CONSTRUCTION OF A 2.5-MB INTEGRATED PHYSICAL AND GENE MAP OF DISTAL 21Q22.3

The gene-rich telomeric region of 21q harbors several loci relevant to human diseases including autoimmune polyglandular disease type I, non syndromic deafness, Knobloch syndrome, holoprosencephaly, and bipolar affective disorder. A contig of genomic clones in this region would fa cilitate the isolation of these genes. However, distal 21q22.3 has yet been poorly mapped, presumably due to the presence of sequences that are underrepresented in yeast artificial chromosome (YAC) libraries. W e generated a framework of YACs and used these clones as starting poin ts for the isolation of a combination of bacterial artificial chromoso me clones, P1-derived artificial chromosome clones, and cosmid clones by chromosome walking procedures. These studies resulted in the constr uction of a high-resolution contig map spanning the 2.5-Mb region from PFKL to the telomere, similar to 2 Mb of which are covered by ready-t o-sequence contigs. Within this map we determined the location and rel ative distance of 21 markers. These include 9 established genetic mark ers, the order of which is cen - PFKL - D21S154 - D21S170 - D21S171 - D21S1903 - D21S1897 - D21S112 - D21S1446 - D21S1575 - tel. Moreover, w e established the precise map position of 13 genes and 4 ESTs includin g the recently isolated genes C21ORF2, SMT3H1, RNA editing deaminase 1 (ADARB1), folate transporter (SLC19A1), COL18A1, lanosterol synthase (LSS-PEN), pericentrin (PCNT), and arginine methyltransferase (HRMT1L1 ). This integrated map provides a useful resource for the mapping and isolation of disease genes and for the construction of a complete tran scription map of distal 21q as well as for large-scale sequencing effo rts. (C) 1998 Academic Press.