Founder Haplotype Research Articles

Lrrk2-associated parkinsonism is a major cause of disease in Northern Spain

Herein we describe a comparative clinical and genetic study of Lrrk2-associated parkinsonism in Northern Spain. In our sample from the Basque region, Lrrk2 R1441G and G2019S account for 15 out of 50 kindreds (30%) with familial Parkinson's disease. We observe common founder haplotypes for both R1441G and G2019S carriers. Our findings highlight the importance of Lrrk2 parkinsonism in this population and may have important consequences for its extended Diaspora in North, Central and South Americas.

A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy

The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle.

A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson's disease

The Leucine-rich repeat kinase 2 ( LRRK2) gene has been identified as a disease susceptibility gene for Parkinson's disease (PD), with G2019 (6055G>A) being the most frequent mutation. This mutation was present in 42% (38/91) of Tunisian families and 2% (1/39) of US families we have studied. A founding haplotype was identified in our data and it is shared by families from Tunisia, US, European and Middle Eastern countries. The most recent common founder of the mutation was dated to 2600 (95% CI: 1950–3850) years ago although additional studies are warranted to ensure an accurate age estimate for this mutation.

Prevalence and clinical features of common LRRK2 mutations in Australians with Parkinson's Disease

We determined the prevalence of two common leucine-rich repeat kinase 2 (LRRK2) gene mutations in Australian patients with Parkinson's disease (PD). Of 830 affected patients, eight were heterozygous for the G2019S mutation, and two were heterozygous for the R1441H (4,322 G > A) mutation. In addition, one familial patient had a novel A1442P (4,324 G > C) mutation. Haplotype analysis showed that all LRRK2 G2019S-positive individuals carried the common founder haplotype 1 and a putative founder haplotype for the R1441H mutation carriers. Clinically, patients with LRRK2 mutations had typical levodopa responsive Parkinsonism with tremor being the commonest presenting feature. Patients with the G2019S mutation in our series had a similar age of onset of symptoms when compared with patients with other LRRK2 mutations or sporadic PD, although they were more likely to have a family history of PD (2.4% of Australian patients with familial PD and 0.3% of Australian patients with sporadic PD). Our results demonstrate that the G2019S mutation carriers share the same ancestors who migrated to Australia originally from Europe and that other LRRK2 mutations (R1441H and A1442P) can be found in this population.

Estimating a founder’s genomic proportion for each descendant in an outbred pedigree

The question of how to estimate a founder's proportion of a single descendant's genome has renewed relevance for outbred pedigrees, given the abundant DNA sequence data for model and nonmodel eukaryotes alike. Here we show that a donor-recurrent shortcut method can provide a robust estimation of founder proportions. In addition, we define the theoretical variance and estimate confidence intervals using a nonparameteric bootstrap method. Using actual marker data from a highly heterozygous outbred Pinus taeda pedigree, it was found that each founder's genomic proportion varied widely for each descendant, ranging from 8.8% to 38.7%. In 1 case, skewed transmission of a founder's genome could be statistically detected. Its founder proportions ranged from 1.54% to 48.46%, and its mean value was 17.59%, well below the expected value of 25%. Two-thirds of its 91 descendants had 1 or the other founder haplotype, despite 2 successive meioses. The donor-recurrent method was robust; variation for estimated founder's proportions was also wide for simulated high-density datasets whether markers were dispersed or clustered. Estimating founder contributions using this computational shortcut has broad application for highly heterozygous outbred pedigrees characterized by large sibships, low population differentiation, and shallow physical mapping resources. The relevance of this computational shortcut for outbred populations used for conservation, domestication, and evolutionary biology research is discussed.

Genetics of Recurrent Early-Onset Major Depression (GenRED): Significant Linkage on Chromosome 15q25-q26 After Fine Mapping With Single Nucleotide Polymorphism Markers

The authors studied a dense map of single nucleotide polymorphism (SNP) DNA markers on chromosome 15q25-q26 to maximize the informativeness of genetic linkage analyses in a region where they previously reported suggestive evidence for linkage of recurrent early-onset major depressive disorder. In 631 European-ancestry families with multiple cases of recurrent early-onset major depressive disorder, 88 SNPs were genotyped, and multipoint allele-sharing linkage analyses were carried out. Marker-marker linkage disequilibrium was minimized, and a simulation study with founder haplotypes from these families suggested that linkage scores were not inflated by linkage disequilibrium. The dense SNP map increased the information content of the analysis from around 0.7 to over 0.9. The maximum evidence for linkage was the Z likelihood ratio score statistic of Kong and Cox (Z(LR))=4.69 at 109.8 cM. The exact p value was below the genomewide significance threshold. By contrast, in the genome scan with microsatellite markers at 9 cM spacing, the maximum Z(LR) for European-ancestry families was 3.43 (106.53 cM). It was estimated that the linked locus or loci in this region might account for a 20% or less populationwide increase in risk to siblings of cases. This region has produced modestly positive evidence for linkage to depression and related traits in other studies. These results suggest that DNA sequence variations in one or more genes in the 15q25-q26 region can increase susceptibility to major depression and that efforts are warranted to identify these genes.

Genetic analysis of early holocene skeletal remains from Alaska and its implications for the settlement of the Americas

Mitochondrial and Y-chromosome DNA were analyzed from 10,300-year-old human remains excavated from On Your Knees Cave on Prince of Wales Island, Alaska (Site 49-PET-408). This individual's mitochondrial DNA (mtDNA) represents the founder haplotype of an additional subhaplogroup of haplogroup D that was brought to the Americas, demonstrating that widely held assumptions about the genetic composition of the earliest Americans are incorrect. The amount of diversity that has accumulated in the subhaplogroup over the past 10,300 years suggests that previous calibrations of the mtDNA clock may have underestimated the rate of molecular evolution. If substantiated, the dates of events based on these previous estimates are too old, which may explain the discordance between inferences based on genetic and archaeological evidence regarding the timing of the settlement of the Americas. In addition, this individual's Y-chromosome belongs to haplogroup Q-M3*, placing a minimum date of 10,300 years ago for the emergence of this haplogroup.

Reduced genetic structure of north Ethiopian cattle revealed by Y-chromosome analysis

Ethiopia is considered to be a putative migratory corridor for both Near-East Bos taurine and Arabian and Indian B. indicus cattle into East Africa. African pastoralism, which is associated with adaptation to specific habitats and farming systems, has contributed to the composite constitution of Ethiopian cattle. We analyse, for the first time, five Y-chromosome microsatellite markers from seven north Ethiopian cattle populations, using a European Holstein-Friesian population as a reference, to assess the paternal gene pool and to explore the mechanisms behind the genetic structure. Our results reveal that the indicine alleles predominate in the present populations, with only one animal in the Arado carrying the taurine alleles. The north Ethiopian cattle populations with one exception (Abergelle) are characterized by a general low Y-chromosome haplotype diversity, as well as by a reduced interpopulation variance (Phi(ST)=4.0%), which can be a result of strong male-mediated selective sweeps. Population structure revealed by multidimensional-scaling analysis differentiates two populations (Arado and Abergelle) from the rest. Analysis of molecular variance does not lend support to the traditional classification for the populations, which is mainly based on physical characteristics. A network analysis indicates two closely related founding haplotypes accounting for a large proportion (50.0% in Abergelle and 85.0-94.7% in others) of north Ethiopian cattle Y-chromosomes. Our findings point to a common, but limited, paternal origin of the north Ethiopian cattle populations and strong male-mediated gene flow among them. The findings also provide insight into the historical immigration of cattle into East Africa.

Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy.

We describe the search for mutations in six unrelated Czech and four unrelated British families with posterior polymorphous corneal dystrophy (PPCD); a relatively rare eye disorder. Coding exons and intron/exon boundaries of all three genes (VSX1, COL8A2, and ZEB1/TCF8) previously reported to be implicated in the pathogenesis of this disorder were screened by DNA sequencing. Four novel pathogenic mutations were identified in four families; two deletions, one nonsense, and one duplication within exon 7 in the ZEB1 gene located at 10p11.2. We also genotyped the Czech patients to test for a founder haplotype and lack of disease segregation with the 20p11.2 locus we previously described. Although a systematic clinical examination was not performed, our investigation does not support an association between ZEB1 changes and self reported non-ocular anomalies. In the remaining six families no disease causing mutations were identified thereby indicating that as yet unidentified gene(s) are likely to be responsible for PPCD.

LRRK2 G2019S founder haplotype in the Chinese population

The G2019S mutation in the LRRK2 (leucine-rich repeat kinase) gene appears very rarely in the Chinese population. Among Chinese subjects who were non-G2019S carriers, we demonstrated the frequency of the LRRK2 G2019S founder haplotype (T-254-A-G-A-154) in Parkinson's disease and controls to be 33% and 30%. This rate is similar to the frequency in European noncarriers, indirectly supporting the association of this haplotype with G2019S carriers. The haplotype is likely to be more ancient than the G2019S mutation because it is also found in a population with a very low carrier rate.

Myocilin Gly252Arg Mutation and Glaucoma of Intermediate Severity in Caucasian Individuals

To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation. All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene. Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean +/- SD age at diagnosis was 46.3 +/- 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean +/- SD, 32.4 +/- 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 individuals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian individuals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant. Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation-carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation. Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.

A founder haplotype for autosomal dominant sensory ataxia in Eastern Canada

We present phenotypic and genotypic data for an additional family with autosomal dominant sensory ataxia, a disease characterized by gait difficulties associated with diminished sensation in the limbs and areflexia. The same disease haplotype spanning the entire SNAX1 locus is observed in affected members of this second family, enabling the locus to be reduced to a 7.3-cM interval.

Characterization of a Susceptibility Locus for SLE, SLEB5, on Chromosome 4p14‐13

Systemic lupus erythematosus is a systemic autoimmune disorder of unknown aetiology but is most likely caused by an interaction between several genetic factors and the environment. In a previously published genome scan we presented linkage to a marker on chromosome 4p13 in Icelandic families. Fine mapping of the region has been performed using 10 multicase families from Iceland and the maximum two-point LOD score was given by marker D4S2974 (Z = 3.57, alpha = 1). Multipoint analyses of the markers in the region suggest a putative disease gene to be located between markers D4S405 and D4S2381. The maximum multipoint LOD score (Z = 3.76) was given for marker D4S2974 in combination with the novel repeat GT4C2. A family-specific haplotype was segregating with the disease in each of eight families although a founder haplotype could not be identified. Analysis of recombination events in the patients delimited the susceptibility locus to approximately 3 cM. The susceptibility locus identified probably contains a mutation that has been enriched in the Icelandic population but is less common in other populations. We also show that this region is not identical to a susceptibility locus for SLE located on 4p16 where we detect no linkage.

Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia

Cartilage-hair hypoplasia (CHH), or metaphyseal dysplasia, McKusick type, is an autosomal recessive disease with diverse clinical manifestations. CHH is caused by mutations in RMRP (ribonuclease mitochondrial RNA processing), the gene encoding the RNA component of the ribonucleoprotein complex RNase MRP. A common founder mutation, 70A>G has been reported in the Finnish and Amish populations. We screened 11 Japanese patients with CHH for RMRP mutations and identified mutations in five probands, including three novel mutations (16-bp dup at +1, 168G>A, and 217C>T). All patients were compound heterozygotes for an insertion or duplication in the promoter or 5'-transcribed regions and a point mutation in the transcribed region. Two recurrent mutations were unique to the Japanese population: a 17-bp duplication at +3 and 218A>G. Haplotype analysis revealed that the two mutations common in Japanese individuals were contained within distinct haplotypes. Through this analysis, we have identified a unique mutation spectrum and founder mutations in the Japanese population.

Modeling the effect of inbreeding among founders in linkage analysis

In this paper, we present a unified mathematical model for linkage analysis that allows for inbreeding among founders in all families. The identical by descent (IBD) configuration of each pedigree is modeled as a Markov process containing two parameters; the inverse inbreeding and kinship coefficient and a rate parameter proportional to the inverse expected length of chromosome segments shared IBD by two different founder haplotypes. We use hidden Markov models and define a forward–backward algorithm for computing the conditional IBD-distribution given marker data, thereby extending the multipoint method of Lander and Green [1987. Construction of multilocus genetic maps in humans, Proc. Natl. Acad. Sci. USA 84, 2363–2367] to situations where founders are inbred. Our methodology is valid for arbitrary pedigree structures. Simulation and theoretical approximations for nonparametric linkage (NPL) analysis based on affected sib pairs reveal that NPL scores are inflated and type 1 errors increased when the inbreeding coefficient or rate parameter is underestimated. When the parents are genotyped, we present a general way of modifying the score function to drastically reduce this effect.

Phylogeography of the mole‐shrew (Anourosorex yamashinai) in Taiwan: implications of interglacial refugia in a high‐elevation small mammal

To test the Pleistocene interglacial refugia hypothesis with a high-elevation mammal, we studied the phylogeography of the mole-shrew (Anourosorex yamashinai) using partial mitochondrial cytochrome b gene sequences (737 bases). This shrew is endemic to Taiwan. It is mainly distributed in the highlands from 1000 to 2500 m in elevation. We examined 103 specimens from 24 localities in three mountain ranges of Taiwan and found 36 haplotypes. These haplotypes separated into two major phylogroups (Northern and Southern) plus a minor phylogroup (Houhuan) of only one haplotype. This demonstrated strong association with geography. The formation of these three phylogroups may be the result of interglacial refugia during the middle Pleistocene. Distinct sublineages were not found within each major phylogroup, suggesting that the populations (phylogroups) explosively expanded from the interglacial refugia of ancestral founder haplotypes. The present distribution pattern of haplotypes suggests that Mount Houhuan is an effective refugium in central Taiwan. It was not possible to specify the refugia for the Northern and Southern phylogroups.

The mildest known case of Fukuyama-type congenital muscular dystrophy

We present a 14-year-old boy with Fukuyama-type congenital muscular dystrophy (FCMD) who shows the mildest muscle weakness ever reported with this affliction and exceptionally mild mental retardation, but who has intractable epilepsy. Magnetic resonance imaging showed the typical abnormalities of FCMD. Molecular genetic analyses revealed a 3 kb insertion mutation in the fukutin gene heterozygously. We could find no mutation in the coding region of the fukutin gene in the chromosome without a 3 kb insertion. The most probable mechanism of clinical manifestation in this patient could be either a mutation in the noncoding regions of the fukutin gene on the chromosome without the ancestral founder haplotype of FCMD, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of α-dystroglycan, such as Fukutin-related protein and LARGE genes.

Origin, genetic diversity, and population structure of Chinese domestic sheep

To characterize the origin, genetic diversity, and phylogeographic structure of Chinese domestic sheep, we here analyzed a 531-bp fragment of mtDNA control region of 449 Chinese autochthonous sheep from 19 breeds/populations from 13 geographic regions, together with previously reported 44 sequences from Chinese indigenous sheep. Phylogenetic analysis showed that all three previously defined lineages A, B, and C were found in all sampled Chinese sheep populations, except for the absence of lineage C in four populations. Network profiles revealed that the lineages B and C displayed a star-like phylogeny with the founder haplotype in the centre, and that two star-like subclades with two founder haplotypes were identified in lineage A. The pattern of genetic variation in lineage A, together with the divergence time between the two central founder haplotypes suggested that two independent domestication events have occurred in sheep lineage A. Considerable mitochondrial diversity was observed in Chinese sheep. Weak structuring was observed either among Chinese indigenous sheep populations or between Asian and European sheep and this can be attributable to long-term strong gene flow induced by historical human movements. The high levels of intra-population diversity in Chinese sheep and the weak phylogeographic structuring indicated three geographically independent domestication events have occurred and the domestication place was not only confined to the Near East, but also occurred in other regions.

The frequent BRCA1 mutation 1135insA has multiple origins: a haplotype study in different populations

BackgroundAnalysis of the chromosomal background upon which a mutation occurs can be used to reconstruct the origins of specific disease-causing mutations. The relatively common BRCA1 mutation, 1135insA, has been previously identified as a Norwegian founder mutation. We performed haplotype analysis of individuals from breast and ovarian cancer families from four different ethnic backgrounds who had been identified as carriers of the BRCA1: 1135insA mutation.MethodsFour microsatellite markers (D17S855, D17S1322, D17S1323 and D17S1325) located within or near the BRCA1 gene were genotyped in mutation carriers from 6 families of French Canadian, Italian and Dutch descent. Haplotypes were inferred from the genotype data and compared between these families and with the previously reported Norwegian founder haplotype.ResultsThe 1135insA mutation was found to occur on three distinct haplotype backgrounds. The families from Norway shared a distinct haplotype while the families of French Canadian, Italian, and Dutch descent were found to occur on one of two additional, distinct backgrounds.ConclusionOur results indicate that while the Norwegian haplotype including 1135insA represents an ancient Norwegian mutation, the same mutation has occurred independently in the other populations examined. In centres where targeted mutation testing is performed, exclusively or prior to gene sequencing, our findings suggest that this recurring mutation should be included in targeted mutation panels, irrespective of the ethnic origin of the persons tested.

A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD

Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 [maximum summed log of the odds (LOD) score of 5.28 at D17S931]. Interestingly, the same DR2-DR8 ancestral haplotype was observed in five additional familial FTLD patients, indicative of a founder effect. In the FTLD series, the DR2-DR8 ancestral haplotype explained 7% (7 out of 98) of FTLD and 17% (7 out of 42) of familial FTLD and was seven times more frequent than MAPT mutations (1 out of 98 or 1%). Clinically, DR2-DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in one carrier the neuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, these results strongly suggest that the DR2-DR8 founder haplotype at 17q21 harbours a tau-negative FTLD causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations.