Legacy of mutiny on the Bounty : founder effect and admixture on Norfolk Island

The population of Norfolk Island, located off the eastern coast of Australia, possesses an unusual and fascinating history. Most present-day islanders are related to a small number of the 'Bounty' mutineer founders. These founders consisted of Caucasian males and Polynesian females and led to an admixed present-day population. By examining a single large pedigree of 5742 individuals, spanning >200 years, we analyzed the influence of admixture and founder effect on various cardiovascular disease (CVD)-related traits. On account of the relative isolation of the population, on average one-third of the genomes of present-day islanders (single large pedigree individuals) is derived from 17 initial founders. The proportion of Polynesian ancestry in the present-day individuals was found to significantly influence total triglycerides, body mass index, systolic blood pressure and diastolic blood pressure. For various cholesterol traits, the influence of ancestry was less marked but overall the direction of effect for all CVD-related traits was consistent with Polynesian ancestry conferring greater CVD risk. Marker-derived homozygosity was computed and agreed with measures of inbreeding derived from pedigree information. Founder effect (inbreeding and marker-derived homozygosity) significantly influenced height. In conclusion, both founder effect and extreme admixture have substantially influenced the genetic architecture of a variety of CVD-related traits in this population.

A recurrent F8 mutation in Irish haemophilia A patients: evidence for a founder effect.

Haemophilia A is a mutationally heterogeneous disorder with approximately 1,000 unique mutations of the Factor VIII (F8) gene recorded to date [1]. With the exception of the intron 22 inversion mutation, which occurs in ~45% of individuals with clinically severe disease, recurrent mutations causing haemophilia A are rare. This reflects a high rate of spontaneous mutation within the F8 gene generally resulting in private mutations within individual kindreds. We have identified a recurrent F8 gene mutation in Irish haemophilia A patients and have used haplotype analysis to investigate its origins.

Evidence for a residual postglacial founder effect in a highly dispersive freshwater invertebrate

In the northern hemisphere, glacial periods have had profound and lasting effects on the population genetics of numerous species, with founder effects often persisting for many generations in formerly glaciated regions. We found an unusual example of this in the freshwater bryozoan Cristatella mucedo, which showed regional differences in haplotype diversity with relatively low levels of haplotype diversity in northern Europe compared to central/southern Europe despite previous evidence for frequent dispersal between C. mucedo populations. Such contradictions between high dispersal and low gene flow have now been reported in several other freshwater taxa and may be attributed to persistent founder effects following colonization of sites by a few individuals whose efficient reproduction leads to rapid population growth. Alternatively, selection may determine which genotypes can thrive in northerly locations, or it may be that C. mucedo has undergone cryptic speciation. Future work on adaptive genomic regions is required before we can understand how gene flow, local adaptation, and speciation influence the current distribution patterns of bryozoans and other freshwater invertebrates.

Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: Founder effect and premutations

Friedreich’s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for ≈17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through “premutation” intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa

Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12–31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.

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.

GH-Releasing Hormone Receptor Gene: A Novel Splice-Disrupting Mutation and Study of Founder Effects

Background: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). Objective: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. Methods: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c. 1146G>A (p.E382E) mutation. Results: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. Conclusion: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD. Copyright (C) 2012 S. Karger AG, Basel

A Spanish founder mutation in the chloride channel gene, CLCNKB, as a cause of atypical Bartter syndrome in adult age

BACKGROUND: Mutations in the chloride channel gene, CLCNKB, usually cause classic Bartter syndrome (cBS) or a mixed Bartter-Gitelman phenotype in the first years of life. METHODS: We report an adult woman with atypical BS caused by a homozygous missense mutation, A204T, in the CLCNKB gene, which has previously been described as the apparently unique cause of cBS in Spain. RESULTS: The evaluation of this patient revealed an overlap of phenotypic features ranging from severe biochemical and systemic disturbances typical of cBS to scarce symptoms and diagnosis in the adult age typical of Gitelman syndrome. The tubular disease caused a dramatic effect on mental, growth and puberal development leading to low IQ, final short stature and abnormal ovarian function. Furthermore, low serum PTH concentrations with concomitant nephrocalcinosis and normocalcaemia were observed. Both ovarian function and serum PTH levels were normalized after treatment with cyclooxygenase inhibitors. CONCLUSIONS: The present report confirms a weak genotype-phenotype correlation in patients with CLCNKB mutations and supports the founder effect of the A204T mutation in Spain. In our country, the genetic diagnosis of adult patients with hereditary hypokalaemic tubulopathies should include a screening of A204T mutation in the CLCNKB gene.

Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families : evidence for common founders and independent mutations

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5' region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents.

Recent emergence of dengue virus serotype 4 in French Polynesia results from multiple introductions from other south pacific islands

BACKGROUND: Infection by dengue virus (DENV) is a major public health concern in hundreds of tropical and subtropical countries. French Polynesia (FP) regularly experiences epidemics that initiate, or are consecutive to, DENV circulation in other South Pacific Island Countries (SPICs). In January 2009, after a decade of serotype 1 (DENV-1) circulation, the first cases of DENV-4 infection were reported in FP. Two months later a new epidemic emerged, occurring about 20 years after the previous circulation of DENV-4 in FP. In this study, we investigated the epidemiological and molecular characteristics of the introduction, spread and genetic microevolution of DENV-4 in FP. METHODOLOGY/PRINCIPAL FINDINGS: Epidemiological data suggested that recent transmission of DENV-4 in FP started in the Leeward Islands and this serotype quickly displaced DENV-1 throughout FP. Phylogenetic analyses of the nucleotide sequences of the envelope (E) gene of 64 DENV-4 strains collected in FP in the 1980s and in 2009-2010, and some additional strains from other SPICs showed that DENV-4 strains from the SPICs were distributed into genotypes IIa and IIb. Recent FP strains were distributed into two clusters, each comprising viruses from other but distinct SPICs, suggesting that emergence of DENV-4 in FP in 2009 resulted from multiple introductions. Otherwise, we observed that almost all strains collected in the SPICs in the 1980s exhibit an amino acid (aa) substitution V287I within domain I of the E protein, and all recent South Pacific strains exhibit a T365I substitution within domain III. CONCLUSIONS/SIGNIFICANCE: This study confirmed the cyclic re-emergence and displacement of DENV serotypes in FP. Otherwise, our results showed that specific aa substitutions on the E protein were present on all DENV-4 strains circulating in SPICs. These substitutions probably acquired and subsequently conserved could reflect a founder effect to be associated with epidemiological, geographical, eco-biological and social specificities in SPICs.

Variants in the human potassium channel gene (KCNN3) are associated with migraine in a high risk genetic isolate

The calcium-activated potassium ion channel gene (KCNN3) is located in the vicinity of the familial hemiplegic migraine type 2 locus on chromosome 1q21.3. This gene is expressed in the central nervous system and plays a role in neural excitability. Previous association studies have provided some, although not conclusive, evidence for involvement of this gene in migraine susceptibility. To elucidate KCNN3 involvement in migraine, we performed gene-wide SNP genotyping in a high-risk genetic isolate from Norfolk Island, a population descended from a small number of eighteenth century Isle of Man ‘Bounty Mutineer’ and Tahitian founders. Phenotype information was available for 377 individuals who are related through the single, well-defined Norfolk pedigree (96 were affected: 64 MA, 32 MO). A total of 85 SNPs spanning the KCNN3 gene were genotyped in a sub-sample of 285 related individuals (76 affected), all core members of the extensive Norfolk Island ‘Bounty Mutineer’ genealogy. All genotyping was performed using the Illumina BeadArray platform. The analysis was performed using the statistical program SOLAR v4.0.6 assuming an additive model of allelic effect adjusted for the effects of age and sex. Haplotype analysis was undertaken using the program HAPLOVIEW v4.0. A total of four intronic SNPs in the KCNN3 gene displayed significant association (P < 0.05) with migraine. Two SNPs, rs73532286 and rs6426929, separated by approximately 0.1 kb, displayed complete LD (r 2 = 1.00, D′ = 1.00, D′ 95% CI = 0.96–1.00). In all cases, the minor allele led to a decrease in migraine risk (beta coefficient = 0.286–0.315), suggesting that common gene variants confer an increased risk of migraine in the Norfolk pedigree. This effect may be explained by founder effect in this genetic isolate. This study provides evidence for association of variants in the KCNN3 ion channel gene with migraine susceptibility in the Norfolk genetic isolate with the rarer allelic variants conferring a possible protective role. This the first comprehensive analysis of this potential candidate gene in migraine and also the first study that has utilised the unique Norfolk Island large pedigree isolate to implicate a specific migraine gene. Studies of additional variants in KCNN3 in the Norfolk pedigree are now required (e.g. polyglutamine variants) and further analyses in other population data sets are required to clarify the association of the KCNN3 gene and migraine risk in the general outbred population.

Linkage disequilibrium analysis in the genetically isolated Norfolk Island population

Norfolk Island is a human genetic isolate, possessing unique population characteristics that could be utilized for complex disease gene localization. Our intention was to evaluate the extent and strength of linkage disequilibrium (LD) in the Norfolk isolate by investigating markers within Xq13.3 and the NOS2A gene encoding the inducible nitric oxide synthase. A total of six microsatellite markers spanning approximately 11 Mb were assessed on chromosome Xq13.3 in a group of 56 men from Norfolk Island. Additionally, three single nucleotide polymorphisms (SNPs) localizing to the NOS2A gene were analyzed in a subset of the complex Norfolk pedigree. With the exception of two of the marker pairs, one of which is the most distantly spaced marker, all the Xq13.3 marker pairs were found to be in significant LD indicating that LD extends up to 9.5-11.5 Mb in the Norfolk Island population. Also, all SNPs studied showed significant LD in both Norfolk Islanders and Australian Caucasians, with two of the marker pairs in complete LD in the Norfolk population only. The Norfolk Island study population possesses a unique set of characteristics including founder effect, geographical isolation, exhaustive genealogical information and phenotypic data of use to cardiovascular disease risk traits. With LD extending up to 9.5-11 Mb, the Norfolk isolate should be a powerful resource for the localization of complex disease genes.

Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.

Partial epilepsy syndrome in a Gypsy family linked to 5q31.3-q32

PURPOSE The restricted genetic diversity and homogeneous molecular basis of Mendelian disorders in isolated founder populations have rarely been explored in epilepsy research. Our long-term goal is to explore the genetic basis of epilepsies in one such population, the Gypsies. The aim of this report is the clinical and genetic characterization of a Gypsy family with a partial epilepsy syndrome. METHODS Clinical information was collected using semistructured interviews with affected subjects and informants. At least one interictal electroencephalography (EEG) recording was performed for each patient and previous data obtained from records. Neuroimaging included structural magnetic resonance imaging (MRI). Linkage and haplotype analysis was performed using the Illumina IVb Linkage Panel, supplemented with highly informative microsatellites in linked regions and Affymetrix SNP 5.0 array data. RESULTS We observed an early-onset partial epilepsy syndrome with seizure semiology strongly suggestive of temporal lobe epilepsy (TLE), with mild intellectual deficit co-occurring in a large proportion of the patients. Psychiatric morbidity was common in the extended pedigree but did not cosegregate with epilepsy. Linkage analysis definitively excluded previously reported loci, and identified a novel locus on 5q31.3-q32 with an logarithm of the odds (LOD) score of 3 corresponding to the expected maximum in this family. DISCUSSION The syndrome can be classified as familial temporal lobe epilepsy (FTLE) or possibly a new syndrome with mild intellectual deficit. The linked 5q region does not contain any ion channel-encoding genes and is thus likely to contribute new knowledge about epilepsy pathogenesis. Identification of the mutation in this family and in additional patients will define the full phenotypic spectrum.

Cutaneous porphyrias : Clinical and histopathological study

The prevalence of variegate porphyria (VP) (2.1:100 000, in 2006 n=108) was higher in Finland than elsewhere in European countries due to a founder effect (R152C). The incidence of VP was estimated at 0.2:1 000 000 based on the number of new symptomatic patients yearly. The prevalence of porphyria cutanea tarda (PCT) was 1.2:100 000 (in 2006 n=63), which is only one fourth of the numbers reported from other European countries. The estimated incidence of PCT was 0.5:1 000 000. Based on measurements of the uroporphyrinogen decarboxylase activity in erythrocytes, the proportion of familial PCT was 49% of the cases. The prevalence of erythropoietic protoporphyria (EPP) was at 0.8:100 000 (in 2006 n=39) including asymptomatic carriers of a mutation in the ferrochelatase (FECH) gene. The incidence of EPP was estimated at 0.1:1 000 000. After 1980 the penetrance was 37% among patients with VP. Of the mutation carriers (n=57) 30% manifested with skin symptoms. Frequency of skin symptom as only clinical sign was stable before or after 1980 (22% vs. 21%), but acute attacks became infrequent (29% vs. 7%). Of the symptomatic patients 30% had both acute attacks and skin symptoms and 80% had skin symptoms. Fragility (95%) and blistering (46%) of the skin in the backs of the hands were the most common skin symptoms. Transient correction of porphyrin metabolism using eight haem arginate infusions within five weeks had no effect on the skin symptoms in three of four patients with VP. In one case skin symptoms disappeared transiently. One patient with homozygous VP had severe photosensitivity since birth. Sensory polyneuropathy, glaucoma and renal failure developed during the 25-year follow-up without the presence of acute attacks. The I12T mutation was detected in both of his alleles in the protoporphyrinogen oxidase gene. Lack of skin symptoms and infrequency of acute attacks (1/9) in the patients with I12T mutation at the heterozygous stage indicate a mild phenotype (the penetrance 11%). Four mutations (751delGAGAA, 1122delT, C286T, C343T) in the FECH gene were characterised in four of 15 families with EPP. Burning pain (96%) and swelling (92%) of the sun-exposed skin were the major skin symptoms. Hepatopathy appeared in one of 25 symptomatic patients (4%). Clinical manifestations and associated factors of PCT were similar in the sporadic and familial types of PCT. The majority of the patients with PCT had one to three precipitating factors: alcohol intake (78%), mutations in hemochromatosis associated gene (50%), use of oestrogen (25% of women) and hepatitis B or C infections (25 %). Fatty liver disease (67%) and siderosis (67%) were commonly found in their liver biopsies. The major histopathological change of the sun-exposed skin in the patients with VP (n=20), EPP (n=8) and PCT (n=5) was thickening of the vessel walls of the upper dermis suggesting that the vessel wall is the primary site of the phototoxic reaction in each type of porphyria. The fine structure of the vessel walls was similar in VP, EPP and PCT consisting of the multilayered basement membrane and excess of finely granular substance between the layers which were surrounded by the band of homogenous material. EPP was characterised by amorphous perivascular deposits extending also to the extravascular space. In direct immunofluorescence study homogenous IgG deposits in the vessel walls of the upper dermis of the sun-exposed skin were demonstrated in each type of porphyria. In EPP the excess material around vessel walls consisted of other proteins such as serum amyloid protein, and kappa and lambda light chains in addition to the basement membrane constituents such as collagen IV and laminin. These results suggest that the alterations of the vessel walls are a consequence of the repeated damage and the repairing process in the vessel wall. The microscopic alterations could be demonstrated even in the normal looking but sun-exposed skin of the patients with EPP during the symptom-free phase suggesting that vascular change can be chronic. The stability of vascular changes in the patients with PCT after treatment indicates that circulating porphyrins are not important for the maintenance of the changes.