Detection of a complex chromosomal rearrangement in a novel mouse mutant by optical genome mapping

Here we highlight the utilities of optical genome mapping (OGM) in determining the genomic rearrangements present in a novel transgenic mouse line (Line 781), which expresses the bacterial lacZ reporter gene under control of the mouse myelin proteolipid protein (Plp1) promoter. Hemizygous transgenic mice from Line 781 present with a mutant phenotype (documented here) which entails small body size and paws and craniofacial aberrations that are 100% penetrant, whereas their non-transgenic littermates are phenotypically normal. OGM was used to determine that the transgene sits at the intersection of an unbalanced reciprocal translocation between chromosomes 1 and 2, with deletion of approximately 3.9 (chr1) and 1.8 (chr2) Mbp from the rearranged (derivative) chromosomes, thus resulting in a monosomy over these regions in the mutant genome. As well, OGM was able to determine the number of full-length copies of transgene that integrated and their orientation. Sanger sequencing of PCR products that span a junction were used to determine the chromosomal breakpoints and transgene integration site, precisely. The complex chromosomal rearrangements in Line 781 span 38 protein-coding genes that result in the transection of 1 gene from chr1 and deletion of 33 and 4 genes from chr1 and chr2, respectively. The resulting mutant phenotype is consistent with 1q24 deletion syndrome in humans having an interstitial deletion of the syntenic region in Chr1. Thus, our mouse mutant may serve as an animal model, in future studies, to explore the molecular and cellular basis of anomalies present in patients with 1q24 deletion syndrome.