THE FINNISH DISEASE HERITAGE AND OTHER GENETIC ISOLATES
The country where I want to be,
You’re so sadly neglected,
And often ignored,
Finland, Finland, Finland,
Finland has it all.
-Monty Python, “Finland”
In modern society it is generally considered impolite to point out the intrinsic differences between ethnic groups; while it is true that people should be treated equally regardless of ethnicity in terms of employment, respect, rights etc, there are genetic differences between ethnicities that can provide invaluable medical information about disease processes. Throughout history there has been a vast amount of inter-ethnic mingling, this has made most genetic differences negligible at best however, as with all things, there are some exceptions. There are numerous small groups that for cultural, historical, or geographical reasons have been somewhat isolated from the genetic churn of most of humanity. These groups are a veritable treasure trove of genetic information that can help researchers understand the development and predisposition of disease both within an isolated genetic group and amongst the general population. This is due to the fact that it is easier to identify the causative factor of a disease in a homogenous group such as the rural Finnish than in a heterogeneous genetic group like the city of Toronto. This paper will discuss the principles of genetic diversity, the origin of various genetic groups, and the impact that their genetic information has had upon society at large. These groups include the Finnish, French Canadians, and Ashkenazi Jews.
Our genetic information is passed down from generation to generation through the transfer of DNA. DNA is essentially a string of four different compounds, adenine, cytosine, thymine, and guanine, commonly shortened to A, C, T, and G respectively. The billions of letters that form our genetic code are split into 23 pairs of chromosomes, with one half of each pair coming from each parent. Aberrant mutations in genes cause many of the severe developmental disorders or other diseases that we see today. In a society with a large gene pool these disadvantageous genes would be bred out of the population through natural selection (historically people with developmental defects are less likely to have children). In small populations with a limited gene pool this is not always possible and a series of factors come into play.
When a small group of people settle a new area they bring with them only a minute sample of the overall genetic diversity in man. As the colony grows and expands the limited gene pool results in inbreeding and eventually consanguinity. Consanguinity refers to the sharing of genetic heritage amongst people, or in other words your relatives. As the small community grows, unless outside genes are brought in through migration, disease genes may spread and recessive genes will become more prominent. There is also the random chance that genes will disappear from the population, thus further reducing the gene pool. This is a phenomenon called genetic drift that is most seen in small genetic groups. The relatively few people who start a colony cause a founder effect as whatever mutations the founders had will be carried on to further generations. If the founders by chance carried a high proportion of disease genes the result would be a high incidence of the disease gene throughout the population compared to the rest of the world. Inbreeding, genetic drift and the founder effect have negligible effect on the general population due to the vast gene pool that is available, however due to geographic isolation (Finland, French Canadians), or cultural values that exclude breeding with “outsiders” (Ashkenazi Jews) groups can genetically segregate and unique genetic characteristics establish themselves.
In the modern world the effects of inbreeding, consanguinity, and founder characteristics, manifest themselves in a plethora of unique genetic traits or predispositions among ethnic groups. A particularly well characterized genetic group are the Finnish people resulting in the Finnish Disease Heritage (FDH).
Nestled at the edge Northern Europe, sandwiched between Sweden and Russia, Finland is a Nordic country with cold winters and a sparse population. The generally accepted theory of Finnish settlement is that the Southern and Western regions of the country were initially settled by a small group of people who carried with them a specific and select mixture of genes. The population of Finland was small and limited to the South and West until the Savo Finns, who had a largely hunting culture, were pushed Northwards by the encroachment of agriculture[1]. The Savo moved slowly northward throughout the sixteenth century into the largely uninhabited areas and settled into communities. This migration occurred in a step wise fashion with small communities forming until crowding became an issue leading some members of the community to move further north and so on. As a result, a large amount of Finland was settled by a small genetic group (the Savo) with the far north being settled by a subgroup of the Savo (a product of the step-wise migration pattern). The sparse isolated communities of the North remained quite isolated up until the twentieth century when many young Northern/Eastern Finns moved to the cities and industrialized areas of the South and West.
The history of genetic isolation within Finland has resulted in a unique series of diseases that are uniquely or predominantly Finnish. Conversely there are several conditions common throughout the world that are very rarely seen in Finland (cystic fibrosis, phenylketonuria) [2]. This unique genetic background is known as the Finnish Disease Heritage (FDH) and almost 40 hereditary diseases are considered part of FDH.
Congenital nephrosis of the Finnish type (CNF) is considered the prototypical FDH disease; it was first described in the 1940’s and characterized in the 1960’s. Physicians were examining many cases of kidney failure in newborns that was resistant to standard treatment and resulted in death. Several factors were initially investigated as a cause of CNF including social and personal habits until the genetic recessive link amongst families was confirmed. To prove the genetic link the genealogy of each affected family was mapped and compared to each other; this is possible because the Lutheran Church (the predominant church in Finland) has kept elaborate genealogical records since the seventeenth century [1]. Using these family histories a high degree of consanguinity was found between spouses within families and between separate families with CNF. The ancestral home of families (as taken by grandparent’s location of birth) carrying this mutation is concentrated within areas of post 1500 “late settlement”. CNF is caused by a few Finnish mutations and 78% of patients have a loss of two base pairs on chromosome 19. This discovery led to the acknowledgement of the FDH and laid the ground work for many FDH studies to come.
There are many other FDH diseases, most of which have been examined in the same way as CNF. Some have a similar area of origin as CNF, Congenital Chloride Diarrhoea (CCD) for example. CCD is caused by the loss of a GGT triplicate on chromosome 7; it causes incessant watery diarrhoea in the newborn which is fatal unless fluids are administered. If the condition is diagnosed quickly and fluids are given then there are no long lasting effects after infancy other than loose stool [3]. The origin of this condition is, much like CNF, mostly from the “late settlement” areas. Meretoja disease on the other hand has an even more specific origin. Also known as corneal lattice dystrophy, Meretoja disease is an autosomal dominant condition that causes the gradual degradation of vision beginning after the age of 30. This condition has been pinpointed to a specific point mutation, a mutation where a single genetic letter has been changed for another on chromosome 9. This rare condition is found only in Finnish families and their grandparents can be traced back to two small geographic regions.
It may seem as though researching the specific diseases of a group such as the Finnish has benefits for only the isolated group, this is not true. While the diseases themselves are distinctly Finnish in character the process of identifying the underlying mutation enlightens our overall understanding of disease pathogenesis and predisposition. A prime example of this is the BRCA1 mutation predominantly found in Ashkenazi Jews.
The Ashkenazi Jewish population of Eastern Europe expanded in number from approximately 25,000 individuals in the fourteenth century to approximately 10 million today. As an ethnic group there has been a strong cultural impetus towards marrying other Ashkenazi, this exclusiveness combined with the relatively small founding population has led to over 20 recessive genetic disorders found predominately or exclusively within the Ashkenazi [4]. One of the most studied groups of Ashkenazi mutations are the breast cancer gene mutations (BRCA1 and BRCA2). Having a BRCA mutation greatly increases someone probability of acquiring breast cancer or ovarian cancer. The prevalence of BRCA mutations among the non-Ashkenazi population is negligible and thus genetic testing is unfeasible; however within the Ashkenazi BRCA testing is informative, cost-effective, and can save lives [5]. The discovery of the BRCA mutation and its link to breast cancer has identified specific protein pathways that, with further research, can expand our knowledge of cancer pathogenesis.
French colonization of Quebec is a classic case of founder effect. The permanent settlers that populated Quebec numbered approximately 8500 and in fact the majority of genetic diversity comes from the initial approximately 2600 French settlers [6]. While relations with the first-nation’s population in Quebec undoubtedly occurred, cultural norms precluded any large scale breeding. As such the French Canadian population has largely been isolated from the general gene pool. Much like the Savo movement into Northern Finland the gradual colonization occurred in a step wise manner from the St. Lawrence River outwards. This would have amplified possible founder effects as each community would be founded by a subset of the original population. An introductory history of French Canadian migration, founder effects and diseases can be found in [6]. Just like other genetically isolated groups, French Canadians provide a great opportunity to analyze the etiology of congenital conditions. Andermann syndrome, a recessive genetic disorder that affects the peripheral nervous system is prominent in Quebec. Through analyzing the genetic data from Quebec the causal gene mutation for Andermann syndrome was discovered which has lead to better understanding of variants of the disease within other cultures [7-9].
Throughout the world there are many genetic isolates similar to the Finnish, Ashkenazi, and French Canadians. Their genetic makeup provides a unique opportunity to better understand our genome and its relation to disease development. Further understanding of genetic isolates can bring improvements to the diagnosis and treatment of affected individuals. While the focus of this paper has been the congenital diseases of specific isolated ethnicities, it is important to stress that there should be no stigma attached to these ethnic groups nor should groups be boastful of their genetic heritage. As Dr. Reijo Norio, a FDH researcher, states “FDH is not and has not been any cause of shame nor pride … our resources for investigating those things are excellent and possibly even the results may be laudable.”[10] The genetic groups described here should be appreciated as a genuinely unique facet of human evolution and an opportunity to better understand ourselves.
References:
1. Norio, R., Finnish Disease Heritage I: characteristics, causes, background. Hum Genet, 2003. 112(5-6): p. 441-56.
2. Peltonen, L., A. Jalanko, and T. Varilo, Molecular genetics of the Finnish disease heritage. Hum Mol Genet, 1999. 8(10): p. 1913-23.
3. Norio, R., The Finnish Disease Heritage III: the individual diseases. Hum Genet, 2003. 112(5-6): p. 470-526.
4. Behar, D.M., et al., The matrilineal ancestry of Ashkenazi Jewry: portrait of a recent founder event. Am J Hum Genet, 2006. 78(3): p. 487-97.
5. Rubinstein, W.S., Hereditary breast cancer in Jews. Fam Cancer, 2004. 3(3-4): p. 249-57.
6. Laberge, A.M., et al., Population history and its impact on medical genetics in Quebec. Clin Genet, 2005. 68(4): p. 287-301.
7. Casaubon, L.K., et al., The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am J Hum Genet, 1996. 58(1): p. 28-34.
8. Howard, H.C., et al., The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet, 2002. 32(3): p. 384-92.
9. Lesca, G., et al., [Andermann syndrome in an Algerian family: suggestion of phenotype and genetic homogeneity] . Rev Neurol (Paris), 2001. 157(10): p. 1279-81.
10. Norio, R., Personal Communication. 2008.