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PubMed2006

Personality traits in Sardinia: testing founder population effects on trait means and variances.

Potential founder population effects on personality trait means and variances were examined in a large, genetically homogeneous sample (N=5,669) from the Ogliastra, an isolated region within Sardinia, Italy. The Italian version of the Revised NEO Personality Inventory showed good psychometric properties: Internal consistency reliabilities ranged from 0.80 to 0.87; the factor structure replicated the American normative structure; and associations with education and gender replicated cross-cultural patterns. The hypothesis that mean trait levels in the Sardinian founder population would differ from mainland Italian values was not supported. Phenotypic variation in this founder population was within the range found in other cultures. However, the hypothesis of restricted phenotypic variation was supported for all five factors and 28 of the 30 facets when a Sardinian subsample matched on age, sex, and education was compared to a mainland Italian sample. The genetic homogeneity effect on the phenotypic expression of complex traits merits further exploration.

Analysis of Variance↗
PubMed2003

A direct experimental test of founder-flush effects on the evolutionary potential for assortative mating.

Founder-flush speciation models propose that population bottlenecks can enhance evolutionary potential for reproductive isolation. To test this prediction, we subjected bottlenecked (three-pair founder-flush) and nonbottlenecked populations of the housefly to 18 generations of selection for assortative mating. After the selection regime, we analysed videotaped courtship bouts in these lines to identify correlated responses to the selection protocol. The realized heritabilities for assortative mating for both the bottlenecked and nonbottlenecked treatments were very low, but still significant. The founder-flush populations had thus responded to selection as well as the nonbottlenecked populations, although not significantly greater (i.e. total increases in assortative mating were 9.6 and 8.6%, respectively). Multivariate analyses on the courtship repertoires found that, although both bottlenecked and nonbottlenecked treatments attained similar levels of assortative mating, the treatments exhibited different evolutionary solutions in their correlated responses. Specifically, the bottlenecked lines demonstrated a significantly more diverse set of evolutionary trajectories (i.e. significant shifts along the second principal component for courtship). This suggests that the bottlenecked lines had greater potential for the evolution of novel phenotypes as predicted by founder-induced speciation models. Our results, however, cannot distinguish whether the more variable evolutionary responses resulted from increased heritabilities in courtship components, reduced potential to follow the convergent evolutionary trajectories noted for the nonbottlenecked lines, or some combination of both general processes in determining the resultant multivariate phenotype.

Animals↗
PubMed2004

Population structure of a colony of dog guides.

The objective of this study was to describe changes in genetic diversity in a colony of dog guides since its founding. Two breeds, German Shepherds (GS) and Labrador Retrievers (LR), were evaluated. Data were pedigrees of 4,699 GS and 3,573 LR dogs bred for use as guides by The Seeing Eye, Inc., Morristown, NJ. Rapid increases in average pairwise numerator relationships occurred in both breeds, although the average was approximately one-third higher in the GS population than in the LR population. A similar trend was observed for average inbreeding. The rate of increase in inbreeding has slowed in recent generations. In the current generation, relationship and inbreeding for all animals averaged 25.3 and 26.2% in GS, and 15.5 and 22.0% in LR, respectively. Effective founder numbers initially decreased in GS until Generation 3, and then increased steadily. Effective founder number in LR constantly increased. There was a constant increase in effective founder number in LR. A similar pattern was noted for effective ancestor number as well. Founder genome equivalents were initially higher in GS but decreased over time in both breeds. Generation intervals averaged 23.7 mo in GS and 23.2 mo in LR. Sires had average service lives of 2.7 and 2.2 generations in GS and LR, respectively. Dams had average service lives of 2.1 generations in both breeds. Litter sizes averaged 5.1 and 7.4 pups per litter for GS and LR, respectively. Effective founder and ancestor numbers have slowly increased over time, and heterozygosity as measured by the number of founder genome equivalents in the population has increased. Limitations on the number of matings permitted for sires and service life of dams has led to a plateau for inbreeding and relationships. The importation of germplasm from other working dog colonies is desirable.

Animals↗
PubMed2004

Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa.

BACKGROUND: Lipoid proteinosis (LiP) is a rare autosomal recessive disorder characterized by a hoarse voice, warty skin infiltration and scarring. Mutations within the extracellular matrix protein 1 (ECM1) gene cause LiP. Since the early 1970s it has been recognized that South Africa has one of the largest groups of LiP patients worldwide, suggesting a probable founder effect. As LiP patients present with considerable clinical variability, this group of patients offers a unique opportunity for genotype-phenotype correlation. OBJECTIVES: To assess the clinical features and the molecular basis of LiP in patients from the Namaqualand area of the Northern Cape province of South Africa and to examine molecular evidence for a founder effect. SUBJECTS AND METHODS: The LiP patient cohort consisted of 29 Coloured patients from Namaqualand and a further seven Caucasoid patients from other areas of South Africa. The control group included 100 healthy geographically and ethnically matched individuals from Namaqualand. Samples were collected after informed consent and with ethics committee approval from the University of the Witwatersrand. LiP patients were examined clinically and a structured recording sheet was completed. A brief neurological evaluation was also performed. The LiP founder effect was investigated at the molecular level by ECM1 mutation detection and haplotype analysis. RESULTS: The most consistent clinical signs for a diagnosis of LiP in this group were a hoarse voice and thickened sublingual frenulum leading to restricted tongue movement. Homozygosity for a nonsense mutation in exon 7 of the ECM1 gene, Q276X, was identified in all patients (Coloured and Caucasoid). Despite this genetic homogeneity, considerable clinical variability in skin presentation and psychiatric involvement was observed. Haplotype analysis using markers from a 9.98-Mb region around the ECM1 locus confirmed the founder effect with a founder core haplotype, 19-Q276X-12 (ND1-ECM1-D1S2343), in all but four LiP-associated alleles (n = 58). A LiP carrier rate of 1 in 9 was observed among the 100 Namaqualand controls, predicting a LiP incidence of 1 in 324 in this community. CONCLUSIONS: Although several consistent clinical features in LiP patients homozygous for the Q276X mutation in the ECM1 gene were observed, there remains considerable clinical variability. This suggests the action of genetic and environmental modifiers of disease severity. Strong molecular evidence supports a single founder effect for the high prevalence of LiP in South Africans, both Coloured and Caucasoid.

Adolescent↗
PubMed2005

Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.

BACKGROUND: In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS: The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS: KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

Cohort Studies↗
PubMed1976

An experimental analysis of competitive indeterminacy in Tribolium.

This report reexamines experimentally the problem of competitive indeterminacy in mixed-species populations of the flour beetles, Tribolium confusum and T. castaneum. Indeterminacy takes the form of alternative competitive outcomes: in some replicate cultures one species exterminates the other with a probability, say p, whereas in others, the opposing species wins with a complementary probability, 1-p. The conventional explanation for this is the genetic founder effect hypothesis--an explanation based on genetic stochasticity. The experiment reported here partitioned indeterminacy into founder effect and nonfounder effect components. The results implicate demographic stochasticity, not classical genetic founder effect, as a factor influencing the identity of the winning species.

Animals↗
PubMedDate not supplied

[Human globin genes: what can we learn from their polymorphism?].

Molecular analysis of human alpha and beta globin genes reveals extensive polymorphism at these loci. Worldwide distribution of the sickle cell trait has been well known for some time. However, the molecular basis and distribution of thalassemia have been more recently studied. These are the commonest monogenic disorders. For most of them, beta-thalassemia is due to single nucleotide substitutions, small deletions or insertions. They are very heterogeneous and widely dispersed in the Old World. alpha-thalassemia is mainly due to the deletion of one to four alpha genes. On the whole, their distribution is quite similar to beta-thalassemia. With some exceptions, both distributions coincide with present and past regions of malarious endemicity. On the other hand, when looking at individual mutations, no two regions are identical. The question of whether selection by malaria plays a role on observed allele frequencies is still a challenge. The only well clear instance is the beta S mutations, which causes sickle cell anaemia. The role of malaria is but one among other hypothesis for explaining thalassemia distribution and frequencies. A possible scenario could be the following: one (or a few) mutation happened in a population and spread because of its selective advantage, along with the founder effect and/or genetic drift. Migration, founder effect and genetic drift must be invoked to account for some observations. It is still difficult to say why a mutation is highly frequent in one population and not in another., even at equivalent malarial endemicity. On the other hand, many genes should contribute simultaneously, or in synergy, in the process of fighting against malaria. Fitness of each mutation could depend on its genetic background when the mutation arose. Selection must work on a set of genes. Populations who are living now, and genetically very different, could very well be the result of selection on many genes by many infectious agents.

Anemia, Sickle Cell↗
PubMed2001

Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population.

To date, two major familial breast cancer predisposition genes, BRCA1 and BRCA2, have been identified with hundreds of germ-line mutations, accounting for 5--10% of all breast cancer and 40--60% of all inherited breast cancer. Unexpectedly elevated incidence of breast cancer, especially in the older age classes, was observed in a Western Finnish region representing a relatively homogeneous population. This study was designed to test the hypothesis that there are inherited BRCA1 or BRCA2 mutations, which confer variable and/or age-dependent penetrance on carriers. Expecting a founder effect, we searched for geographical clustering of breast cancer cases and searched for associations between the affected phenotype and shared genomic segments in the BRCA1 and BRCA2 genomic regions. Our haplotype association study did not reveal any founder effects for either BRCA1 or BRCA2. However, there were two mutations prevalent in this geographical area with minor founder effects, BRCA2 T8555G and 999del5. This is one of the few geographically ascertained, population-based studies that indicate an overall frequency of BRCA1 and BRCA2 mutations at about 2--3% in all breast cancer cases. The geographical clustering of breast cancer cases was not explained by BRCA1 or BRCA2 genes.

Age of Onset↗
PubMed2000

Recurrent germline mutation in MSH2 arises frequently de novo.

INTRODUCTION: An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. METHODS: We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. RESULTS: Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. DISCUSSION: As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

The evolutionary history of Drosophila buzzatii. XXXVI. Molecular structural analysis of Osvaldo retrotransposon insertions in colonizing populations unveils drift effects in founder events.

Previous work on transposable element distribution in colonizing populations of Drosophila buzzatii revealed a high frequency of occupancy in several chromosomal sites. Two explanatory hypotheses were advanced: the founder hypothesis, by which founder genetic drift was responsible, and the unstable hypothesis that assigns this unusual distribution to bursts of transposition toward some chromosomal sites. Here, we study the molecular structure of three euchromatic Osvaldo clones isolated from sites occupied at high (A4 and B9) and low frequency (B4) in colonizing populations, to test these hypotheses. Large insertions, duplications, and indels in the Osvaldo coding region and LTR were detected in the A4 clone and a truncated Osvaldo with many substitutions was found in the B9 clone. These altered sequences indicate that the two copies of this retroelement are precolonization insertions. Interestingly, the LTR of the A4 clone and the reverse transcriptase region of B9 show identical sequences in all colonizing populations indicating, most probably, that they are identical by descent. Moreover, Osvaldo is inserted at the same nucleotide site in all colonizing populations. On the other hand an almost identical LTR sequence, except by 1 base deletion, was found in the B4 clone compared to the canonical active Osvaldo element. These results suggest that Osvaldo copies in highly occupied sites are, most probably, identical by descent and strongly favor the founder hypothesis. On the other hand, low-insertion-frequency sites could represent recent transposition events. This work emphasizes the importance of molecular population studies to disentangle the effects of genetic drift and transposition in colonization.

Animals↗
PubMed2001

Evolution of genetic variability in a population of the edible snail, Helix aspersa Müller, undergoing domestication and short-term selection.

The evolution of genetic variability is studied in six successive generations of a population originating from wild Helix aspersa. During the first three generations (G1 to G3), no artificial selection was applied. During the next three generations (G4 to G6), two lines were reared: a control line (C) and a line (S) selected for increased adult weight. Genetic variability is described by genealogical parameters (inbreeding, number of founders, effective number of founders and ancestors, effective number of remaining genomes) and by the additive genetic variance in adult weight. A large decrease in all parameters was observed between G1 and G2, suggesting strong natural selection: additive genetic variance in adult weight (transformed data) decreased from 0.0119 +/- 3.8 x 10(-3) to 0.0070 +/- 1.7 x 10(-3) (P < 0.05) and effective number of ancestors from 97.4 to 67.0. Selection also caused a large decrease during the first generation: additive genetic variance was 0.0079 +/- 2.1 x 10(-3) in G3 and 0.0040 +/- 1.1 x 10(-3) after the first selection cycle (P < 0.02). At the same time, the effective number of ancestors decreased from 59.2 to 29.5 and 24.2. This decrease is consistent with the theory of selection and the Bulmer effect.

Animals↗
PubMed2005

Inbreeding in Danish dairy cattle breeds.

The purpose of this study was to monitor current and predict future rates of inbreeding in the Danish dairy breeds. Calves born from 1999 until 2003 and registered as Danish Holstein (1,883,983), Danish Jersey (336,966), or Danish Red (261,047) were reference populations. Average complete generation equivalent was approximately 7. For calves born in 2003, average inbreeding was 3.9, 3.4, and 1.4% for Holstein, Jersey, and Danish Red, respectively. In recent years, effective population sizes were 49, 53, and 47, respectively. Based on coancestry statistics, future effective population sizes will be 43, 42, and 51, respectively. The effective number of founders, effective number of ancestors, and effective number of founder genomes were calculated. These measures of genetic diversity were all low for Holstein and Jersey and somewhat larger for Danish Red. The most important ancestors of Danish Holstein were Elevation (13.8%), Chief (10.9%), and Bell (8.5%). The most important ancestor of Danish Red was Momentum (9.4%), a Red Holstein-Friesian. The most important ancestor for Danish Jersey was FYN Lemvig (12.1%) with a large number of progeny in the reference population. The results of this study indicate the necessity for active management of the rate of inbreeding in the future.

Animals↗
PubMed1996

Small mammal differentiation on islands.

The reason for the distinctiveness of small mammals on islands has traditionally attracted some imaginative story-telling, usually invoking isolation (as a relict) followed by adaptation and/or random genetic changes. Studies of voles on Orkney, long-tailed field mice on the Hebrides and Shetland, and house mice on the Faroe archipelago show that the main factor in differentiating island races from their mainland ancestors is the chance genetic composition of the founding animals. Subsequent change has necessarily to be based on the genes and frequencies carried by this colonizing group. Probably most post-colonization change is adaptive, although possibly limited in extent both by the initial paucity of variation and by the conservative effect of intragenomic interactions. It is probably helpful to recognize that the 'founder effect' or principle commonly invoked in discussions about evolution on islands involves a founder 'event', followed by founder 'selection'. Island differentiation is not necessarily a precursor to speciation, although the wide occurrence of island endemics suggests that founder effects should not be rejected as a driving force initiating speciation. Notwithstanding, island forms provide a valuable 'laboratory' for testing new genetic combinations, a small proportion of which may prove evolutionarily exciting. Only more empirical studies will uncover their evolutionary importance.

Animals↗
PubMed2004

[Clinical and biochemical characteristics of familial ligand-defective apo B-100 in a South European population].

BACKGROUND AND OBJECTIVE: To compare the lipoprotein phenotype between FDB and heterozygous familial hypercholesterolemia (FH); to study the prevalence and possible founder effect of familial ligand-defective apo B100 (FDB) in a Mediterranean population, and to analyze the clinical and biochemical characteristics of FDB patients. SUBJECTS AND METHOD: We studied 19 heterozygous FDB subjects (8 males) from 12 related families, carriers of the R3500Q mutation on the apo B gene, and 57 heterozygous FH (24 males) genetically characterized, randomly selected from a total of 213 FH. The genetic diagnosis was established with Southern blot analysis, PCR-SSCP analysis and automatic sequencing. In all subjects, plasma lipids and apolipoprotein levels were determined with standard procedures. RESULTS: We demonstrated a founder effect for the R3500Q mutation in a geographically isolated rural area from our community. The prevalence of FDB in this area is high: 4/350. Heterozygous FDB subjects showed a statistical significantly lower prevalence of xanthomas and coronary heart disease, plasma concentrations of total and LDL cholesterol, HDL cholesterol, apo B and apo A-I values than heterozygous FH subjects. CONCLUSIONS: A founder effect for the R3500Q mutation was found in a rural population with a high prevalence of FDB. In our population, FDB patients showed a mild clinical expression and lipoprotein phenotype compared with FH patients.

Adult↗
PubMed1998

Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait.

Congenital chloride diarrhea (CLD) is an inherited intestinal disorder caused by mutations in the down-regulated in adenoma gene. In Finland, the disease is prevalent because of a founder effect, and all but one of the CLD-associated chromosomes carry the same mutation, V317del. In Poland, another area with a high incidence of CLD, as many as seven different mutations have been detected so far. A third known cluster of CLD, around the Persian Gulf, has not been genetically studied. We studied the allelic diversity of CLD in Poland, in Saudi Arabia and Kuwait, and in three isolated families from North America and Hong Kong. Altogether, eight novel mutations were identified, making a total of 19 known CLD gene mutations. The Polish major mutation I675-676ins was found in 47% of the Polish CLD-associated chromosomes. Haplotype analysis and clustering of the I675-676ins mutation supported a founder effect and common ancestral origin. As in Finland, a major founder effect was observed in Arab patients: 94% of the CLD-associated chromosomes carried a nonsense mutation, G187X, which occurred in either a conserved ancestral haplotype or its derivative. Our data confirm that the same locus is mutated in all cases of CLD studied so far. In Poland, a relatively common founder mutation is likely to highlight a set of rare mutations that would very rarely produce homozygosity alone. This suggests that mutations in the CLD locus are not rare events. Although the disease is thought to be rare, undiagnosed patients may not be uncommon.

Chlorides↗
PubMed1987

Familial hypercholesterolemia in South African Afrikaners. PvuII and StuI DNA polymorphisms in the LDL-receptor gene consistent with a predominating founder gene effect.

Familial hypercholesterolemia (FH), at a prevalence of more than 1 in 100, is at least five times more common in one South African population group than in populations in North America and Europe. Fourteen homozygotic familial hypercholesterolemic subjects from this South African group were genotyped for two intragenic DNA restriction fragment length polymorphisms (RFLPs) in the LDL-receptor gene. A StuI polymorphism is located in exon 8, and a PvuII polymorphism, in intron 15. Of ten unrelated FH homozygotes genotyped for both RFLPs, nine were homozygous for an S + P- haplotype, and one was heterozygous for an S + P-/S-P + haplotype. The remaining four were genotyped for PvuII only and were homozygous for P-. Compared with a previously determined population frequency for the latter, this represents an association (P less than 0.05) between the frequency for the P- allele and FH in this population, and this finding is consistent with the "founder gene effect" previously postulated to be present on genealogical and biochemical evidence.

DNA Restriction Enzymes↗
PubMed1999

[Population genetic study of Huntington's disease--prevalence and founder's effect in the San-in area, western Japan].

In order to confirm the prevalence rate of Huntington's disease (HD) in San-in area, the epidemiological study was performed in 1997. Ten patients were found, so that the prevalence rate of HD was 0.72 per 100,000 population. D4S136 and CCG polymorphism were investigated in HD patients in western Japan, Chugoku Districts, including the San-in area. The frequency of D4S136A3(242bp) type was higher in HD group of San-in area than Chugoku District (each 38.5% and 9.1%). Twelve of 13 HD chromosomes in the San-in area had the (CCG)7 polymorphism, while only 36.4% of HD chromosomes of Chugoku District had the (CCG)7 polymorphism. Although the HD patients in the San-in area may have a common ancestor except for only one patient, the HD patients in other areas of Japan may have the different HD ancestor from the San-in area.

Founder Effect↗
PubMed2001

Random amplified polymorphic DNA diversity of marginal and central populations in Pinus contorta subsp. latifolia.

Fifteen populations of lodgepole pine (Pinus contorta subsp. latifolia) were surveyed for diversity across 52 random amplified polymorphic DNAs (RAPDs). The objective was to compare single-locus and multilocus structures in four marginal, three intermediate, and eight central populations. Single-locus estimates indicated average observed and expected heterozygosity to be 0.19 and 0.17, respectively. When these estimates were split into population categories, a clear trend of increasing diversity was detected in the direction of marginal to central populations. F-statistics indicated an excess of heterozygotes, with F(IS) ranging from -0.08 for marginal populations to -0.15 for central populations and averaging -0.12 over 15 populations. The estimates of F(ST) decreased towards the margins of the species range, indicating increased population differentiation. Forty-nine of 52 RAPDs tested neutral in the Ewens-Watterson analysis. Multilocus analysis showed significant two-locus and high-order gametic disequilibria in all 15 populations. The most prominent components of the two-locus analysis were the variance of disequilibrium (VD, 46.2%) and the multilocus Wahlund effect (31.9%). This high value for VD indicated that founder effects could explain much of the observed multilocus associations. When analyzed by population categories, the VD showed a decreasing trend indicating that variation due to founder effects was more prominent in marginal populations. The two-locus Wahlund effect (WC) that is characteristic of strong population subdivision was highest in the central populations. This indicated significant levels of gene flow between populations with different allelic combinations.

DNA Primers↗