Linkage Map Of Human Chromosome Research Articles

Comparative Linkage Mapping of Human Chromosome 13 and Bovine Chromosome 12

A comparative linkage map of human chromosome 13 and bovine chromosome 12 was constructed using eight polymorphic microsatellite markers associated with six specific genes. Linkage of these was also examined relative to five previously mapped anonymous microsatellite markers. Seven gene-linked markers were developed from bovine large-insert genomic clones containing one of five genes of interest (serotonin receptor subtype 2, fms-related tyrosine kinase, coagulation factor 10, retinoblastoma susceptibility gene, collagen type IV alpha 1), and one additional marker was developed from a microsatellite resident within an intron of the bovine dopachrome tautomerase gene. Four of these loci were previously assigned to bovine chromosome 12 by analysis of a somatic cell hybrid panel. This study provides linkage information for examining gene order in this conserved synteny group. The comparative linkage mapping results indicate that the q arm of human chromosome 13 is almost entirely conserved in bovine chromosome 12. One intrachromosomal rearrangement was detected in this linkage group relative to human, and this rearrangement was confirmed by fluorescencein situhybridization results.

A 37-Marker PCR-Based Genetic Linkage Map of Human Chromosome 9: Observations on Mutations and Positive Interference

Refinement of an "index" marker genetic linkage map of human chromosome 9 using the CEPH reference pedigrees has been achieved through the addition of 11 markers to the previous map of 26 markers. Five of the 11 markers added to the map are new markers of the GATA repeat type, 1 is a complex repeat, and the remaining 5 as well as the original 26 markers are all GT/CA repeats. Twelve definite and five probable mutations were detected in this analysis and were more common for the GATA repeats than the GT/CA repeats. Strong evidence for positive interference was seen over the length of the chromosome, but there were significantly more double recombination events in the pericentromeric region than elsewhere, suggesting that interference is less strong in that region.

The tetranucleotide repeat polymorphism D21S1245 demonstrates hypermutability in germline and somatic cells.

Six novel polymorphic short sequence repeats were identified and localized on the linkage map of human chromosome 21 by genotyping the CEPH reference pedigrees. One of these markers, the tetrameric (AAAG)n repeat D21S1245, was found to be hypermutable. In the DNAs from lymphoblastoid cell lines of members of the 40 CEPH families a total of 18 new alleles were detected. These new alleles, sometimes appearing in mosaic forms, arose equally in paternal and maternal DNAs, and could be equally larger or smaller than the alleles from which they were derived. The larger alleles of D21S1245 are more prone to be converted to new alleles. None of the new alleles with mosaicism were present in the corresponding genomic blood DNA, and therefore originated during or after the establishment of the lymphoblastoid cell lines; half of the new alleles without mosaicism were also found in genomic blood DNA of the appropriate CEPH individuals. The range of germline mutation rate observed in the 716 meioses examined was 0.56-1.4 x 10(-2); the range of somatic mutations observed in the 405 cell lines examined was 1.96-3.46 x 10(-2). This is one of the most hypermutable microsatellite repeat polymorphism in the human genome detected to date. D21S1245, is highly polymorphic (heterozygosity of 0.96) and maps between D21S231 and D21S198.

A PCR-Based Genetic Linkage Map of Human Chromosome 16

A high-resolution cytogenetic-based physical map and a genetic linkage map of human chromosome 16 have been developed based on 79 PCR-typable genetic markers and 2 Southern-based RFLP markers. The PCR-based markers were previously characterized polymorphic (AC)n repeats. Two approaches have led to the characterization of 47 highly informative genetic markers spread along chromosome 16, some of which are closely linked to disease loci. In addition, 22 markers (D16S401-423) previously genetically mapped were also physically mapped. Ten markers characterized by other laboratories were physically mapped and genotyped on the CEPH families. These 32 markers were incorporated into the PCR-based map. Seventy-two markers have heterozygosities >0.50 and 51 of these markers >0.70. By multipoint linkage analysis a framework genetic map and a comprehensive genetic map were constructed. The length of the sex-averaged framework genetic map is 152.1 cM. The average distance and the median distance between markers on this map are 3.2 and 2.7 cM, respectively, and the largest gap is 15.9 cM. These maps were anchored to the high-resolution cytogenetic map (on average 1.5 Mb per interval). Together these integrated genetic and physical maps of human chromosome 16 provide the basis for the localization and ultimately the isolation of disease genes that map to this chromosome.

A Linkage Map of Human Chromosome 21: 43 PCR Markers at Average Intervals of 2.5 cM

A genetic linkage map of human chromosome 21q (HC21q) containing 43 markers genotyped by the polymerase chain reaction in the CEPH pedigrees is presented. The markers placed on this map are highly polymorphic with an average heterozygosity of 61%. The average interval size of the markers localized at 1000:1 odds is 2.5 cM. The map has a total length of 65.5 cM, with male and female lengths of 47.7 and 83.3 cM, respectively. The genotypes used in the construction of this map were subjected to rigorous error checking, which is reflected in the shorter map length compared to previous maps; the estimated error rate in genotyping is less than 0.04%. As noted in previous linkage maps there is increased recombination in females on proximal HC 21q and in the male in a region near the telomere. This map of HC 21 represents a highly informative and dense meiotic linkage map and will be useful in linking disease phenotypes to loci on this chromosome.

A PCR-Based Linkage Map of Human Chromosome 1

A genetic linkage map of human chromosome 1 based entirely on PCR-typable markers has been developed using 38 simple sequence repeat (SSR) polymorphisms. These SSRs include 36 dinucleotide repeats and 2 tetranucleotide repeats. The average heterozygosity at these markers was 0.73 and ranged from 0.52 to 0.95. Multipoint linkage analysis was used to develop a map of these 38 markers in which the relative placement of each locus is supported by likelihood odds >1000:1. This PCR-based map was anchored at the centromere by the D1Z5 α-satellite polymorphism, and the ends of the map were defined by D1Z2 and D1S68, which are the most distal loci in the CEPH consortium map of chromosome 1. The sex-averaged, male, and female maps extend for 328, 273, and 409 cM, respectively. The average distance between markers on the sex-averaged map is 8 cM, and the largest interval is 32 cM. This map of highly informative PCR-based markers will provide a rapid means of screening human chromosome 1 for the presence of disease genes.

DNA Polymorphisms in the 3′ Untranslated Region of Genes on Human Chromosome 21

DNA polymorphisms can be used to place loci and phenotypes on the linkage maps of human chromosomes. In an effort to localize genes on the linkage map of human chromosome 21 better, we examined their 3' untranslated (3'UT) regions for the presence of polymorphisms. We amplified the 3'UT region of 17 genes of chromosome 21 by the polymerase chain reaction and subjected the product to single-stranded conformation analysis (SSCA). We have found eight polymorphisms in the 3'UT region of genes. The total area examined was 8144 nucleotides and therefore the variability detected by this method was 1 in 1018 nucleotides. This is not different from the estimated variability of DNA sequences based on restriction analysis. Sequence analysis revealed that all polymorphisms found are due to single nucleotide substitutions. Additional polymorphisms were identified in the last intron of BCEI gene and in the 3'-flanking region of the S100B gene. We conclude that the 3'UT region of genes is a relatively rich source of polymorphisms and that SSCA is an effective method of detecting the normal sequence variation in the human genome.

Linkage mapping of the cystathionine ?-synthase (CBS) gene on human chromosome 21 using a DNA polymorphism in the 3? untranslated region

We used single-strand conformation polymorphism (SSCP) to detect DNA polymorphisms in the 3' untranslated (3'UT) region of the gene for cystathionine beta-synthase (CBS). A polymorphism due to a T-to-C substitution at nucleotide 549 of the 3'UT region with heterozygosity of 46% has been identified. Genotypes for this polymorphism have been obtained in all of the informative CEPH families, and CBS has been placed in the linkage map of human chromosome 21.

A genetic linkage map of the chromosome 4 short arm

We have generated an 18-interval contiguous genetic linkage map of human chromosome 4 spanning the entire short arm and proximal long arm. Fifty-seven polymorphisms, representing 42 loci, were analyzed in the Venezuelan reference pedigree. The markers included seven genes (ADRA2C, ALB, GABRB1, GC, HOX7, IDUA, QDPR), one pseudogene (RAF1P1), and 34 anonymous DNA loci. Four loci were represented by microsatellite polymorphisms and one (GC) was expressed as a protein polymorphism. The remainder were genotyped based on restriction fragment length polymorphism. The sex-averaged map covered 123 cM. Significant differences in sex-specific rates of recombination were observed only in the pericentromeric and proximal long arm regions, but these contributed to different overall map lengths of 115 cM in males and 138 cM in females. This map provides 19 reference points along chromosome 4 that will be particularly useful in anchoring and seeding physical mapping studies and in aiding in disease studies.

Dinucleotide repeat (GT) n markers on chromosome 21

To further develop the linkage map of human chromosome 21 (HC21), we have concentrated on identifying highly polymorphic markers based on dinucleotide repeat sequences such as (GT)n, as these are often highly polymorphic, are widespread throughout the human genome, and can be rapidly analyzed by the polymerase chain reaction. We report here nine (GT)n polymorphic markers from HC21.

A genetic linkage map of human chromosome 9q

A genetic linkage map of human chromosome 9q, spanning a sex-equal distance of 125 cM, has been developed by genotyping 26 loci in the Venezuelan Reference Pedigree. The loci include 12 anonymous microsatellite markers reported by Kwiatkowski et al. (1992), several classical systems previously assigned to chromosome 9q, and polymorphisms for the genes tenacin (HXB), gelsolin (GSN), adenylate kinase 1 (AK1), arginosuccinate synthetase (ASS), ABL oncogene (ABL1), ABO blood group (ABO), and dopamine beta-hydroxylase (DBH). Only a marginally significant sex difference is found along the entire length of the map and results from one interval, between D9S58 and D9S59, that displays an excess of female recombination. A comparison of the genetic map to the existing physical data suggests that there is increased recombination in the 9q34 region with a recombination event occurring every 125-400 kb. This map should be useful in further characterizing the relationship between physical distance and genetic distance, as well as for genetic linkage studies of diseases that map to chromosome 9q, including multiple self-healing squamous epithelioma (MSSE), Gorlin syndrome (NBCCS), xeroderma pigmentosum (XPA), nail-patella syndrome (NPS1), torsion dystonia (DYT1), and tuberous sclerosis (TSC1).

Linkage mapping of the AML1 gene on human chromosome 21 using a DNA polymorphism in the 3′ untranslated region

We have detected a polymorphism in the 3' untranslated region of the AML1 gene, which is located at the breakpoint on chromosome 21 in the t(8;21)(q22;q22.3) translocation often associated with patients with acute myeloid leukemia. Informative CEPH families were genotyped for this polymorphism and used to localize the gene on the linkage map of human chromosome 21. The AML1 gene is located between the markers D21S216 and D21S211, in chromosomal band 21q22.3.

Molecular and genetic characterization and physical mapping of 11 new markers detecting multiallele restriction fragment length polymorphisms on the short arm of human chromosome 3.

Genetic markers with high degrees of polymorphisms are of vital importance in the construction of high resolution (2-4 cM) linkage maps of human chromosomes as specified in the short-term goals of the Human Genome Initiative. In this paper, we report on molecular and genetic characterization and physical localization of 11 new multiallele restriction fragment length polymorphism markers on human chromosome 3p. Ten of these represent three- and four-allele polymorphisms of the base substitution type probably at two adjacent restriction sites. One has been identified as a novel mini-satellite sequence comprising a variable copy number tandem repeat array of a G/T-rich 79-bp sequence. This collection of multiallele polymorphic (PIC values: 0.40-0.60) markers should prove valuable and increase the resolution power of the available chromosome 3p genetic markers.

Continuous linkage map of human chromosome 14 short tandem repeat polymorphisms

Nine moderately to highly informative short tandem repeat polymorphisms were assigned to chromosome 14 using somatic cell hybrids and were mapped using linkage analysis. The nine markers formed a continuous linkage map covering almost the entire long arm from 14q11.2 to q32. The markers filled a large gap within previously reported linkage maps for this chromosome. Best order of the new loci from q11.2 to q32 was D14S50, D14S54, D14S49, D14S47, D14S52, D14S53, D14S55, D14S48, and D14S51. The order shown for all adjacent pairs of loci was very strongly favored with the exception of loci pair D14S55 and D14S48, for which the order was moderately favored. Map lengths for the nine loci were 142 cM in females and 72 cM in males. Female recombination frequencies exceeded male recombination frequencies in the middle and distal portions of the map.

Linkage mapping of the carbonyl reductase (CBR) gene on human chromosome 21 using a DNA polymorphism in the 3′ untranslated region

A DNA polymorphism has been found in the 3′ untranslated region of the carbonyl reductase gene (CBR). Genotypes of the members of the CEPH pedigrees have been obtained and used in linkage analysis to map the CBR gene in the linkage map of human chromosome 21. The gene maps between the interferon-α receptor (IFNAR) and the D21S55 loci.

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.

A genetic linkage map of human chromosome 5 with 60 RFLP loci

A genetic map of human chromosome 5 that contains 60 restriction fragment length polymorphism (RFLP) loci in one linkage group has been constructed. Segregation data using these markers and 40 large multigenerational families supplied by the Centre d'Étude du Polymorphisme Humain have been collected. Linkage analyses were performed with the program package CRI-MAP; using odds greater than 1000:1, 30 RFLP loci could be placed on the map. This genetic map spans 289 cM sex-equal, 353 cM in females, and 244 cM in males. While the relative rate of recombination for female meioses is nearly twice that of males over much of the chromosome, several instances of statistically significant excess male recombination were observed. The order of probes on the genetic map has been confirmed by their physical order as determined by somatic cell hybrid lines containing deletions of normal chromosome 5. There is concordance between the physical positions of markers and their genetic positions. Our most distal probes on the genetic map are cytologically localized to the most distal portions of the chromosome. This suggests that pur genetic map spans most of chromosome 5.

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 α-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 > 15 cM, and the mean genetic distance between the 58 uniquely placed loci is 6.7 cM.

Genetic linkage map of 46 DNA markers on human chromosome 16.

We have constructed a genetic linkage map of human chromosome 16 based on 46 DNA markers that detect restriction fragment length polymorphisms. Segregation data were collected on a set of multigenerational families provided by the Centre d'Etude du Polymorphisme Humain, and maps were constructed using recently developed multipoint analysis techniques. The map spans 115 centimorgans (cM) in males and 193 cM in females. Over much of the chromosome there is a significantly higher frequency of recombination in females than males. Near the alpha-globin locus on the distal part of the short arm, however, there is a significant excess of male recombination. Twenty-seven (59%) of the markers on the map have heterozygosities greater than or equal to 0.50. The largest interval between loci on the sex-average map is 14 cM and the average marker spacing is 3 cM. Using loci on this map, one could detect linkage to a dominant disease on chromosome 16 with as few as 10-15 phase-known meioses.

Linkage analysis of the human HMG14 gene on chromosome 21 using a GT dinucleotide repeat as polymorphic marker

A (GT) n repeat in intron 4 of the functional human HMG14 gene on chromosome 21 was used as polymorphic marker to map this gene relative to the genetic linkage map of human chromosome 21. Variation in the length of the (GT) n repeat was detected by electrophoresis on polyacrylamide gels of DNA amplified by the polymerase chain reaction using primers flanking the repeat. The observed heterozygosity of this polymorphism in 40 CEPH families was 58% with six different alleles. Linkage analysis localized the HMG14 gene close to the ETS2 gene and locus D21S3 in chromosomal band 21q22.3.