A refined linkage map for DNA markers around the pericentromeric region of chromosome 10.

A refined genetic linkage map for the pericentromeric region of human chromosome 10 has been constructed from data on 12 distinct polymorphic DNA loci as well as the locus for multiple endocrine neoplasia type 2A (MEN 2A), a dominantly inherited cancer syndrome. The map extends from D10S24 (at 10p13-p12.2) to D10S3 (at 10q21-q23) and is about 70 cM long. Overall, higher female than male recombination frequencies were observed for this region, with the most remarkable female excess in the immediate vicinity of the centromere, as previously reported. Most of the DNA markers in this map are highly informative for linkage and the majority of the interlocus intervals are no more than 6 cM apart. Thus this map should provide a fine framework for future efforts in more detailed mapping studies around the centromeric area. A set of ordered cross-overs identified in this work is a valuable resource for rapidly and accurately localizing new DNA clones isolated from the pericentromeric region.

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)

The beta subunit locus of the human fibronectin receptor: DNA restriction fragment length polymorphism and linkage mapping studies.

The beta subunit of the human fibronectin receptor (FNRB) is a transmembrane protein belonging to the VLA (very late antigens of activation) family. Using pGEM-32, a 2.5-kb partial cDNA clone corresponding to the 3' portion of the human FNRB locus, multiple restriction fragment length polymorphisms (RFLPs) were revealed on DNAs from unrelated Caucasians. RFLPs detected by five enzymes, BanII, HinfI, KpnI, BglII, and SacI, are of the simple two-allele form, and pairwise linkage analyses of these RFLPs with numerous known DNA markers from the chromosome-10 pericentromeric region not only confirmed the chromosome-10 assignment of the functional FNRB gene but also supported its localization at p11.2 suggested by in situ hybridization. An infrequent MspI RFLP was detected by pB/R2, a 4.6-kb genomic clone from the FNRB locus. Another type of DNA polymorphism was also revealed by the cDNA clone and it was visualized on the Southern blot analyses as the presence or absence of an extra band (or a set of extra bands). It seems to stem from a stretch of DNA sequence present in some individuals at one single locus but absent in others, and is of non-chromosome-10 origin based on linkage analyses with known chromosome 10 markers. This "presence/absence" type of polymorphism could be revealed by all of the 25 restriction enzymes tested and is similar in nature to that previously reported with one of the human dihydrofolate reductase pseudogenes, DHFRP1. Dissection of the pGEM-32 clone demonstrated that the region revealing the non-chromosome-10 sequences is within a fragment about 1.7 kb in length extending from about 600 nucleotides preceding the stop codon down to the end of the cloned FNRB 3' untranslated region. Due to its high polymorphism information content (PIC) value (0.71 for haplotypes of BanII, HinfI, and KpnI RFLPs) and proximity to the centromere. FNRB will prove to be a highly useful marker for genetic linkage studies of multiple endocrine neoplasia type 2A (MEN2A) as well as for chromosome-10 linkage studies in general.