Sequence and analysis of two regions of mouse chromosome 1 involved in interferon response and bone mineral density regulation.

Abstract

The second region of mouse chromosome Iq corresponds to a Quantitative Trait Locus (QTL) of Bone Mineral Density (BMD), and is located near the Ifi200 gene cluster. Bone mineral density is the strongest determinant of osteoporotic fracture, and 60 to 70% of the normal variability in human bone density is genetically determined. To accelerate the identification of genes present in QTL of BMD, 6 BACs, totaling about 1.4 Mb, were sequenced. Their sequences were merged with the sequences of 7 other BAC clones mapped to the same region to create two contigs of approximately 1.4 Mb and 0.37 Mb, containing at least 40 genes. At least 5 putative calcium-ATPase genes, whose function may be involved in BMD regulation, were present in the QTL. A metabolic disorder caused, at least partially, by an increased bone resorption, and known as absorptive hypercalciuria (AH), was mapped to the QTL of BMD (Reed et al., 1999). Putative calcium-ATPases may be involved in maintaining calcium homeostasis inside the bone cell, and a calcium-ATPase-encoding gene defect therefore could be responsible for AH.

The random shotgun sequencing approach was used to sequence two regions totaling ∼ 2 Mb of mouse chromosome 1q21--25.

One region contains the murine interferon-activatable Ifi200 gene cluster. Two new 200 family genes, Ifi203a and Ifi203c, were localized in this region in addition to two pseudogenes ("203-like" and Ifi202c), and six genes (Ifi201, Ifi202a, Ifi202b, Ifi203, Ifi204 and "204-like"). A putative spliced variant of the "204-like" gene product exhibited over 86% sequence identity with an mRNA encoded for another member of the 200 family of proteins (D3). The sequences of the Ifi202a and b genes, as well as of the Ifi203a and b genes, were over 99% identical. The translation product of Ifi203b differed from that of Ifi203a by only 1 amino acid out of 408. Identification of an additional transcribed coding segment in introns 4 of Ifi203a and b suggests the possibility of a previously unreported alternatively splice product. Comparative analysis of the mouse and the human 200 clusters indicated a relative absence of sequence conservation non-coding regions.