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This paper derives theoretical values for joint polymorphism information content for two markers from a family structure consisting of four grandparents, two parents, and many offspring. These data determine the efficiency of linkage map construction.
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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.
This paper describes the Centre d'Etude du Polymorphisme Humain (CEPH) consortium linkage map of chromosome 2. The map contains 36 loci defined by genotyping generated from the CEPH family DNAs. A total of 73 different markers were typed by 14 contributing laboratories; of these, 36 loci are ordered on the map with likelihood support of at least 1000:1. Markers are placed along the length of the chromosome but no markers were available to anchor the map at either telomere or the centromere. Multilocus linkage analysis has produced male, female, and sex-averaged maps extending for 261, 430, and 328 cM, respectively. The sex-averaged map contains five intervals greater than 15 cM and the mean genetic distance between the 36 uniquely placed loci is 9.1 cM.
The genes encoding the regulatory subunits RI beta (locus PRKAR1B) and RII beta (locus PRKAR2B) of human cAMP-dependent protein kinase have been mapped in the basic CEPH (Centre d'Etude du Polymorphisme Humain) family panel of 40 families to chromosome 7p and 7q, respectively, using the enzymes HindIII and BanII recognizing the corresponding restriction fragment length polymorphisms (RFLPs). Previous data from the CEPH database and our present RFLP data were used to construct a six-point local framework map including PRKAR1B and a seven-point framework map including PRKAR2B. The analysis placed PRKAR1B as the most distal of the hitherto mapped 7p marker loci and resulted in an unequivocal order of pter-PRKAR1B-D7S21-D7S108-D7S17-D7S149- D7S62-cen, with a significantly higher rate of male than female recombination between PRKAR1B and D7S21. The 7q regulatory gene locus, PRKAR2B, could also be placed in an unambigous order with regard to the existing CEPH database 7q marker loci, the resulting order being cen-D7S371-(COL1A2,D7S79)-PRKAR2B-MET-D7S87++ +-TCRB-qter. Furthermore, in situ hybridization to metaphase chromosomes physically mapped PRKAR2B to band q22 on chromosome 7.
A region of chromosome 9, surrounding the interferon-beta (IFNB1) locus and the interferon-alpha (IFNA) gene cluster on 9p13-p22, has been shown to be frequently deleted or rearranged in a number of human cancers, including leukemia, glioma, non-small-cell lung carcinoma, and melanoma. To assist in better defining the precise region(s) of 9p implicated in each of these malignancies, a combined genetic and physical map of this region was generated using the available 9p markers IFNB1, IFNA, D9S3, and D9S19, along with a newly described locus, D9S126. The relative order and distances between these loci were determined by multipoint linkage analysis of CEPH (Centre d'Etude du Polymorphisme Humain) pedigree DNAs, pulsed-field gel electrophoresis, and fluorescence in situ hybridization. All three mapping approaches gave concordant results and, in the case of multipoint linkage analysis, the following gene order was supported for these and other closely linked chromosome 9 markers present in the CEPH database: pter-D9S33-IFNB1/IFNA-D9S126-D9S3-D9S19 -D9S9/D9S15-ASSP3-qter. This map serves to extend preexisting chromosome 9 maps (which focus primarily on 9q) and also reassigns D9S3 and D9S19 to more proximal locations on 9p.
An (AC)n repeat within the anonymous DNA sequence D21S171 was shown to be highly polymorphic in members of the 40 Centre d'Etude du Polymorphisme Humaine (CEPH) families. Ten different alleles at this marker locus were detected by electrophoresis on polyacrylamide gels of DNA amplified by the polymerase chain reaction (PCR) using primers flanking the (AC)n repeat. The observed heterozygosity was 66%. PCR amplification of DNA from somatic cell hybrids mapped D21S171 to human chromosome 21, and linkage analysis localized this marker close to the loci CD18, PFKL, D21S113 and D21S112 in chromosomal band 21q22.3. In CEPH family 12 a de novo allele has been observed in a maternally derived chromosome.
The human amylase gene cluster includes a (CA)n repeat sequence immediately upstream of the gamma-actin pseudogene associated with the AMY2B gene. Analysis of this (CA)n repeat by PCR amplification of genomic DNA from the 40 families of the Centre d'Etude du Polymorphisme Humain (CEPH) reference panel revealed extensive polymorphism. A total of six alleles with (CA)n lengths of 16-21 repeats were found. The average heterozygosity for this polymorphism was 0.70. Multipoint linkage analysis showed that the amylase gene cluster is located distal to the nerve growth factor beta-subunit gene (NGFB) and is within 1 cM of the anonymous locus D1S10. The amylase (CA)n repeat provides a convenient marker for both the physical and the genetic maps of human chromosome 1p.
Nineteen polymorphic lymphocyte proteins were previously detected by two-dimensional protein electrophoresis (2DE). In this report, we describe the genetic linkage mapping of six of these polymorphic proteins (PNIA1-PNIA6), the identification by genetic linkage of a seventh (glyoxalase 1 on 6p21), and support for the mapping of an eighth (plastin or LCP1) to near the ESD locus on Chr 13. PNIA1-PNIA6 were assigned, respectively, to 10q26, 16p13.3, 10q, 11p15, 3q, and 19q13. These genetic linkages were achieved by classical linkage analysis of 2DE protein charge polymorphisms to the panel of RFLPs previously typed in nine pedigrees in the Centre D'Etude du Polymorphisme Humain (CEPH) collection.
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.
The GABAA receptor is the major inhibitory neurotransmitter receptor in the mammalian brain. To date, 14 genes that encode subunits of this receptor have been identified; these appear to be scattered throughout the human genome and are under investigation as candidate loci for a number of neurological and psychiatric disorders. We report here a highly polymorphic (dC-dA)n repeat within the human alpha 1-subunit gene (GABRA1). Typing of this marker in the Centre d'Etude du Polymorphisme Humain (CEPH) panel of families confirms the previous assignment of the GABRA1 locus to the distal portion of chromosome 5q by demonstrating linkage to the markers CRI-L45 (D5S61) (Zmax = 11.00, theta max = 0.15), CRI-V1022 (D5S54) (Zmax = 7.25, theta max = 0.20), and CRI-P148 (D5S72) (Zmax = 5.71, theta max = 0.24).
We have studied the genetic segregation of human T-cell receptor beta-chain (TCR beta) genes on chromosome 7q in 40 CEPH (Centre d'Etude du Polymorphisme Humain) families by using restriction fragment length polymorphisms (RFLPs). We constructed haplotypes from eight RFLPs by using variable- and constant-region cDNA probes, which detect polymorphisms that span more than 600 kilobases of the TCR beta gene complex. Analysis of allele distributions between TCR beta genes revealed significant linkage disequilibrium between only 6 of the 28 different pairs of RFLPs. This linkage disequillibrium strongly influences the most efficient order to proceed for typing of these RFLPs in order to achieve maximum genetic informativeness, which in this study revealed a 97.3% level of heterozygosity within the TCR beta gene complex. Our results should provide new insight into recent reports of disease associations with the TCR beta gene complex and should assist in designing future experiments to detect or confirm the existence of disease-susceptibility loci in this region of the human genome.
A cDNA coding for a mucin expressed in intestine has recently been cloned (Gum et al. 1989). We describe here the use of this cDNA to map the gene (MUC2) to human chromosome 11 using somatic cell hybrids, and to make the regional localization to 11p15 by in situ hybridization. Analysis of the CEPH (Centre d'Etude du Polymorphisme Humain) families revealed that MUC2 forms part of the tight linkage group on 11p15 which contains HRAS, INS, TH and HBBC.
The gene MUC3 which codes for a mucin expressed in intestine (Gum et al. 1990) has previously been mapped, using somatic cell hybrids, to chromosome 7. We describe here the regional localization of MUC3 to chromosome 7q22 by in situ hybridization. Preliminary linkage analysis using CEPH (Centre d'Etude du Polymorphisme Humain) families supports this assignment and places MUC3 in the same linkage group as COL1A2 and CFTR.
We present eight computer programs written in the C programming language that are designed to analyze genotypic data and to support existing software used to construct genetic linkage maps. Although each program has a unique purpose, they all share the common goals of affording a greater understanding of genetic linkage data and of automating tasks to make computers more effective tools for map building. The PIC/HET and FAMINFO programs automate calculation of relevant quantities such as heterozygosity, PIC, allele frequencies, and informativeness of markers and pedigrees. PREINPUT simplifies data submissions to the Centre d'Etude du Polymorphisme Humain (CEPH) data base by creating a file with genotype assignments that CEPH's INPUT program would otherwise require to be input manually. INHERIT is a program written specifically for mapping the X chromosome: by assigning a dummy allele to males, in the nonpseudoautosomal region, it eliminates falsely perceived noninheritances in the data set. The remaining four programs complement the previously published genetic linkage mapping software CRI-MAP and LINKAGE. TWOTABLE produces a more readable format for the output of CRI-MAP two-point calculations; UNMERGE is the converse to CRI-MAP's merge option; and GENLINK and LINKGEN automatically convert between the genotypic data file formats required by these packages. All eight applications read input from the same types of data files that are used by CRI-MAP and LINKAGE. Their use has simplified the management of data, has increased knowledge of the content of information in pedigrees, and has reduced the amount of time needed to construct genetic linkage maps of chromosomes.
Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individuals, have been typed for the HLA class II genes DRB1, DQA1, DQB1, and DPB1 using nonradioactive sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA. This population, which consists of 266 independent chromosomes, contains 27 DRB1, 7 DQA1, 12 DQB1, and 17 DPB1 alleles. Analysis of the distribution of allele frequencies using the homozygosity statistic, which gives an indication of past selection pressures, suggests that balancing selection has acted on the DRB1, DQA1, and DQB1 loci. The distribution of DPB1 alleles, however, suggests a different evolutionary past. Family data permits the estimation of recombination rates and the unambiguous assignment of haplotypes. No recombinants were found between DRB1, DQA1, and DQB1; however, recombinants were detected between DQB1 and DPB1, resulting in an estimated recombination fraction of greater than or equal to 0.008 +/- 0.004. Only 33 distinct DRB1-DQA1-DQB1 haplotypes were found in this population which illustrates the extreme nonrandom haplotypic association of alleles at these loci. A few of these haplotypes are unusual (previously unreported) for a Caucasian population and most likely result from past recombination events between the DR and DQ subregions. Examination of disequilibrium across the HLA region using these data and the available serologic HLA-A and HLA-B types of these samples shows that global disequilibrium between these loci declines with the recombination fraction, approaching statistic nonsignificance at the most distant interval, HLA-A to HLA-DP.DR-DQ haplotypes in linkage disequilibrium with DPB1 and B are noted and, finally, the evolutionary origin of certain class II haplotypes is addressed.
Indirect tracking of mutation by DNA polymorphisms is still essential for carrier and prenatal diagnosis of Duchenne/Becker muscular dystrophy, at least in the families where no deletion can be detected. Because of the relatively high level of intragenic recombination, informative and easily testable markers at both ends of the gene are necessary for efficient and accurate diagnosis. We report the characterization of two polymorphic microsatellite sequences (TG repeats) at the 5' end of the dystrophin gene, within 40 kb of the muscle-specific promoter. The most useful one (5' DYS MSA) has 10 alleles with a 57% heterozygosity and can be tested on small polyacrylamide gels in a nonradioactive PCR-based assay. Despite its large number of alleles, this microsatellite shows strong linkage disequilibrium with a two-allele polymorphism reported by Roberts et al., an indication of the stability of this type of sequences. We have used the new microsatellites at the 5' end, along with one we reported previously for the 3' end, to type the families in the CEPH (Centre d'Etude du Polymorphisme Humain) panel. While the number of informative families has increased by a factor of about two with respect to the study of Abbs et al., the estimates of the recombination fractions are in good agreement with this previous report, suggesting a 11% recombination across the gene (3% between the 5' end and the pERT87 region, 8% between pERT87 and the 3' end), which is about fivefold more than expected. However, these estimates still have wide confidence limits.
We have studied the segregation of an RFLP detected with a human ETS-1 genomic probe in 25 families containing members affected with ataxia-telangiectasia (AT) and in 27 families from the Centre d'Etude du Polymorphisme Humain (CEPH) panel. We have recently mapped a gene for AT to 11q22-23 by linkage to the markers THY1 and D11S144. Multipoint linkage analysis of the CEPH families indicated that ETS-1 is located on chromosome 11q approximately 19.2 centimorgans telomeric to THY1. Analysis of the segregation of ETS-1 alleles in AT families yields strongly negative LOD scores, excluding an AT gene from a region extending 15 cM to either side of ETS-1. Multipoint mapping of ETS-1, D11S144, THY1, and AT also excludes the possibility that an AT gene is telomeric to ETS-1.