Progressive Myoclonus Epilepsy EPM1 Locus Maps to a 175-kb Interval in Distal 21q

The EPM1 locus responsible for progressive myoclonus epilepsy of Unverricht-Lundborg type (MIM 254800) maps to a region in distal chromosome 21q where positional cloning has been hampered by the lack of physical and genetic mapping resolution. We here report the use of a recently constituted contig of cosmid, BAC, and P1 clones that allowed new polymorphic markers to be positioned. These were typed in 53 unrelated disease families from an isolated Finnish population in which a putative single ancestral EPM1 mutation has segregated for an estimated 100 generations. By thus exploiting historical recombinations in haplotype analysis, EPM1 could be assigned to the ~175-kb interval between the markers D21S2040 and D21S1259.     

Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis.

Hemochromatosis (HC), an inherited disorder of iron metabolism, shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scots/Irish) origin. Australian HC patients thus provide an ideal group in which to examine HC-gene-region haplotypes, to analyze the extent of linkage disequilibrium and genetic heterogeneity in HC. We have analyzed chromosomes from 26 multiply affected HC pedigrees, and we were able to assign HC status unambiguously to 107 chromosomes--64 as affected and 43 as unaffected. The haplotypes examined comprise the following highly polymorphic markers: the serological marker HLA-A and the microsatellites D6S248, D6S265, HLA-F, and D6S105. All show highly significant allelic association with HC and no evidence of separation from the disease locus by recombination. Analysis identified a predominant ancestral haplotype comprising alleles 5-1-3-2-8 (marker order: D6S248-D6S265-HLA-A-HLA-F-D6S105), present in 21 (33%) of 64 affected chromosomes, and exclusively associated with HC (haplotype relative risk 903). No other common haplotype was significantly associated with HC. Haplotype analysis in Australian HC patients thus provides strong evidence for (a) the introduction of HC into this population on an ancestral haplotype, (b) a common mutation associated with HC in Australian patients, and (c) a candidate HC-gene region extending between and including D6S248 and D6S105.     

Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD)

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe muscular dystrophy associated with brain anomalies. After our initial mapping of the FCMD locus to 9q31–33, we performed linkage disequilibrium analysis, which led us to suspect that the FCMD gene lay within a region of less than 100 kb containing D9S2107. In the present study, we developed two new microsatellites (D9S2170 and D9S2171) in close vicinity to D9S2107 and examined haplotypes of FCMD chromosomes by using four markers (cen-D9S2105-D9S2170-D9S2171-D9S2107-tel). As 82% of the FCMD chromosomes that we examined shared the founder haplotype (138–192–147–183) and 94% of the FCMD patients in our panel carried founder haplotypes on one or both chromosomes, the data supported the hypothesis of a single founder of this disease in the Japanese population. Eight haplotypes different from the founder’s were observed in FCMD chromosomes, indicating that eight different FCMD mutations in addition to the founder’s have occurred in Japan. Moreover, we have detected several historical recombinations that have disrupted the founder haplotype at D9S2105 or D9S2170 and conclude that the FCMD gene is probably located just centromeric to D9S2170. Received: 16 May 1998 / Accepted: 10 June 1998     

Fine mapping of the human biotinidase gene and haplotype analysis of five common mutations

Biotinidase deficiency is an autosomal recessive defect in the recycling of biotin that can lead to a variety of neurologic and cutaneous symptoms. The disease can be prevented or effectively treated with exogenous biotin. The biotinidase locus (BTD) has been maped to 3p25 by in situ hybridization. The gene has been cloned, the coding region sequenced, the genomic organization determined, and a spectrum of mutations has been characterized in more than 90 individuals with profound or partial biotinidase deficiency. We have conducted haplotype analysis of 10 consanguineous and 39 nonconsanguineous probands from the United States and 8 consanguineous probands from Turkey to localize BTD with respect to polymorphic markers on 3p and to investigate the origins of five common mutations. The inbred probands were homozygous for overlapping regions of 3p ranging in size from 1.1 to 80 cM which were flanked most narrowly by D3S1259 and D3S1293. Radiation hybrids and haplotype analysis of markers within this region suggest that BTD is located within a 0.1-cM region flanked by D3S3510 and D3S1286. The radiation hybrid data suggest that the BTD gene is oriented 5' to 3' between the centromere and the 3p telomere. Association studies indicate that the gene is closer to a third locus D3S3613 than D3S3510, two markers which cannot be resolved by existing linkage data. The BTD locus and D3S3613 must therefore lie between D3S3510 and D3S1286. Comparison of haplotypes reveals evidence for possible founder effects for four of the five common mutations.     

Friedreich ataxia in Louisiana Acadians: demonstration of a founder effect by analysis of microsatellite-generated extended haplotypes.

Eleven Acadian families with Friedreich ataxia (FA) who were from southwest Louisiana were studied with a series of polymorphic markers spanning 310 kb in the D9S5-D9S15 region previously shown to be tightly linked to the disease locus. In particular, three very informative microsatellites were tested. Evidence for a strong founder effect was found, since a specific extended haplotype spanning 230 kb from 26P (D9S5) to MCT112 (D9S15) was present on 70% of independent FA chromosomes and only once (6%) on the normal ones. There was no evident correlation between haplotypes and clinical expression. The typing of an additional microsatellite (GS4) located 80 kb from MCT112 created a divergence of the main FA-linked haplotype, generating four minor and one major haplotype. A similar split was observed with GS4 in a patient homozygous for a rare 26P-to-MCT112 haplotype. These results suggest that GS4 is flanking marker for the disease locus, although other interpretations are possible.     

Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, a birdlike face, growth retardation, immunodeficiency, lack of secondary sex characteristics in females, and increased incidence of lymphoid cancers. NBS cells display a phenotype similar to that of cells from ataxia-telangiectasia patients, including chromosomal instability, radiation sensitivity, and aberrant cell-cycle-checkpoint control following exposure to ionizing radiation. A recent study reported genetic linkage of NBS to human chromosome 8q21, with strong linkage disequilibrium detected at marker D8S1811 in eastern European NBS families. We collected a geographically diverse group of NBS families and tested them for linkage, using an expanded panel of markers at 8q21. In this article, we report linkage of NBS to 8q21 in 6/7 of these families, with a maximum LOD score of 3.58. Significant linkage disequilibrium was detected for 8/13 markers tested in the 8q21 region, including D8S1811. In order to further localize the gene for NBS, we generated a radiation-hybrid map of markers at 8q21 and constructed haplotypes based on this map. Examination of disease haplotypes segregating in 11 NBS pedigrees revealed recombination events that place the NBS gene between D8S1757 and D8S270. A common founder haplotype was present on 15/18 disease chromosomes from 9/11 NBS families. Inferred (ancestral) recombination events involving this common haplotype suggest that NBS can be localized further, to an interval flanked by markers D8S273 and D8S88.     

Linkage disequilibrium mapping places the gene causing familial Mediterranean fever close to D16S246.

This report presents refined genetic mapping data for the gene causing familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation. We sampled 65 Jewish, Armenian, and Arab families and typed them for eight markers from chromosome 16p. Using a new algorithm that permits multipoint calculations for a dense map of markers in consanguineous families, we obtained a maximal LOD score of 49.2 at a location 1.6 cM centromeric to D16S246. A specific haplotype at D16S283-D16S94-D16S246 was found in 76% of Moroccan and 32% of non-Moroccan Jewish carrier chromosomes, but this haplotype was not overrepresented in Armenian or Arab FMF carriers. Moreover, the 2.5-kb allele at D16S246 was significantly associated with FMF in Moroccan and non-Moroccan Jews but not in Armenians or Arabs. Since the Moroccan Jewish community represents a relatively recently established and genetically isolated founder population, we analyzed the Moroccan linkage-disequilibrium data by using Luria-Delbrück formulas and simulations based on a Poisson branching process. These methods place the FMF susceptibility gene within 0.305 cM of D16S246 (2-LOD-unit range 0.02-0.64 cM).     

Genetic archaeologic perspective on the origin of Yakuts

Published data on two cases of linkage disequilibrium in Yakuts are analyzed. These are the disequilibria between loci HLA-A and HLA-B and between the mutation of gene SCA1 responsible for type 1 spinocerebellar ataxia and its flanking microsatellites D6S274 and D6S89. Both cases are regarded as consequences of the founder effect. The genetic archeological approach has been used to calculate the historical period when the mutant SCA1 gene and the HLA-A1\B17 haplotype spread in the population. It has been found that this was approximately 60-70 generations (1500-1750 years) ago in both cases. The time of the segregation of haplotype HLA-A1\B17 has also been calculated for some other populations. Caucasoids have proved to be the oldest carriers of this gene, which agrees with the well-known notion that HLA-A1 originated in Indo-Europeans. The general distribution of HLA genes in Yakuts is similar to that in east-central Asian Mongoloids; therefore, it is concluded that that Yakuts are east-central Asian Mongoloids by origin, except for the founder that had haplotype A1\B17. Historically, the time of the appearance of this haplotype coincided with the period when Saks conquered east-central Asia; therefore, it is hypothesized that the aforementioned founder was a Sak.     

Variants at the APOA5 locus, association with carotid atherosclerosis, and modification by obesity: the Framingham Study

Genetic variation at the apolipoprotein A5 gene (APOA5) is associated with increased triglyceride concentrations, a risk factor for atherosclerosis. Carotid intimal medial thickness (IMT) is a surrogate measure of atherosclerosis burden. We sought to determine the association of common APOA5 genetic variants with carotid IMT and stenosis. A total of 2,273 Framingham Offspring Study participants underwent carotid ultrasound and had data on at least one of the five APOA5 variants (-1131T>C, -3A>G, 56C>G, IVS3+476G >A, and 1259T>C). Although none of the individual variants was significantly associated with carotid measures, the haplotype defined by the presence of the rare allele of the 56C>G variant was associated with a higher common carotid artery (CCA) IMT compared with the wild-type haplotype (0.75 vs. 0.73 mm; P < 0.05). The rare allele of each of the -1131T >C, -3A>G, IVS3+476G>A, and 1259T>C variants and the haplotype defined by the presence of the rare alleles in these four variants were each significantly associated with CCA IMT in obese participants. These associations remained significant even after adjustment for triglycerides. APOA5 variants were associated with CCA IMT, particularly in obese participants. The mechanism of these associations and the effect modification by obesity are independent of fasting triglyceride levels.     

Allelic association of microsatellites of 6p in Italian hemochromatosis patients

Hemochromatosis (HC) is an inherited disorder of iron metabolism and is frequently seen in Caucasians. The biochemical defect and the responsible gene are unknown, but the HC locus is closely linked to HLA-A on human chromosome 6 in the region 6p21.3. Although extensive studies have been performed in several populations, the precise location of the gene is still undefined. Linkage disequilibrium with HC has been detected for loci that are 3 cM apart: HLA class I and D6S105, which is located on the telomeric side of HLA-A. We have analyzed the inheritance of several multi-allele polymorphisms that map to 6p (D6S265, Y52, HLA-F, D6S306, D6S105, D6S464, D6S299) in 34 Italian HC families and in 17 unrelated patients. Significant association with HC was shown for alleles of multiple markers in the HLA-A region, for the distant marker D6S105, but not for the D6S299 marker at 4 cM from HLA-A on the telomeric side. HC status was unambiguously assigned to 70 affected and 63 unaffected chromosomes from family studies. Thirty five different haplotypes were found in 70 HC chromosomes when considering four markers most tighly associated with the disease. A predominant haplotype comprising alleles 1-3-1-8 (marker order D6S265, HLA-A, Y52, D6S105) accounted for 30% of the HC chromosomes and was absent in normals. A minority of other HC haplotypes could be related to the major haplotype by assuming single crossover events. Results of haplotype studies suggest a founder effect in the Italian population, as previously shown in Australian patients, and a possible common mutation shared with affected individuals of Celtic origin. Received: 16 May 1995 / Revised 21 August 1995     

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.     

Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D

Background

Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects.

Methods

We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis.

Results

We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis.

Conclusion

DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-011-0233-y) contains supplementary material, which is available to authorized users.     

Partial physical map of human chromosome 21 from fibroblast and lymphocyte DNA

A partial physical map of the human chromosome 21 including 26 genes and anonymous sequences was established by pulsed-field gel electrophoresis analysis of restriction fragments obtained from lymphocyte and fibroblast DNAs. The sizes of the restriction fragments obtained by total digestion with eight different enzymes were compared in these two tissues. Differences resulting from the variations in the methylation state of the restriction sites were frequently observed. These differences and partial digestions were used to estimate the order and the distances between genes and sequences. Six linkage groups were defined: D21S13-D21S16, D21S1-D21S11, D21S65-D21S17, (D21S55,ERG)-ETS2, BCEI-D21S19-D21S42-D21S113-CBS-CRYA1, and COL6A2-S100B. For six intergenic distances the resolution of previous maps was significantly increased.     

Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies.

A high prevalence of myotonic dystrophy (DM) has been described in South African Caucasoid Afrikaans-speaking families in the northern Transvaal. Evidence is presented for a strong founder effect, with a single haplotype occurring on 68% of all Caucasoid DM chromosomes; among the Afrikaans speakers, the proportion was 83%. In addition to this major haplotype, five minor DM haplotypes in the Caucasoids and two minor haplotypes in DM individuals of mixed ancestry were found. All DM chromosomes, however, had a common haplotype core, namely, Alu (ins), HinfI-2 (intron 9), and TaqI-2 (D19S463). We have detected significant linkage disequilibrium between the DM mutation and particular alleles of the extragenic markers D19S112 and D19S207. Significant differences were found in allele and haplotype distributions in the Caucasoid DM and non-DM chromosomes and Negroid non-DM chromosomes. These findings together with the strong association of allele 3 at the D19S63 locus on 93% (14/15) of the South African DM chromosomes suggest that the majority of present-day DM mutations in South African Caucasoids may have originated from a common initial founder who introduced one of the European ancestral mutations.     

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.     

A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16

Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population.     

Repositioning the hereditary paraganglioma critical region on chromosome band 11q23

Hereditary paragangliomas (PGL, glomus tumors, MIM no.168000) are mostly benign, slow-growing tumors of the head and neck region. The gene (or genes) affecting risk to PGL are subject to genomic imprinting: children of affected fathers exhibit an autosomal dominant pattern of disease inheritance, whereas children of affected mothers rarely if ever develop the disease through maternal transmission. We previously confined the disease gene to an approximately 6 Mb critical region on chromosome band 11q23 (PGL1). Based on haplotype analysis of an extended Dutch pedigree, a 2 Mb sub-region between D11S938 and D11S1885 was proposed as the PGL1 critical interval. In this study, we excluded this interval by analysis of two new single tandem repeat polymorphisms (STRP) contained therein. Instead, we predicted a non-overlapping, more proximal 2 Mb critical interval between D11S1647 and D11S897, and evaluated this new region using nine STRP (D11S1986, five new, closely-linked STRP, D11S1347, D11S3178, and D11S1987). Consistent with our prediction, we observed substantial haplotype-sharing within the Dutch pedigree. We also analyzed four new American PGL families. A recombination event detected in one family further defined D11S1347 as the new telomeric border. We observed significant haplotype-sharing within this new interval among three unrelated American PGL families, strongly suggesting that they originated from a common ancestor. Thus, we confined PGL1 to an approximately 1.5 Mb region between D11S1986 and D11S1347, and showed identity-by-descent sharing for a group of American PGL families. Received: 2 November 1998 / Accepted: 21 December 1998     

The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population.

Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1 in 1500. We recently assigned the locus for vLINCL, CLN5, to 13q21.1-q32. In the present study, the haplotype analysis of Finnish CLN5 chromosomes provides evidence that one single mutation causes vLINCL in the Finnish population. Eight microsatellite markers closely linked to the CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared haplotype analysis. One single haplotype formed by flanking markers D13S160 and D13S162 in strong linkage disequilibrium (P < .0001) was present in 81% of disease-bearing chromosomes. Allele 4 at the marker locus D13S162 was detected in 94% of disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by virtue of its restricted geographical distribution, church records were used to identify the common ancestors for 18 vLINCL families diagnosed in Finland. The pedigrees of the vLINCL ancestors merged on many occasions, which also supports a single founder mutation that obviously happened 20 to 30 generations ago (i.e., approximately 500 years ago) in this isolated population. Linkage disequilibrium was detected with seven markers covering an extended genetic distance of 11 cM, which further supports the young age of the CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 gene was predicted to lie approximately 200 - 400 kb (total range 30 - 1360 kb) from the closest marker D13S162.     

Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations

Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately .03), whereas the 84GG insertion (q approximately .003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations. Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population. On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes. This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe.     

Mapping autosomal recessive vitamin D dependency type I to chromosome 12q14 by linkage analysis.

Linkage analysis in French-Canadian families with vitamin D dependency type I (VDD1) demonstrated that the gene responsible for the disease is linked to polymorphic RFLP markers in the 12q14 region. We studied 76 subjects in 14 sibships which included 17 affected individuals and 17 obligate heterozygotes. Significant results for linkage were obtained with the D12S17 locus at the male recombination fraction (theta m) .018 (Z[theta m theta f] = 3.20) and with D126 at (theta m = .025 (Z[theta m theta f] = 3.07). Multipoint linkage analysis and studies of haplotypes and recombinants strongly suggest the localization of the VDD1 locus between the collagen type II alpha 1 (COL2A1) locus and clustered loci D12S14, D12S17, and D12S6, which segregate as a three-marker haplotype. Linkage disequilibrium between VDD1 and this three-marker haplotype supports the notion of a founder effect in the studied population. The current status of the localization of the disease allows for carrier detection in the families at risk.