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PubMed2006

Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families.

The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.

Adult↗

PubMed2004

Multiple sclerosis in western Finland: evidence for a founder effect.

We have previously demonstrated that there is a high-risk focus for multiple sclerosis (MS) in the southern Ostrobothnian region of western Finland (population 376121 in 1993). Of the two southern Ostrobothnian health-care districts, Vaasa and Seinäjoki, the incidence and prevalence of MS were especially high in the latter. In recent genetic studies, we identified haplotypes of the myelin basic protein (MBP) gene in a group of MS patients originating from southern Ostrobothnia, suggesting a founder effect. This finding led us to explore the population history of the southern Ostrobothnia and correlate it with MS epidemiology. Southern Ostrobothnia can be divided into three distinct regions with respect to its historical settlement: Vaasa, Seinäjoki-south, and Seinäjoki-north. Vaasa, the coastal region was settled by Swedes, who immigrated during the 13th century. In Vaasa, the prevalence of clinically definite MS (CDMS) in 1993 was 107/10(5) (95% CI 90-124). Seinäjoki-south was populated from the 13th century onwards from southwestern Finland, a region which has been recognised as a high-risk focus of MS. In Seinäjoki-south, the prevalence of CDMS in 1993 was 219/10(5) (95% CI 190-247). Seinäjoki-north was inhabited rather late starting in the 16th century from eastern Finland. In Seinäjoki-north the prevalence of CDMS in 1993 was 136/10(5) (95% CI 108-164). The historical settlement pattern of the southern Ostrobothnia indicates that its population is quite heterogeneous. Seinäjoki-south has a very high prevalence of MS, significantly higher than its two neighbouring regions. The distinctive settlement history of Seinäjoki-south, the historical link with the other southwestern high-risk foci and molecular genetic evidence, suggest that a founder effect plays an important role in the high-risk of MS in western Finland.

Catchment Area, Health↗

PubMed1997

Gene frequency clines produced by kin-structured founder effects.

Two mechanisms are commonly invoked to explain geographic gradients in gene frequencies (clines): gene flow and natural selection. Thus gene frequency clines in Europe have been attributed to gene flow because expanding Neolithic farmers from the Near East spread and absorbed resident foragers, a process Cavalli-Sforza and his colleagues labeled demic diffusion. Alternatively, gradients in natural selection can produce the same genetic pattern. A third mechanism to explain European clines has recently been proposed by Barbujani et al. (1995). They found that European allele frequencies were consistent with distributions generated by a simple model of total replacement of foragers by expanding farmers. Clines were produced by repeated founder effects in colonizing farmer groups. Here, I present a simulation model using different population parameters to test the generality of the Barbujani model. Results of the simulation show that steep clines (measured by spatial autocorrelation statistics) can be produced by kin-structured founder effects. The implication of these findings is that several genetic mechanisms are consistent with the allele distributions in Europe. To discriminate among these alternatives, other information, such as better archeological and demographic characterization of interactions between farmers and foragers, is required. In any case, the mere presence of genetic clines does not necessarily validate the demic diffusion model.

Demography↗

PubMed2001

Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities.

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.

Arteriosclerosis↗

PubMed1997

Localization of the gene causing keratolytic winter erythema to chromosome 8p22-p23, and evidence for a founder effect in South African Afrikaans-speakers.

Keratolytic winter erythema (KWE), also known as "Oudtshoorn skin disease," or "erythrokeratolysis hiemalis," is an autosomal dominant skin disorder of unknown etiology characterized by a cyclical erythema, hyperkeratosis, and recurrent and intermittent peeling of the palms and soles, particularly during winter. Initially KWE was believed to be unique to South Africa, but recently a large pedigree of German origin has been identified. The disorder occurs with a prevalence of 1/7,000 in the South African Afrikaans-speaking Caucasoid population, and this high frequency has been attributed to founder effect. After a number of candidate regions were excluded from linkage to KWE in both the German family and several South African families, a genomewide analysis was embarked on. Linkage to the microsatellite marker D8S550 on chromosome 8p22-p23 was initially observed, with a maximum LOD score (Z(max)) of 9.2 at a maximum recombination fraction (theta(max)) of .0 in the German family. Linkage was also demonstrated in five of the larger South African families, with Z(max) = 7.4 at theta(max) = .02. When haplotypes were constructed, 11 of 14 South African KWE families had the complete "ancestral" haplotype, and 3 demonstrated conservation of parts of this haplotype, supporting the hypothesis of founder effect. The chromosome segregating with the disease in the German family demonstrated a different haplotype, suggesting that these chromosomes do not have a common origin. Recombination events place the KWE gene in a 6-cM interval between D8S550 and D8S552. If it is assumed that there was a single South African founder, a proposed ancestral recombinant suggests that the gene is most likely in a 1-cM interval between D8S550 and D8S265.

Chromosome Mapping↗

PubMed2002

FMR1 haplotype analyses among Indians: a weak founder effect and other findings.

This study on allelic/haplotypic fragile X associations evaluated using STR (DXS548, FRAXAC1, FRAXAC2) and SNP (ATL1) markers flanking the (CGG)(n) locus of FMR1is the first report from the large ethnically complex Indian population. Results have been compared with allele/haplotype distributions reported for other major ethnic groups, including White Caucasians, Africans, and Pacific Asians. Though overall allele frequency distributions at the individual loci are more similar to Western Caucasians compared with others, significant differences are observed in haplotypic associations with the mutated X. The striking findings are: (1) high diversity and heterozygosity of haplotypes among fragile X chromosomes ( n=40) and controls ( n=262), including four haplotypes found exclusively in this study sample; (2) weak association of DXS548-FRAXAC1-FRAXAC2 haplotypes, 2-1-3, 6-3-3+ and 7-4-6+ with the disorder, and absence of White Caucasian fragile X haplotypes 6-4-4 and 6-4-5; (3) weak founder effect for the fragile X expansion mutation in the Indians; (4) lack of a continuum of haplotype-based FMR1 alleles between intermediate (CGG)(n) size ranges and expanded alleles; (5) exclusion of ATL1 as a candidate genetic indicator of FMR1 instability. The high STR-based haplotype diversity observed among fragile X lineages, irrespective of ethnic alliances, strongly suggests the inappropriateness of using STR haplotypes to infer predisposition to instability among ethnically separated fragile X pedigrees and may reiterate the need for identifying newer SNPs from this region to not only determine true founder effects for the fragile X mutation, but also decipher possible mechanisms leading to CGG instability.

Adolescent↗

PubMed2003

FOunder effect in patients with Unverricht-Lundborg disease on reunion island.

PURPOSE: Unverricht-Lundborg disease (ULD) is the most frequent form of progressive myoclonus epilepsy. ULD is caused mostly by a homozygous expansion of a dodecamer repeat in the cystatin B gene (CSTB) promoter. We present here a clinical and molecular study of 14 ULD patients originating from Reunion Island, a French island in the Indian Ocean. METHODS: These ULD patients were clinically evaluated, and the diagnosis of ULD was confirmed molecularly. We analyzed 12 microsatellites flanking CSTB and estimated the date of introduction of the ULD mutation on Reunion Island. RESULTS: These cases were clinically very similar, with the typical myoclonus syndrome associated with generalized tonic-clonic seizures, cerebellar involvement and, in some cases, mild mental deterioration. The mean age at onset was 9.6 years (range, 5-14 years), and the mean disease duration was 27 years (range, 5-47 years). The 14 patients harbored the typical ULD mutation, with variable degrees of expansion (mean of 56.3 repeats; range, 49-63). A founder effect was detected, with all but one of the Reunion ULD chromosomes displaying expansions belonging to the same haplotype, 1-1-1-2-6-4-3. We estimated the date of arrival of the most recent common ancestor (MRCA) of these patients on Reunion Island to the middle of the eighteenth century. CONCLUSIONS: These Reunion ULD patients displayed a homogeneous phenotype. Our molecular results are compatible with the instability of the repeat expansion and revealed a founder effect in Reunion ULD patients and the existence of a MRCA about 12 generations ago.

Adolescent↗

PubMed2005

Interaction between founder effect and selection during biological invasion in an aquatic plant.

Long-distance colonization and rapid range expansion associated with biological invasion may have major evolutionary consequences via both stochastic processes and selection. Using large-scale population genetic surveys, we demonstrate a major shift in the relative frequency of sexually fertile diploid versus sexually sterile triploid populations associated with the invasion of North America by a clonal aquatic plant, Butomus umbellatus. Most populations across the native European range were triploid (84% of 108), whereas most introduced populations were diploid (71% of 136). We evaluated the roles of stochastic processes versus natural selection in causing this shift by surveying predominantly neutral genetic variation at 28 RAPD loci. In Europe (EU) we detected 47 distinct genotypes among 142 plants sampled from 71 populations, whereas in North America (NA) we detected only six genotypes among 138 plants from 69 populations. Of the six NA genotypes, a set of four closely related genotypes were found only in triploid populations and a pair of closely related genotypes were found only in diploid populations, and these were genetically divergent from the triploid genotypes. This result is consistent with severe founder effect. Because sex creates genotypic variation and produces offspring with greater dispersal potential than those produced clonally, we tested the hypothesis that sexual reproduction characteristic of diploids has given them a colonization advantage that accounts for their high frequency in NA. However, we found little or no evidence of sexual recruitment in introduced diploids. One very widespread heterozygous genotype occurred in 95% of 38 introduced diploid populations (i.e., 72 of 76 plants surveyed) suggesting predominant clonal reproduction. Moreover genotypic diversity was not higher within or among diploid than triploid populations in either the native or introduced range. Low genetic diversity in diploid populations was also supported by a comparison of within-population quantitative variation for plant size under a common greenhouse environment. Thus, diploids have not been favored during colonization owing to their sexual fertility. However, concurrent studies have shown that NA diploids exhibit a much higher capacity for clonal reproduction, via small vegetative bulbils, than NA triploids, which almost never produce bulbils. The same difference in clonal capacity is not a consistent feature of the native EU populations. Taken together, these results suggest that strong founder effect has set the stage for a major increase in diploid frequency due to the particular, and possibly idiosyncratic, features of the diploid and triploid lineages introduced to North America.

Alismatales↗

PubMed2004

BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect.

OBJECTIVE: The purpose of this study was to determine whether two mutations detected frequently in a population of breast and/or ovarian cancer families originating from the northeastern part of France could be due to a founder effect. METHODS: 83 index cases of families ascertained to have a familial breast and/or ovarian cancer history, were screened for mutations in all coding exons of the BRCA1 gene, using combined DGGE and direct sequencing. For haplotype analysis, six polymorphic markers were used for allelotyping of mutation carriers and non carriers from nine families with 3600del11 mutation and four families with G1710X mutation. RESULTS: Of 83 index cases, 27 (32%) had 14 different BRCA1 mutations, one of which (G1710X), had not been reported in other populations. Two mutations were particularly common: 3600del11 in exon 11 accounted for 37% and the nonsense mutation G1710X in exon 18 for 15% of all mutations. We identified a common haplotype for each mutation suggesting a common founder for each recurrent mutation. No specific phenotype could be assigned to any of the common mutations. CONCLUSIONS: These data demonstrate geographical clustering and suggest a founder effect for particular BRCA1 mutations, which identification will facilitate carrier detection in French families with breast cancer and breast and/or ovarian cancer.

Adult↗

PubMedDate not supplied

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe.

Medium-chain acyl CoA dehydrogenase (MCAD) deficiency is a potentially fatal inherited defect of fatty acid beta-oxidation. Approximately 90% of the disease-causing alleles in diagnosed patients are due to a single base mutation, an A (adenine) to G (guanine) transition at position 985 of MCAD cDNA (G985). In a limited number of cases it was found that this mutation was always associated with a particular haplotype, defined by three intragenic restriction fragment length polymorphisms, indicating a founder effect [Kølvraa et al.; Hum Genet 1991; 87: 425-429]. In addition, recent studies of American patients and their ancestors suggested the existence of a founder from northern Europe [Yokota et al.; Am J Hum Genet 1991; 49: 1280-1291]. In the present study we document (1) that the G985 heterozygous frequency in the Caucasian population of North Carolina in the USA is 1/84, which is 5- to 10-fold higher than in non-Caucasian Americans; (2) that there exists a 100% association of the G985 mutation in 17 families with MCAD-deficient patients to a certain haplotype, defined by the restriction endonucleases BanII, PstI and TaqI; (3) that MCAD deficiency due to the G985 mutation is more frequent in the Netherlands, Ireland, England, Belgium and Denmark than in other western European countries, and (4) that the frequency distribution of G985 mutation carriers is 1/68-1/101 in newborns in the United Kingdom and Denmark, and 1/333 in Italy. These results support the notion of a founder effect in northwestern Europe.

Acyl-CoA Dehydrogenase↗

PubMed1995

Founder-effect speciation theory: failure of experimental corroboration.

The theory of founder-effect speciation proposes that colonization by very few individuals of an empty habitat favors rapid genetic changes and the evolution of a new species. We report here the results obtained in a 10-year-long and large-scale experiment with Drosophila pseudoobscura designed to test the theory. In our experimental protocol, populations are established with variable numbers of very few individuals and allowed to expand greatly for several generations until conditions of severe competition for resources are reached and the population crashes. A few random survivors are then taken to start a new population expansion and thus initiate a new cycle of founding events, population flushes, and crashes. Our results provide no support for the theories proposing that new species are very likely to appear as by-products of founder events.

Animals↗

PubMed1997

Detection of a R173W mutation in the porphobilinogen deaminase gene in the Nova Scotian "foreign Protestant" population with acute intermittent porphyria: a founder effect.

OBJECTIVES: Acute intermittent porphyria (AIP) is caused by mutations in the porphobilinogen deaminase (PBGD) gene that disrupt the function of the enzyme. Many mutations that lead to decreased PBGD activity have been described. An Arg to Trp substitution at codon 173 (CGG-->TGG in exon 10) and designated R173W, which leads to a CRIM-negative phenotype, has been reported in Swedish, Finnish, Scottish, and South African kindreds, and in a Nova Scotian proband with fatal AIP. In this work, we investigated the presence of this mutation in a Nova Scotian patient population presenting with AIP. DESIGN AND METHODS: Single-strand conformation polymorphism analysis and DNA sequencing by TA cloning and Sanger's dideoxy chain termination method, were used to confirm the maternal transmission of this mutation to the proband. The mutation also eliminates an Ncil (also Mspl) endonuclease restriction site, which allows for detection of the mutant allele by polymerase chain reaction amplification and restriction enzyme digestion. RESULTS: The family of the Nova Scotian proband and four other AIP kindreds showed the presence of the same mutation. These five families are descendants of German, Swiss, and French immigrants historically known as the "Foreign Protestants," who were recruited to Nova Scotia in the 1750s. CONCLUSION: In all these families, descent from one couple that settled in Nova Scotia in 1751 has been identified by genealogy research, consistent with a founder effect within this population. This is the first identified mutation in PBGD causing AIP that has been linked to a founder effect in descendants of an immigrant population to North America, and which could be traced to such a distant background, similar to the South African variegate porphyria mutation.

Adult↗

PubMed2025

Combined Evidence Reveals the Origin of a Rapid Range Expansion Despite Retained Genetic Diversity and a Weak Founder Effect.

Many species are currently experiencing range shifts in response to changing environmental conditions with potentially serious genetic consequences. Repeated founder events and strong genetic drift are expected to erode genetic variation at the range front, reducing adaptive potential and slowing or even halting the expansion. However, the severity of these consequences for common and highly mobile species undergoing environment-driven range shifts (c.f. invasions) is less clear. Here, we combined historical observations and contemporary movement data of the common reed warbler (Acrocephalus scirpaceus) with genomic evidence from across its European breeding range to (1) infer the origin and (2) quantify the genetic consequences of a recent and rapid northward range expansion. Although there were no reductions in levels of nucleotide diversity or allelic richness, nor a signal of founder effect in the directionality index (ψ), our combined dataset approach was able to infer an expansion origin from the southwest. Furthermore, we found that private allelic richness retained a slight but significant linear decline along the colonisation route. These results suggest that high dispersal capabilities can allow even philopatric species to avoid the loss of genetic diversity during rapid range expansions. Nevertheless, if multiple lines of evidence enable identification of an expansion pathway, we may still detect genetic signals of expansion.

Founder Effect↗

PubMed1993

Founder effect in a Belgian-Dutch fragile X population.

For many years, the high prevalence of the fragile X syndrome was thought to be caused by a high mutation frequency. The recent isolation of the FMR1 gene and identification of the most prevalent mutation enable a more precise study of the fragile X mutation. As the vast majority of fragile X patients show amplification of an unstable trinucleotide repeat, DNA studies can now trace back the origin of the fragile X mutation. To date, de novo mutations leading to amplification of the CGG repeat have not yet been detected. Recently, linkage disequilibrium was found in the Australian and US populations between the fragile X mutation and adjacent polymorphic markers, suggesting a founder effect of the fragile X mutation. We present here a molecular study of Belgian and Dutch fragile X families. No de novo mutations could be found in 54 of these families. Moreover, we found significant (P < 0.0001) linkage disequilibrium in 68 unrelated fragile X patients between the fragile X mutation and an adjacent polymorphic microsatellite at DXS548. This suggests that a founder effect of the fragile X mutation also exists in the Belgian and Dutch populations. Both the absence of new mutations and the presence of linkage disequilibrium suggest that a few ancestral mutations are responsible for most of the patients with fragile X syndrome.

Alleles↗

PubMed1996

High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population.

A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5-10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299-->Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype, suggesting that the observed high prevalence of the Gly299-->Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.

Adult↗

PubMed2005

Island colonization and founder effects: the invasion of the Guadeloupe islands by ship rats (Rattus rattus).

The stepwise colonization of islands within an archipelago is typically punctuated by successive founder effects, with each newly founded population being a subsample of the gene pool of the source island. Thus, the genetic signature of successive bottlenecks should be detected when analysing the genetic structure between islands of an archipelago. To test this prediction, we investigated introduced ship rat populations, Rattus rattus (Linnaeus, 1758), in the Guadeloupe Archipelago. Three different methods, commonly named the heterozygosity excess, the mode-shift indicator and the M ratio method, were used to detect bottlenecks from genetic data obtained with eight microsatellite markers on Guadeloupe and two neighbouring islands, Petite-Terre and Fajou. Moreover, a recent eradication failure on Fajou allowed us to test the accuracy of the methods in an 'experimental-like' situation. The results indicate that rats were introduced on Guadeloupe first, which then became the source population for independent secondary colonization of Fajou and Petite-Terre. Moreover, the heterozygosity excess and the mode-shift indicator only detected bottlenecks for the recent colonization of Petite-Terre and the eradication failure on Fajou. However, bottlenecks were detected for all the populations using the M ratio method. This could be interpreted as the remaining signature of the early introduction of the ship rat in the archipelago.

Alleles↗

PubMed1995

Geographic and ethnic distributions of the more frequent cystic fibrosis mutations in Europe show that a founder effect is apparent for several mutant alleles.

Examination of the European geographic patterns of the 10 relatively most frequent cystic fibrosis mutations, other than the DF508 one, shows that a founder effect is apparent for a number of them. The most evident examples are for the W1282X mutation in Jews, with a probable Asian origin, and the G551D and R117H mutations in Celts. Geographic distributions indicate that the main focus of the 621 + 1 G-->T and DI507 mutations is probably located in Wales. Also, the R1162X mutation probably originates from a circumscribed north Italian region. The N1303K mutation has a wide range in Europe with a clear preponderance in southern countries. Even the relatively common G542X and 1717.1 G-->A mutations have a local preponderance in Spain and Sicily and in northern Italy, respectively. Likelihood estimates for recurrent mutation and identity by descent strongly support the hypothesis of recurrence for the (mainly German) mutation R553X.

Cystic Fibrosis↗

PubMed1995

[Prevalence and founder effect of Huntington's disease in the San-in area of Japan].

After the DNA diagnosis, we evaluated the prevalence of Huntington's disease (HD) in the San-in area of Japan, and confirmed the founder effect. The population of the area was 1,387,000 on October 1st, 1993. There were 10 patients with HD in the San-in area, who were diagnosed clinically. They all had involuntary movement, mental disturbance, changes of character and atrophy of the caudate nucleus. However, one of the patients showed no positive family history of HD. The other nine patients had members with HD in their families, although those family members of the patients had already died. The expansion of the CAG repeat was observed in nine of the patients. In the patient who had no positive family history, expansion of the CAG repeat was not seen. According to the nine patients with expansion of the CAG repeat, the prevalence was 0.65/100,000. Haplotypes using polymorphism markers of D4S111 and D4 S136 were studied. The haplotypes which were observed in only 2.7% of the normal population were shown in all nine HD patients. Thus, the obvious disequilibrium was seen. These results suggested a common ancestor of these HD patients.

Adult↗