistent with an origin of the mutation in Southern Scandinavia. The Scandinavian population, the Vikings, could subsequently have spread the mutation. A similar concept has been proposed by Fairbanks (5).
The aim of the present study was to evaluate the validity of these two hypotheses. Which one can most accurately explain the distribution pattern of the C282Y mutation within the European populations?


Methods

The analysis is based on recently published frequencies of the C282Y mutation of the HFE gene in European populations and population subgroups. We have preferably included studies comprising at least 100 individuals (12-68).
We performed literature studies of the Celts, their origin, migratory activities and settlements (69-71). Similar studies were performed on the origin of the Vikings, their migratory activities and settlements (72-78). The authors consulted the Danish historical experts on the Celts and the Vikings, Assistant Keeper Flemming Kaul, Professor Else Roesdahl and Professor Niels Lund.


Results


The Celts

The era of the Celts dates from approximately 800-300 BC (Table 1) (69-71). Around 800-600 BC, in the lands just North of the Alps, peoples appeared, whom their literate Greek neighbors to the south called Keltoi. The Celtic homeland was an area of present-day Austria, near Southern Germany. The name 'Celt' probably came from the dominant tribe of Hallstatt in present-day Austria and became a unifying concept for the culture. Archeological excavations in Hallstatt have given name to the Celtic 'Hallstatt' Culture which was the first of the Iron Age cultures beginning around 800 BC. Archeological findings at the Lake Neuchâtel in present-day Switzerland have given name to the Celtic 'La Têne' Culture, which began around 450 BC and lasted to around 100 BC.
The Celts dominated Central and Western Europe for many hundred years (Fig. 1). They appeared to have moved from east along the main trading arteries of the time, especially the river Danube, into Germany, Austria, Switzerland and France. Around 500 BC, the Celtic group of peoples consisted of different tribes and various races spread over a wide area of Central and Western Europe. Their unity was not that of a nation or empire in the Greek or Roman sense, but was cultural and religious in nature, with no common central authority. The Celts were related in part by their language, which belonged to the Celtic branch of the Indo-European family of languages, and in part by their religion, administrated by a priestly caste, the Druids. The Celts were brave in battle and Celtic tribes formed military confederacies. The Celts had no written language and therefore transmitted their culture orally. This accounts for the sparse knowledge about them prior to their contact with the classical civilizations of Greece and Rome. They were generally well educated and the Romans often employed Celtic tutors for their children.
The areas inhabited by the Celts and their migrations are shown in Fig. 1. The Celts were at their height during the 4th and 5th centuries BC. During this period, they waged three great wars. Around 500 BC, they conquered the Iberian Peninsula from Cartage. Around 400 BC, they took Northern Italy from the Etruscans and settled in great numbers. They even conquered Rome in 387 BC. At the end of the 4th century, they conquered the Illyrians and took Pannonia.
Around 300 BC, the Celtic region started to break apart and the tribes began wandering in search of new land. Some went to Greece, some to Northern Italy, and some to Asia Minor where they founded Galatia. The Celts migrated to Britain and Ireland from Europe, conquering the original inhabitants. They settled in France where the largest tribe, called the Galli by the Romans, gave their name to the region and the people the Gauls, who were engaged in the invasion of Northern Italy in the 4th century BC.


Denmark before the Vikings

The period before the Vikings is named the Germanic Iron Age and covers the period from 400 to 700 AD. The Iron Age population in Denmark came of the Germanic group of peoples in present-day Northern Germany. Denmark was divided into minor territories ruled by local chiefs and kings and the country had no central authority. In 700 AD, Denmark had become partly united and was ruled by a relatively strong royal power. Around 700 AD, the Merovingian domination crumbled. This paved the way for a Danish display of power in the southern parts of the North Sea area with Saxony and Friesland. When Charlemagne and the Carolingians attempted to re-establish the power of the Franks around 800 AD, it resulted in clashes with the Danes under king Godfred who had established a trading center in Hedeby, and fortified Denmark's southern border with a new rampart. King Godfred's battles with Charlemagne were clashes between two empire builders.


The Vikings

During the Jelling dynasty, which came to power at the beginning of the 10th century, the unification of Denmark was accomplished. King Harald Bluetooth claims on his runic stone in Jelling to have conquered all of Denmark and Norway (77).
The era of the Vikings dates from approximately 800-1066 AD (Table 2) (72, 77). The Viking homelands consisted of the three present-day Scandinavian kingdoms of Denmark, Norway and Sweden together with the Aaland Islands, i.e. the area corresponding to Southern Scandinavia (Fig. 2). The border of the Danish Viking kingdom was at the base at the Jutland peninsula, in an area, which today lies in North Germany. We do not know why the Vikings started their raids towards Western Europe in the late 8th century. The hypotheses include overpopulation, political pressure from the Christian communities situated south of Denmark, or search for treasures, adventure and glory. The Vikings were sea-borne, very mobile and travelled extensively. In addition to sailing at open sea and along coastlines, they travelled inland along the rivers in Europe and made overland journeys. The Vikings even penetrated by the rivers into the Russian territory. The initial aggressive behavior was followed by immigration when the Vikings established settlements in many places in Northern and Western Europe (Fig. 2). Viking fleets reached deep into the Mediterranean at Marseilles, Genoa, Naples, the Peninsula of Sorrento, Athens and Constantinople, but they did not settle there.
Iceland was a major Viking settlement. The island was colonized and populated by the Vikings from approximately 870 AD and some decades onwards. Other important settlements were the Faeroe Islands, the Shetlands, the Orkney Islands, the Hebrides, the Island of Man, parts of Scotland, Ireland (Dublin area and other coastal settlements), England (Danelaw) and Normandy. In Eastern England, the Vikings assimilated the Anglo-Saxon population. The Anglo-Saxons had emigrated from Saxony in Northern Germany to Eastern England in 400-500 AD where they assimilated the original Celtic population.
The Normans were descendants of the Vikings. Under William the Conqueror, at the battle of Hastings in 1066, they succeeded in the conquest of England. Later the Normans expanded into the Mediterranean basin where they established settlements around Naples and on Sicily in Palermo (73).


Allele frequencies of the HFE C282Y mutation

The allele frequencies of the C282Y mutation in Europe are shown in Figs 1, 2 and Table 3. The highest frequencies (5.1-9.7%) of the C282Y mutation are observed in populations in the Northern part of Europe, i.e. in Scandinavia, Faeroe Islands, Iceland, Eastern part of England (Danelaw) and the Dublin area, all established Viking homelands or settlements. Typically, the highest allele frequencies are reported in populations living along coastlines, i.e. in Iceland, Faeroe Islands, the Shetlands, Norway, Sweden, Denmark, Ireland, Wales, England, Jersey Islands, Normandy and Brittany.

Also, the allele frequencies of the C282Y mutation decline from Northern to Southern Europe. Intermediate allele frequencies (3.1-4.8%) are seen in the populations in Central Europe, which is the original Celtic homeland. Low allele frequencies (0-3.1%) are recognized in populations in Southern Europe and in the Mediterranean area, Spain, Italy and Greece.


Discussions

Using a haplotype phylogeny for chromosomes carrying the hemochromatosis gene, it has been estimated that the C282Y mutation appeared approximately 60-70 generations ago (79, 80). There exists no valid documentation of the mean lifetime in the Iron Age or the Viking era. If we assume a mean generation time of 20 years, the mutation should have appeared around 600-800 AD. If we assume a mean generation time of 25 years, the mutation should have emerged at 250-500 AD, and at a generation time of 30 years the period would be 100 BC to 200 AD.

The Celtic group of peoples consisted of many tribes and probably also several races that were associated by religious and cultural bands. They seem to have come from Eastern Europe, travelling through Central Europe (present-day Austria, Switzerland, Germany) and Western Europe (present-day Spain, France, Belgium) to England, Wales, Scotland and Ireland. The Celts were landsmen and had no great naval traditions. They seemed to favor living inland and had no preference for coastal areas. In Europe, the ancient Celtic culture has disappeared, except in Gaelic speaking parts of Brittany, Scottish Highlands and Western Ireland. The Gaelic language has probably survived in these areas due to their isolation. The Celts were at their height at around 400 BC and their region broke apart at 300-200 BC, when Celtic tribes settled in other parts of Europe and in Asia Minor. Assuming a generation time of 30 years, the C282Y mutation would have appeared at the earliest at 100 BC, when the Celtic tribes had already settled and the Celts no longer had a common region or culture.

To the Greeks and Romans, the continental Celts were striking in appearance, because of their height, blond or reddish hair and pale complexion. This has puzzled modern people as many 'Celts' today, such as the Welsh and Bretons, are stereotyped as relatively short and dark. The differing perceptions merely underline the fact that both ancient and modern Celts are a cultural and linguistic grouping, and not a biologically distinct race (69).

Supposing the mutation had occurred within the Celtic group of peoples, this would have been in the region occupied by the specific tribe, in which the mutation had appeared. As the migratory activities of Celts had already ceased at 100 BC, it is hard to imagine how the mutation could have been spread to the other parts of Northern and Western Europe.

Furthermore, there is no evidence to support the theory that Celtic people settled in Denmark, along the coastline of Northern Sweden, in Southern and Western Norway, on the Faeroe Islands or Iceland. Indicated by the burial rites and design of jewellery, the Northernmost Celts lived around Cologne in Germany. In the same period, the population who lived in Denmark and in the plains South of Denmark and along the southern coastline of the Baltic Sea belonged to the Germanic group of peoples.

The Vikings, whether as warriors, tradesmen or colonisers, reached almost every part of the known world and discovered new lands. From the Scandinavian kingdoms, their ships explored the western European coastlines, and sailed through the Strait of Gibraltar into the Mediterranean Sea. From the Baltic, they penetrated into the continent, sailing up Russian rivers and waterways to the Black Sea and the Caspian Sea. They sailed the whole of the North Atlantic, discovered and settled on the Faeroe Islands, Iceland and Greenland, and settled in parts of England, Wales, Scotland, Ireland and Normandy. They even discovered North America, where a Viking settlement has been discovered in Newfoundland, Canada.

It is evident from the maps (Figs 1 and 2) that the Vikings travelled more extensively than the Celts. It is interesting that the C282Y mutation is encountered in almost every population who has been in contact with the Vikings. The allele frequency is high in areas where the Vikings have settled in large numbers, e.g. Eastern England, Eastern Ireland, and Normandy. In contrast, it is low in areas with few Viking invaders or settlers, such as Central Europe, the Balkans, the Mediterranean countries, Central Finland and Russia.

England was invaded and conquered several times by people of Scandinavian heritage: first by the Vikings in the period 800-1016 AD and subsequently by their descendants the Normans in the battle of Hastings in 1066 AD. The settlements in England are among the most important of the Viking settlements in Europe. The original Anglo-Saxon population was not extinguished or expelled but remained in the country. The long period of Viking dominance favored their genetic influence on the original population, and the second invasion by the Normans can be interpreted as a genetic booster. Vikings and Normans obtained a high rank in the society. Due to the social structure, this may have increased their reproductive potential and promoted spreading of their genes.

A puzzling feature that has initiated the Celtic theory is the high frequency of the C282Y mutation in Brittany where Celtic culture is supposed to have survived (4). However, in nearby Normandy the Vikings were the dominant settlers (73, 75, 78). It is therefore likely that they could have settled in some places along the coastline of Brittany. The Vikings conducted warfare in Brittany. In 919 AD, Brittany's nobility fled to Francia and England, and the Vikings under Rognvald conquered the entire country, making their capital at Nantes. The Vikings ruled Brittany until Alain Barbetorte, after his return from England, defeated them in 937 AD. Although a large Viking boat grave has been found at Ile de Groix at the southern coast of Brittany, there is no clear evidence of Viking settlements in central Brittany (73-78). However, the Vikings ruled Brittany for almost 20 years, so a genetic founder effect combined with subsequent geographic isolation and a high frequency of consanguineous marriage may help explain the high prevalence of the C282Y mutation in the Bretons. In other coastal areas where Viking settlers were few by numbers, they probably also had a high social rank, which may have facilitated their reproduction and enhanced a possible founder effect.

A strong argument in favor of the Vikings carrying the C282Y mutation is the high allele frequency on the Faeroe Islands and Iceland, which were settled by predominantly Norwegian Vikings in the 9th century. However, recent DNA mapping of the Icelandic population suggests an additional emigration from Ireland to Iceland of 2nd to 3rd generation Nordic people. This emigration took place after the defeat of the Vikings in Dublin in 902 AD. Also, the C282Y mutation frequency is high in the population of the coastal areas of Western Norway, which is one of the homelands of the Vikings.

The history and the populations of Denmark and Norway are closely linked together. There has always been trading routes between Northern Jutland and Southern Norway. Settlers from Denmark have enriched the population in Southern and Western Norway and vice versa. The Danish Viking King Canute the Great conquered Norway in 1022 and ruled until his death in 1035 AD. From 1042 to 1047, Denmark and Norway were united under the Norwegian king, and in the period 1379-1814 AD the two countries were united under the Danish king.

In conclusion, arguments in favor of the 'Viking hypothesis' are: (1) the allele frequencies of the C282Y mutation are high in the Scandinavian countries including Iceland and the Faeroe Islands, which were colonized exclusively by the Vikings; (2) the allele frequencies decline from Northern to Southern Europe; (3) the allele frequencies are high along the European coastlines where the Vikings landed and settled; (4) the allele frequencies are lowest in locations where few Vikings have been such as Central Europe, the Balkans, the Mediterranean countries and Russia; and (5) in the homelands of the Celts, the allele frequencies are intermediate. Assuming the C282Y mutation was spread initially with the Vikings and later with the Normans, the allele frequency must have been high in the Viking population. Future population studies of haplotype markers linked to the HFE gene as well as DNA analyzes of Danish skeletons from the Iron Age and the Viking era may yield more definite proof on the origin of the C282Y mutation.


Table 3. Frequency of the C282Y mutation of the HFE gene in European populations
Country - Location - Reference - Subjects examined (n) C282Y allele frequency (%)


Austria Datz et al. 1997 (23) 271 4.1
Kazemi-Shirazi et al. 1999 (38) 487 4.8
Austria total 758 4.6
Bulgaria Ivanova et al. 1999 (34) 100 0.0
Czech Republic Zdarsky et al. 1999 (68) 139 5.0
Hrachovinova et al. 1999 (33) 100 4.5
Czech Republic total 239 4.8
Denmark Aalborg Steffensen et al. 1998 (62) 200 6.8
Merryweather-Clarke et al. 1999 (43) 219 8.2
Copenhagen Simonsen et al. 1999 (61) 420 6.2
Copenhagen Ellervik et al. 2001 (25) 9174 5.6
Copenhagen Milman et al. (unpublished) 1889 5.7
Denmark total 11,902 5.7
Estonia Mikelsaar et al. 1999 (46) 442 3.5
Faeroe Islands Milman et al. (unpublished) 200 8.0
Merryweather-Clarke et al. 1999 (43) 187 5.1
Faeroe Islands total 387 6.6
Finland North Beckman et al. 1997 (14) 173 5.2
East Tuomainen et al. 1999 (65) 1150 3.4
Finland total 1323 3.7
France Amiens Merryweather-Clarke et al. 2000 (41) 991 5.0
Paris Mercier et al. 1998 (40) 126 4.0
Brittany Mercier et al. 1998 (40) 62 5.6
Brittany/Brest Merryweather-Clarke et al. 2000 (41) 7000 7.9
Brittany Mura et al. 1999 (49) 410 7.7
Brittany/Rennes Jouanolle et al. 1998 (37) 1000 6.5
West Brittany Jézequel et al. 1998 (36) 254 9.4
Brittany total 8726 7.7
Toulouse Borot et al. 1997 (17) 95 4.2
Basques/Biarritz Mercier et al. 1998 (40) 92 1.6
Catalans/Perpignan Mercier et al. 1998 (40) 166 2.1
South France total 353 2.6
Germany Frankfurt/Main Nielsen et al. 1998 (51) 157 4.8
Frankfurt/Main Gottschalk et al. 2000 (28) 251 3.6
Cologne Hohler et al. 2000 (32) 205 3.2
Central Hellerbrand et al. 2001 (31) 126 2.4
South Braun et al. 1998 (18) 180 7.2
Germany total 919 4.2
Greece Merryweather-Clarke et al. 1997 (42) 139 1.4
Papanikolaou et al. 2000 (52) 158 0.3
Greece total 297 1.0
Greenland Merryweather-Clarke et al. 1999 (43) 200 2.3
Hungary Tordai et al. 1998 (64) 277 5.6
Andrikovics et al. 2001 (13) 996 3.4
Szakony et al. 1999 (63) 448 2.1
Hungary total 1721 3.4
Iceland Merryweather-Clarke et al. 1997 (42) 90 6.7
Merryweather-Clarke et al. 1999 (43) 231 4.5
Iceland total 321 5.1
Ireland Murphy et al. 1998 (50) 404 9.9
Ryan et al. 1998 (58) 109 14.0
Merryweather-Clarke et al. 2000 (41) 150 6.0
Ireland total 663 9.7
Italy North-East Borgna-Pignatti et al. 1998 (16) 131 2.3
Genoa Racchi et al. 1999 (55) 130 4.2
Milan Piperno et al. 1998 (53) 139 1.1
Milan Sampietro et al. 1998 (59) 128 0.8
Modena Casanelli et al. 2001 (21) 2100 1.6
Modena Pozzato et al. 2001 (54) 149 3.4
Modena Merryweather-Clarke et al. 1997 (42) 91 0.5
Piemonte Longo et al. 1999 (39) 189 1.1
South Campo et al. 2001 (19) 100 0.0
Italy total 3158 1.7
Mordovia Saransk Beckman et al. 1997 (14) 85 1.8
the Netherlands Roest et al. 1999 (57) 555 4.1
Norway Merryweather-Clarke et al. 1997 (42) 94 6.4
Oslo Undlien et al. 1998 (66) 144 7.9
Oslo Distante et al. 2000 (24) 1900 6.6
Norway total 2138 6.6
Poland Moczulski et al. 2001 (47) 871 3.1
Portugal North/Central Cardoso et al. 2001 (20) 259 5.2
South Cardoso et al. 2001 (20) 381 2.2
Spain Madrid Moreno et al. 1999 (48) 174 2.3
Central Alvarez et al. 2001 (12) 125 2.0
Cantabria Fabrega et al. 1999 (26) 213 4.4
Catalonia Gimferrer et al. 1999 (27) 108 3.7
Catalonia Sanchez et al. 1998 (60) 512 3.0
Balearic Islands Guix et al. 2000 (30) 210 2.6
Spain total 1342 3.1
Sweden Sami People Beckman et al. 1997 (14) 151 2.0
Umeå Beckman et al. 1997 (14) 206 7.5
Switzerland Claeys et al. 2002 (22) 89 5.1
Geneva Beris et al. 1999 (15) 100 2.5
Switzerland total 189 3.7
UK England Merryweather-Clarke et al. 1997 (42) 368 6.0
N.-E. England Grove et al. 1998 (29) 117 7.7
Jersey Islands Merryweather-Clarke et al. 1998 (44) 411 8.3
Orkney Islands Merryweather-Clarke et al. 2000 (41) 103 4.9
Scotland Miedzybrodzka et al. 1999 (45) 184 8.4
Wales Roberts et al. 1997 (56) 101 5.9
Wales Willis et al. 1997 (67) 200 8.5
Wales Merryweather-Clarke et al. 2000 (41) 323 8.5
Wales Jackson et al. 2001 (35) 10,556 8.2
Wales total 11,180 8.2


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