Faculty Bibliography

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-alpha receptor (IFNAR) and the D21S55 loci.

Microsatellite DNA consists of tandemly repeated simple DNA sequence motifs, the number of these repeats being polymorphic. These recently described polymorphisms are ubiquitously distributed throughout the human genome and are highly informative, making them ideal markers for linkage analysis. Physical localization of these microsatellites is an important prerequisite for aligning physical and genetic maps. We have physically mapped the microsatellite at D13S71, which has previously been assigned to chromosome 13. Band-specific mapping of D13S71 to the distal part of band 13q32, near 13q33, was achieved by microdissection of GTG-banded chromosomes and subsequent enzymatic amplification with a heminested PCR approach. Analysis of a panel of somatic cell hybrids confirmed this localization. The technique presented may also be useful in a variety of complex mapping situations and whenever the precise localization of very small (as small as 70 bp) DNA probes is necessary.

We have studied DNA polymorphisms at loci in the pericentromeric region on the long arm of chromosome 21 in 200 families with trisomy 21, in order to determine the meiotic origin of nondisjunction. Maintenance of heterozygosity for parental markers in the individual with trisomy 21 was interpreted as resulting from a meiosis I error, while reduction to homozygosity was attributed to a meiosis II error. Nondisjunction was paternal in 9 cases and was maternal in 188 cases, as reported earlier. Among the 188 maternal cases, nondisjunction occurred in meiosis I in 128 cases and in meiosis II in 38 cases; in 22 cases the DNA markers used were uninformative. Therefore meiosis I was responsible for 77.1% and meiosis II for 22.9% of maternal nondisjunction. Among the 9 paternal nondisjunction cases the error occurred in meiosis I in 2 cases (22.2%) and in meiosis II in 7 (77.8%) cases. Since there was no significant difference in the distribution of maternal ages between maternal I error versus maternal II error, it is unlikely that an error at a particular of maternal ages between maternal I error versus maternal II error, it is unlikely that an error at a particular meiotic stage contributes significantly to the increasing incidence of Down syndrome with advancing maternal age. Although the DNA polymorphisms used were at loci which map close to the centromere, it is likely that rare errors in meiotic-origin assignments may have occurred because of a small number of crossovers between the markers and the centromere.(ABSTRACT TRUNCATED AT 250 WORDS)

Two polymorphic loci within the interferon-alpha receptor (IFNAR) gene on human chromosome 21 have been identified and mapped by linkage analysis in 40 CEPH families. These markers are (1) a multiallelic RFLP with an observed heterozygosity of 0.72 and (2) a variable (AT3)n short sequence repeat at the poly(A) tail of an Alu sequence (AluVpA) with an observed heterozygosity of 0.83. This locus is close to D21S58 (theta = 0.02, zeta = 36.76) and D21S17 (theta = 0.02, Zeta = 21.76) with chromosomal band 21q22.1. Multipoint linkage analysis suggests the most likely locus order to be 21cen-D21S58-IFNAR-D21S17-21qter. Given its high heterozygosity, the IFNAR gene can be used as an index marker on human chromosome 21.

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.