The genetic defect in multiple endocrine neoplasia type 2A maps next to the centromere of chromosome 10

Multiple endocrine neoplasia type 2A (MEN2A) is a rare cancer syndrome that is inherited in an apparently autosomal dominant fashion. Previous linkage studies had assigned the MEN2A locus to chromosome 10 in the pericentromeric region. We recently have described several new easily scorable RFLPs for the chromosome 10-specific alpha satellite DNA (the D10Z1) locus that is known, on the basis of previous in situ hybridization experiments, to lie at the centromere. We report here tight linkage between MEN2A and D10Z1, as demonstrated by a maximum lod score of 12.02 at the recombination frequency of zero (1-lod-unit support interval 0-4 cM), indicating that the genetic defect in MEN2A lies in the immediate vicinity of the centromere. By means of a set of ordered polymorphic DNA markers from the pericentromeric region, multipoint as well as pairwise linkage analyses place the MEN2A locus at the middle of a small region (approximately 11 cM) bracketing the centromere with FNRB (at 10p11.2) and RBP3 (at 10q11.2) on either side, providing further support for the centromeric location of the MEN2A locus. Marked sex difference in recombination frequencies exists in this pericentromeric region: significantly (P less than .01) more female than male crossovers were observed across all of the adjacent intervals D10S24-FNRB, FNRB-D10Z1, and D10Z1-RBP3. However, a sex difference was not seen in the 7-cM interval from RBP3 to D10S5, suggesting that large variation in the sex difference in recombination can occur over small chromosomal regions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19.

Multiple epiphyseal dysplasia (MED) is an inherited chondrodystrophy that results in deformity of articular surfaces and in subsequent degenerative joint disease. The disease is inherited as an autosomal dominant trait with high penetrance. An MED mutation has been mapped by genetic linkage analysis of DNA polymorphisms in a single large pedigree. Close linkage of MED to 130 tested chromosomal markers was ruled out by discordant inheritance patterns. However, strong evidence for linkage of MED to markers in the pericentromeric region of chromosome 19 was obtained. The most closely linked marker was D19S215, with a maximum LOD score of 6.37 at theta = .05. Multipoint linkage analysis indicated that MED is located between D19S212 and D19S215, a map interval of 1.7 cM. Discovery of the map location of MED in this family will facilitate identification of the mutant gene. The closely linked DNA polymorphisms will also provide the means to determine whether other inherited chondrodystrophies have underlying defects in the same gene.     

A new DNA marker (D4S90) is located terminally on the short arm of chromosome 4, close to the Huntington disease gene

Genetic linkage studies have mapped Huntington's disease (HD) to the distal portion of the short arm of chromosome 4 (4p16.3), 4 cM distal to D4S10 (G8). To date, no definite flanking marker has been identified. A new DNA marker, D4S90 (D5); which maps to the distal region of 4p16.3, is described. The marker was used in a genetic linkage study in the CEPH reference families with seven other markers at 4p16. The study, together with knowledge of the physical map of the region, places D4S90 as the most distal marker, 6 cM from D4S10. A provisional linkage study with HD gave a maximum lod score of 2.14 at a theta of 0.00 and no evidence of linkage disequilibrium. As D4S90 appears to be located terminally, it should play an important role in the accurate mapping and cloning of the HD gene.     

Linkage map and congenic strains to localize blood pressure QTL on rat Chromosome 10

Our purposes were to develop a linkage map for rat Chromosome (Chr) 10, using chromosome-sorted DNA, and to construct congenic strains to localize blood pressure quantitative trait loci (QTL) on Chr 10 with the map. The linkage mapping panel consisted of three F₂ populations totaling 418 rats. Thirty-two new and 29 known microsatellite markers were placed on the map, which spanned 88.9 centiMorgans (cM). The average distance between markers was 1.46 cM. No markers were separated by more than 6.8 cM. Four congenic strains were constructed by introgressing various segments of Chr 10 from the Milan normotensive strain (MNS) onto the background of the Dahl salt-sensitive (S) strain. A blood pressure QTL with a strong effect on blood pressure (35–42 mm Hg) when expressed on the S background was localized to a 31-cM region between D10Mco6 and D10Mcol. The region does not include the locus for inducible nitric oxide synthase (Nos2), which had been considered to be a candidate locus for the QTL. Received: 25 September 1996 / Accepted: 9 November 1996     

A linkage group of five DNA markers on human chromosome 10

Five chromosome 10 DNA markers (D10S1, D10S3, D10S4, D10S5, and RBP3) were typed in five large pedigrees with multiple endocrine neoplasia type 2A (MEN-2A) and in five non-MEN-2A pedigrees. Linkage analyses showed that these loci and the locus for MEN-2A (MEN2A) are in one linkage group spanning at least 70 cM. The order of the marker loci is RBP3-D10S5-D10S3-D10S1-D10S4, with interlocus recombination frequencies of 7, 13-19, 19, and 19%, respectively, all on the same side of MEN2A. Analyses of sex-specific recombination frequencies indicated no significant differences between males and females for any of the map intervals studied. Previous localization of D10S5 and RBP3 to the proximal region of the long arm and the pericentric region, respectively, comparison of results with other studies, and our preliminary results with other chromosome 10 markers suggest that the D10S4 end of the map extends into the long arm. Our linkage map has been constructed using only two- and three-locus analyses. It will be possible to combine our results with those of other groups to construct a more detailed and accurate genetic map of chromosome 10.     

Isolation and high-resolution mapping of new DNA markers from the pericentromeric region of chromosome 10.

The gene responsible for multiple endocrine neoplasia type 2A (MEN 2A) has been localized to the pericentromeric region of chromosome 10. Several markers that fail to recombine with MEN2A have been identified, including D10Z1, D10S94, D10S97, and D10S102. Meiotic mapping in the MEN2A region is limited by the paucity of critical crossovers identified and by the dramatically reduced rates of recombination in males. Additional approaches to mapping loci in the pericentromeric region of chromosome 10 are required. We have undertaken the generation of a detailed physical map by radiation hybrid mapping. Here we report the development of a radiation hybrid panel and its use in the mapping of new DNA markers in pericentromeric chromosome 10. The radiation-reduced hybrids used for mapping studies all retain small subchromosomal fragments that include both D10S94 and D10Z1. One hybrid was selected as the source of DNA for cloning. One hundred five human recombinant clones were isolated from a lambda library made with pp11A DNA. We have completed regional mapping of 22 of those clones using our radiation hybrid mapping panel. Seven markers have been identified and, when taken together with previously meiotically mapped markers, define eight radiation hybrid map intervals between D10S34 and RBP3. The identical order is found for a number of these using either the radiation hybrid mapping panel or the meiotic mapping panel. We believe that this combination cloning and mapping approach will facilitate the precise positioning of new markers in pericentromeric chromosome 10 and will help in refining further the localization of MEN2A.     

A genetic linkage map of human chromosome 20 composed entirely of microsatellite markers.

Twenty-six (CA)n polymorphic microsatellites were isolated from a flow-sorted chromosome 20 library. To reduce the number of sequencing gels, these microsatellites were genotyped on 15 CEPH families using a procedure derived from the multiplex sequencing technique of G. M. Church and S. Kieffer-Higgins (1988, Science 240:185-188). A primary map with a strongly supported order was constructed with 15 (CA)n markers. Regional localizations for the 11 other microsatellites were obtained with regard to the primary map. The 26 loci span approximately 160 cM. Regional localizations for a set of index markers (D20S4, D20S6, D20S16, and D20S19) and for other markers from the CEPH Public Database (D20S5, D20S15, D20S17, and D20S18) have also been determined. The total map spans a genetic distance of approximately 195 cM extending from the (CA)n marker IP20M7 on 20p to D20S19 on 20q. The density of microsatellite markers is markedly higher in the pericentromeric region, with an average distance of 3 to 4 cM between adjacent markers over a distance of 43 cM. Two-thirds of these randomly isolated microsatellites are clustered in that region between D20S5 and D20S16 representing approximately one-fourth of the linkage map. This might suggest a nonrandom distribution of (CA)n simple sequence repeats on this chromosome.     

Linkage analysis of human chromosome 4: exclusion of autosomal dominant retinitis pigmentosa (ADRP) and detection of new linkage groups

As part of our ongoing linkage studies of degenerative retinal diseases, we tested seven DNA markers and two classical genetic markers from chromosome 4 in two extended families with autosomal dominant retinitis pigmentosa (ADRP). Our goals were (1) to detect or exclude linkage of ADRP to markers spanning most of chromosome 4 and (2) to contribute useful new information regarding the linkage map of this chromosome. Our results exclude linkage of ADRP from more than 82% of chromosome 4. We detected four new linkage relationships: loose linkage of K082 (D4S10) and G1E5 (D4S21) at a distance of 21 cM; loose linkage of 4F2 (D4S18) and GC protein at a distance of 19 cM; tight linkage (i.e., no recombinants) between B3D (D4S44), B5A (D4S40), and the MNS blood group; and tight linkage between 4F2 and GDS5 (D4S23). These data, combined with previously reported data, exclude ADRP from approximately 35% of the human genome.     

Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. A genomewide scan of families with SDS was terminated at approximately 50% completion, with the identification of chromosome 7 markers that showed linkage with the disease. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum two-point LOD score was 8.7, with D7S473, at a recombination fraction of 0. The maximum multipoint LOD score was 10, in the interval between D7S499 and D7S482 (5.4 cM on the female map and 0 cM on the male map), a region delimited by recombinant events detected in affected children. Evidence from all 15 of the multiplex families analyzed provided support for the linkage, consistent with a single locus for SDS. However, the presence of several different mutations is suggested by the heterogeneity of disease-associated haplotypes in the candidate region.     

Evidence for asthma susceptibility genes on chromosome 11 in an African-American population

Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage in the presence of disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM with a confidence interval spanning the linkage peak. Evidence from both linkage and association analyses suggest that this region of chromosome 11 contains one or more susceptibility genes for asthma in these AA families.     

Regional mapping panel for human chromosome 17: Application to neurofibromatosis type 1

A somatic cell hybrid mapping panel was constructed to localize cloned DNA sequences to any of 15 potentially different regions of human chromosome 17. Relatively high-resolution mapping is possible for 50% of the chromosome length in which 12 breakpoints are distributed over approximately 45 megabases, with an average spacing estimated at 1 breakpoint every 2-7 megabases. This high-resolution capability includes the pericentromeric region of 17 to which von Recklinghausen neurofibromatosis (NF1) has recently been mapped. Using 20 cloned genes and anonymous probes, we have tested the expected order and location of panel breakpoints and confirmed, refined, or corrected the regional assignment of several cloned genes and anonymous probes. Four markers with varying degrees of linkage to NF1 have been physically localized and ordered by the panel: the loosely linked markers myosin heavy chain 2 (25 cM) to p12----13.105 and nerve growth factor receptor (14 cM) to q21.1----q23; the more closely linked pABL10-41 (D17S71, 5 cM) to p11.2; and the tightly linked pHHH202 (D17S33) to q11.2-q12. Thus, physical mapping of linked markers confirms a pericentromeric location of NF1 and, along with other data, suggests the most likely localization is proximal 17q.     

Localization of an ataxia-telangiectasia locus to a 3-cM interval on chromosome 11q23: Linkage analysis of 111 families by an international consortium

Linkage of at least two complementation groups of ataxia-telangiectasia (AT) to the chromosomal region 11q23 is now well established. We provide here an 18-point map of the surrounding genomic region, derived from linkage analysis of 40 CEPH families. On the basis of this map, 111 AT families from Turkey, Israel, England, Italy, and the United States were analyzed, localizing the AT gene(s) to an 8-cM sex-averaged interval between the markers STMY and D11S132/NCAM. A new Monte Carlo method for computing approximate location scores estimates this location as being at least 10(8) times more likely than the next most likely interval, with a support interval midway between STMY and D11S132 that is either 5.2 cM (sex-averaged and conservatively based on 3 lod scores from the maximum-location score) or 2.8 cM (male specific, based on a 2.72:1 interval-specific female-to-male distance ratio.     

Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage.

We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P相似文献   

A genetic linkage map of 96 loci on the short arm of human chromosome 3.

We constructed a genetic map of 96 loci on the short arm of human chromosome 3 (3p) in 59 families provided by the Centre d'Etude du Polymorphisme Humaine (CEPH). Twenty-nine continuously linked loci were placed on the map with likelihood support of at least 1000:1; one locus, D3S213, was placed on the map with likelihood support of 871:1; D3Z1, an alpha satellite centromeric repeat probe, was placed on the map with likelihood support of 159:1; 65 loci were assigned regional locations. The average heterozygosity of the uniquely ordered markers was 49%. The map extends from 3p26, the terminal band of 3p, to the centromere (from D3S211 to D3Z1). Multipoint linkage analysis indicated that the male, female, and sex-averaged maps extend for 102, 147, and 116 cM, respectively. The mean genetic distance between uniquely ordered loci on the sex-averaged map was 4.0 cM. Probe density was greatest for the region of 3p between D3F15S2e and the telomere. The sex-averaged map contained two intervals greater than 10 cM. Seventeen probes were localized by fluorescence in situ hybridization. The loci described in this report will be useful in building an integrated genetic and physical map of this chromosome.     

Addition of MT, D16S10, D16S4, and D16S91 to the linkage map within 16q12.1-q22.1.

A 10-point genetic linkage map of the region 16q12.1 to 16q22.1 has been constructed using the CEPH reference families. Four loci, MT, D16S10, D16S91, and D16S4, not previously localized on a multipoint linkage map, were incorporated on the map presented here. The order of loci was cen-D16S39-MT, D16S65-D16S10-FRA16B-D16S38, D16S4, D16S91, D16S46-D16S47-HP-qter. The interval between D16S10 and 4D16S38 is 3.1 cM in males and 2.3 cM in females, and contains FRA16B. The cloning strategy for FRA16B will now be based on YAC walking from D16S10 and D16S38. The location of FRA16B between D16S10 and D16S38 provides a physical reference point for the multipoint linkage map on the short arm of chromosome 16.     

A new DNA marker (D4S90) is located terminally on the short arm of chromosome 4, close to the Huntington disease gene

Genetic linkage studies have mapped Huntington's disease (HD) to the distal portion of the short arm of chromosome 4 (4p16.3), 4 cM distal to D4S10 (G8). To date, no definite flanking marker has been identified. A new DNA marker, D4S90 (D5), which maps to the distal region of 4p16.3, is described. The marker was used in a genetic linkage study in the CEPH reference families with seven other markers at 4p16. The study, together with knowledge of the physical map of the region, places D4S90 as the most distal marker, 6 cM from D4S10. A provisional linkage study with HD gave a maximum lod score of 2.14 at a θ of 0.00 and no evidence of linkage disequilibrium. As D4S90 appears to be located terminally, it should play an important role in the accurate mapping and cloning of the HD gene.     

The CEPH consortium linkage map of human chromosome 1

This paper describes the Centre d'Etude du Polymorphisme Humain (CEPH) consortium linkage map of human chromosome 1. The map contains 101 loci defined by genotypes generated from CEPH family DNAs with 146 different contributions from 11 laboratories. A total of 58 loci are uniquely placed on the map with likelihood support of at least 1000:1. The map extends from loci in the terminal bands of both chromosome arms (locus D1Z2 in 1p36.3 and D1S68 in 1q44) and is anchored at the centromere by the D1Z5 alpha-satellite polymorphism. With the exception of a single locus, the remaining loci are arrayed on the fixed map in short intervals and their possible locations are indicated. Multipoint linkage analyses provided estimates that the male, female, and sex-averaged maps extend for 308, 478, and 390 cM, respectively. The sex-averaged map contains only four intervals greater than 15 cM, and the mean genetic distance between the 58 uniquely placed loci is 6.7 cM.     

Eight closely linked loci place the Wilson disease locus within 13q14-q21

Wilson disease (WD) is an autosomal recessive disorder resulting in an accumulation of copper in the liver, brain, and other organs. The WD locus (WND) has previously been linked to esterase D (ESD) and localized to 13q14-22. With the large Centre d'Etude Polymorphisme Humain cohort, a refined map of DNA markers from this region was constructed, with the following locus order: D13S1-D13S21-D13S22-D13S10-ESD-RB-WND-D 13S26-D13S12-D13S2. A significant excess of male recombination was observed between D13S21 and D13S22. Intervals distal to D13S22 showed an excess of female recombination. When these markers were tested on 19 WD families from a variety of ethnic backgrounds, the two closest loci were shown to be RB and D13S26. The retinoblastoma gene locus (RB) was shown to be proximal to WND at a distance of 4.4 centimorgans (cM), and D13S26 was placed distal to WND at a distance of 4.0 cM. ESD was assigned proximally at a distance of 9.4 cM. In all families studied WND was linked to one or more of the loci ESD, RB, or D13S26.     

The CEPH consortium linkage map of human chromosome 15q

The CEPH consortium map of chromosome 15q is presented. The map contains 41 loci defined by genotypes generated from CEPH family DNAs with 45 different probe and restriction enzyme combinations contributed by 10 laboratories. A total of 29 loci have been placed on the map with likelihood support of at least 1000:1. The map extends from 15q13 to 15q25-qter. Multipoint linkage analyses provided estimates that the male, female, and sex-averaged maps extend for 127, 190, and 158 cM, respectively. The largest interval is 21 cM and is between D15S37 and D15S74. The on-average locus spacing is 5.6 cM and the mean genetic distance between the 21 uniquely placed loci is 8 cM.     

A map of 22 loci on human chromosome 22.

We constructed a genetic linkage map of the entire long arm of human chromosome 22 with 30 polymorphic markers, defining 22 loci. The map consists of a continuous linkage group 110 cM long, when male and female recombination fractions are combined; average distance between the loci is 5.2 cM. All loci were placed on the map with high support against alternative orders (odds in excess of 1000:1). The order of loci presented in our map is in full agreement with that of the previous linkage maps of chromosome 22 and with the physical assignment of markers. Two markers included in this map, KI-831 (D22S212) and pEFZ31 (D22S32), allowed us to better define the region of the (11;22) translocation breakpoint specific for Ewing sarcoma. Ten additional polymorphic markers were placed on the 22-loci map with odds lower than 1000:1 against alternative locations. In total, we have introduced 29 new markers on the linkage map of chromosome 22.