Introduction
Genetic isolates is the sub populations resulting from the founder effect of a small number of individuals, as a consequences of some type of bottleneck in the history of a population’s gene pool. They exist in geographical, cultural or geographical and cultural isolation over many generations without genetic interchange from other populations. Recently, there has been success in mapping genes causing several diseases, mainly those exhibiting rare classical Mendelian recessive modes of inheritance. The initial successes came out in many cases by studying isolated populations such as the Finnish and the Amish. These particular communities, who were the focus of historical, anthropological and population genetic studies, are now the interest of large gene-mapping consortia.
Genetically isolated populations offer many advantages for genome-wide mapping studies. In the first place, most of them arise as the result of a founder effect. The high degree of inbreeding has produced an increased incidence of recessive disorders. Typically, confined, well-documented, extended and multigenerational pedigrees with several cases of rare diseases sharing a homogeneous phenotype and similar environment can only be found in these special isolates. Although some theoretical restrictions on the levels of linkage disequilibrium have been described, it has been shown empirically that special
non-parametric strategies, such as those using linkage disequilibrium (i.e. case-control population trials and transmission disequilibrium test (TDT), a method to detect linkage in the presence of linkage disequilibrium) and haplotype sharing between affected individuals can be applied successfully in isolated populations to the fine-mapping of critical DNA regions (Peltonen et al 2000). All of these features encouraged geneticists in designing several projects on linkage and linkage disequilibrium studies to map complex traits (i.e. those which demonstrate familial clustering, but do not follow a simple Mendelian mode of inheritance). Today, these efforts have resulted in the identification of chromosomal locations for major genes predisposing to several complex diseases such as asthma, schizophrenia, bipolar disorder, high blood pressure and multiple sclerosis among others. The results have not achieved the same success as the positional cloning of genes for Mendelian disorders.
However, preliminary reports suggest that genetic isolates will play an important role in discovering genes predisposing to complex disorders.
Definition and use of population isolates in genetic research
The population genetics studies the polymorphism variation throughout time in biological populations. The basic approach to characterize patterns and polymorphism differences among populations is by defining the genetic structure of populations. This genetic structure is defined by the allele structure (the allele counts or allele frequency distribution for a locus or loci) and the genotype structure (the genotype counts or genotype frequency distribution for a locus or loci). Theoretically, a population is in genetic equilibrium only if certain assumptions hold true: a large, randomly mating population, no appreciable mutation, equal fitness to reproduce and no migration. These populations in genetic equilibrium are commonly denoted in population genetics texts as Mendelian populations. In the context of Mendelian populations, the Hardy–Weinberg theorem (HWT) established that the genotype frequencies will remain constant and follow a multinomial distribution (binomial for a one locus, two allele model). In other words, the allelic and the genotypic structures remain unchanged throughout time. Thus, Mendelian populations will not be subject to biological evolution.
For instance:
- No population is infinitely large, and even in postulating a very large and expanding population, the presence of panmixia (random mating) will not be possible after a short number of generations since the necessary energy to assure totally random mating among the more distant individuals will be so high that no biological system could support it. In fact, even in cosmopolitan communities, assortative mating has been demonstrated empirically to occur at short distances between places of residence or of birth and also by socio-economic status. This phenomenon generates geographical heterogeneity unless the area investigated is extremely small. Furthermore, assortative mating is highly influenced by religious practices which could produce patterns of genetic isolation without geographical restrictions,
as is the case in the Jewish communities. - The mutation rate in multiple loci is enough to produce a high level of diversity in a short time period. In fact, Kimura introduced the diffusion equation approach to understanding the impact of genetic drift. Their elegant work has contributed greatly to our basic knowledge concerning the interplay of genetic drift and other factors such as selection, mutation and gene flow. By analyzing populations in which specific disorders segregate, several lines of strong evidence
suggest that selection, defined as the differential capacity to produce fertile descendants, have been acting at several loci, as demonstrated for alleles in thalassemia and Duffy loci associated with protection from malaria among other genes. - Populations undergo complex patterns of migration because of natural growth and the subsequent need for geographical expansion. Historically, short migration to nearby localities is easier than travelling very far. As a consequence, when two populations are compared, their allele frequencies will tend to be similar at short spatial distances. For human populations, this clustering of a group of people has been historically limited to the displacement of a small number of individuals moving to a new locality mostly selected by the availability of food. In these new enclaves, and in a short period of time, these newly formed communities grow, in most cases exponentially, isolated from the others as a result of geographical barriers such as mountains, seas or deserts, and cultural barriers such as linguistic and religious differences. When this process of isolation persists over several generations, the main consequence is genetic isolation, which could be interpreted in the context of population genetics as the recurrent process of inbreeding and gametic sampling error (also termed genetic sampling or genetic drift) leading to micro-differentiation or population subdivision. Based on the theory of evolution, all individuals of a species are to some extent inbred, since all are descended from remote common ancestors. However, the common ancestor must not be too remote or the concept becomes meaningless.
Population genetics of selected isolates
Finnish: The probable reasons for the isolation of Finnish community are dual founder effect, geographical and cultural isolation. Two models have been proposed for the origin of the Finns. These two models agree that the Finnish population has remained isolated for approximately 2000years. The first model assumes a single migration about 2000years ago by a small number of Estonian settlers coming form an area south of the Gulf of Finland that includes present day Estonia, followed by a long period of relative isolation. Internal migration was minimal until the seventeenth century, when population movements into the north and east of Finland began. During this period of isolation, population growth was apparently not constant because of wars, famine and disease. The second model, the dual origin model, assumes an earlier migratory wave of the eastern Uralic speakers, near Ladoga Lake 4000years ago, probably accompanied by a language replacement of the natives and a later migration wave some 2000years ago from the south via the Gulf of Finland. Evidence supporting the dual origin model was obtained from haplotype analysis of the Y-chromosome and archaeological data demonstrating considerable cultural differences between eastern and western Finland dating back almost 1000years (Kittles et al., 1998). The Finnish population represents one of the larger European communities who do not speak an Indo-European language, which probably reflects their relative isolation from other communities inhabiting Europe. Finnish is a language derived from the Uralic family (Ruhlen, 1987).
Other communities speaking related Uralic languages inhabit Estonia, Hungary, Sweden, Norway and Russia (Ruhlen, 1987). Finland has been relatively isolated from neighboring countries for both geographical and socio-cultural reasons. Within the last 300 years, the population has expanded from an estimated 250000 to more than 5 million. Although some comparative studies of classical blood antigen and protein loci suggest that Finns are distinct from other Europeans, recent studies using
nuclear DNA marker loci (i.e. mini and microsatellites) have not confirmed these findings. In particular, with reference to the uneven distribution of recessive disorders, the population structure observed in the Finnish population is compatible with the existence of subpopulations or ‘internal isolates’. The concept of Finnish disease heritage was coined because of the high prevalence of recessive disorders. Today, the study of the Finnish community represents the most successful effort in mapping genetic disorders in a population isolate.
Amish: Founder effect and cultural isolation are the most probable cause of isolation in Amish Population. The Amish community is a religious isolate descended from a limited number of founders who emigrated 150–200years ago to the USA from the Rhineland in the south-west of Germany. Originally, they had emigrated in the 1690s from the Canton of Berne, Switzerland. The Amish population of Lancaster County, Pennsylvania, has a high incidence of a recessive disorder known as six-finger dwarfism or Ellis-van Creveld (EvC) (Mckusick, 1978). From a population of about 13,000, 82 affected individuals in 40 affected sibships were diagnosed as having this disease. If inbreeding is taken into account, the frequency of the recessive allele is estimated to be about 0.066 and the incidence of the disease is about 0.005. Indicative of the restricted number of founders in this population, 80 parents in these 40 sibships all trace their ancestry to Samuel King and his wife, early members of the community. From this pedigree information, it appears quite certain that the high incidence can be primarily attributed to founder effect. Either Samuel King or his wife carried the recessive allele; and because many individuals in the population are their descendents, the incidence of the disease is now high.
Tristan da Cunha: The tiny volcanic island of Tristan da Cunha is a small, remote island in the South Atlantic about 2900 km west of South Africa. The island’s population of 300 is descended from a handful of founders, mostly shipwreck survivors, who settled there in the 19th century. From genealogical records, the contributions of only seven women remain: M.L. who came in 1816; M.W., S.W., and M.W. in 1827; S.P. in 1863; and E.S. and A.S. in 1908. Because mtDNA is maternally inherited with no
recombination, present day mtDNA types can be used to trace the ancestry to the founding females. The mtDNA types found in 161 present-day individuals for nine different mtDNA regions first found by SSO probes and then described by sequence differences (Soodyall et al., 1997). S.W. and M.W. were described as sisters from the historical data, but the mtDNA show that they have distinct mtDNA types. M.W. and M.W. were mother and daughter and E.S. and A.S. were sisters, both of which are confirmed by the mtDNA data. In other words, from the genealogical information, four founder mtDNA types were expected, but five were observed. The estimated level of mtDNA diversity using expression 2.18c is 0.768 here are seven family names use in Tristan, corresponding to the number of founding fathers with present-day descendants from public records (Soodyall et al., 2003). Because Y chromosomes are paternally inherited with no recombination, present-day Y-chromosome haplotypes can be used to trace ancestry to the founding males. Within each family, there was a haplotype that could be traced to the known ancestors (Table 1(b)). However, two other haplotypes were also observed, one in family 3 that appears to be from a migrant. In addition, in families 5, 6, and 7, haplotypes from other families were also found that appear from pedigree examination to be the result of four instances of non paternity and the subsequent descendants. Overall, there are nine Y haplotypes, and the estimated level of Y-chromosome diversity using expression 2.18c is 0.847.
Hutterites : Founder effect and cultural isolation are the most probable cause of isolation in Hutterites Population. The Hutterites are an Anabaptist Christian group who originated in the Tyrolean Alps of Austria in the sixteenth century. They migrated eastward over the next two centuries in response to religious persecution (Hostetler 1985). Between 1700 and the mid-1800s, during their stay in Russia (specifically in Ukraine), the population grew in size from 120 to 1265 (Hostetler 1974). They migrated en masse to the USA between 1874 and 1877. The majority homesteaded individual farms, but 443 individuals (101 couples) continued to live in community. These individuals, along with three large families who joined the Hutterites between 1883 and 1892, and a few migrants, constitute the ancestors of the current Hutterites. The population has expanded dramatically since migrating to the USA and the current Hutterite community exceeds 40000. Hutterites are endogamous (Bleibtreu 1964.) and they are divided into three distinct kinship groups, namely, the Schmiedeleut, the Dariusleut and the Lehrerleut. Currently, Hutterites live in 427 communal, autonomous, agrarian colonies in Canada and the USA. The Hutterites have a relatively uniform environment, including dietary habits and an austere lifestyle. Drug abuse is almost absent and the use of alcohol is moderate, and a low prevalence of psychosis has been described. Mainly complex disorders such as asthma and cardiovascular disorders have been studied in these communities (Newman et al., 2001). In fact, Ober et al. (2000), in a recent and extensive paper described the analysis for 20 quantitative traits. In particular, the presence of a significantly higher proportion of heterozygotes at HLA loci has been interpreted as a consequence of assortative mating between individuals carrying different genotypic forms.
Paisa community from Antioquia, Colombia : This population represents a particular case of the multi founder effect (an Amerindian–Caucasian admixture with heterogeneous patterns of genetic flow correlated to gender) experiencing cultural and
geographical isolation from the total population in Colombia in South America. The current Colombian population stems mostly from the result of both a spatial and a temporal mixture that occurred among Europeans, Africans and the native Amerindian communities. These processes started early in the sixteenth century and continue up to today. Historically, it is known that a heterogeneous pattern of migration was established in settling Colombia. Parsons (1949) was the first to describe the ‘Antioquian’ population as the most clearly defined in Colombia. However, the name ‘Antioquian’ is inadequate because it makes reference to the geographic and political divisions occurring in Colombia in this time. Today, this political division has changed and most people belonging to the former state of Antioquia belong to the self-designated ‘Paisa’ community. It is very important to point out that the genetic isolate (‘Paisas’) is really a community dispersed from north to south in Colombia. The Paisas, located between the central and western branches of the Andean Mountains, share cultural and demographic features. Its ethno-historical origin stems most likely from Spaniards, Sephardic Jews (Christianized Sephardim or Marranos) and Basques. The admixture with the African and Amerindian populations has been historically documented to be low. Several lines of genetic evidence show that this community exhibits the features of a genetic isolate. The Paisa community represents one of the most important populations in mapping genes. The advantages of this community include the large size of their genealogies (including in some cases up to five generations and sibships with more than 10 children), and the availability of the community. Finally, records indicate that the Paisas arose from multiple founder families 20 generations ago, which is likely to increase linkage disequilibrium of adjacent loci. In fact, the occurrence of linkage disequilibrium could be caused by the following: recent mutation, founder effect, the recent racial admixture of divergent populations and epistatic selection
(Chakraborty et al., 1988). Linkage disequilibrium will decrease in a few generations because of the genetic recombination except for closely linked loci (Chakraborty et al., 1988). It appears contradictory that two evolutionary forces, i.e. admixture and isolation, lead to the perpetuation of linkage disequilibrium. Because of the importance of this phenomenon and because of the existence of some genetic isolates resulting from this phenomenon, a potentially powerful tool in gene mapping exists. In
fact, the Finnish and Pisa communities resulted from a multi founder effect, and therefore, the levels of linkage disequilibrium could be larger than the ones present in those genetic isolates arising as the result of a unique founder effect. In theory, linkage disequilibrium between two genes spaced 10–20cM apart remains in populations with a recent history of genetic admixture between different racial groups. Mapping by admixture disequilibrium contrasts differential gametic disequilibrium among linked and non-linked genes.