Browsing by Author "Conlon, Ronald A."

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    An evolutionary driver of interspersed segmental duplications in primates
    (BMC, 2020-08-10) Cantsilieris, Stuart; Sunkin, Susan M.; Johnson, Matthew E.; Anaclerio, Fabio; Huddleston, John; Baker, Carl; Dougherty, Max L.; Underwood, Jason G.; Sulovari, Arvis; Hsieh, PingHsun; Mao, Yafei; Catacchio, Claudia Rita; Malig, Maika; Welch, AnneMarie E.; Sorensen, Melanie; Munson, Katherine M.; Jiang, Weihong; Girirajan, Santhosh; Ventura, Mario; Lamb, Bruce T.; Conlon, Ronald A.; Eichler, Evan E.; Medical and Molecular Genetics, School of Medicine
    Background The complex interspersed pattern of segmental duplications in humans is responsible for rearrangements associated with neurodevelopmental disease, including the emergence of novel genes important in human brain evolution. We investigate the evolution of LCR16a, a putative driver of this phenomenon that encodes one of the most rapidly evolving human–ape gene families, nuclear pore interacting protein (NPIP). Results Comparative analysis shows that LCR16a has independently expanded in five primate lineages over the last 35 million years of primate evolution. The expansions are associated with independent lineage-specific segmental duplications flanking LCR16a leading to the emergence of large interspersed duplication blocks at non-orthologous chromosomal locations in each primate lineage. The intron-exon structure of the NPIP gene family has changed dramatically throughout primate evolution with different branches showing characteristic gene models yet maintaining an open reading frame. In the African ape lineage, we detect signatures of positive selection that occurred after a transition to more ubiquitous expression among great ape tissues when compared to Old World and New World monkeys. Mouse transgenic experiments from baboon and human genomic loci confirm these expression differences and suggest that the broader ape expression pattern arose due to mutational changes that emerged in cis. Conclusions LCR16a promotes serial interspersed duplications and creates hotspots of genomic instability that appear to be an ancient property of primate genomes. Dramatic changes to NPIP gene structure and altered tissue expression preceded major bouts of positive selection in the African ape lineage, suggestive of a gene undergoing strong adaptive evolution.
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    Rhodopsin Mislocalization Drives Ciliary Dysregulation in a Novel Autosomal Dominant Retinitis Pigmentosa Knock-In Mouse Model
    (Wiley, 2024) Takita, Shimpei; Jahan, Sultana; Imanishi, Sanae; Harikrishnan, Hemavathy; LePage, David; Mann, Rachel J.; Conlon, Ronald A.; Miyagi, Masaru; Imanishi, Yoshikazu; Ophthalmology, School of Medicine
    Rhodopsin mislocalization encompasses various blind conditions. Rhodopsin mislocalization is the primary factor leading to rod photoreceptor dysfunction and degeneration in autosomal dominant retinitis pigmentosa (adRP) caused by class I mutations. In this study, we report a new knock-in mouse model that harbors a class I Q344X mutation in the endogenous rhodopsin gene, which causes rod photoreceptor degeneration in an autosomal dominant pattern. In RhoQ344X/+ mice, mRNA transcripts from the wild-type (Rho) and RhoQ344X mutant rhodopsin alleles are expressed at equal levels. However, the amount of RHOQ344X mutant protein is 2.7 times lower than that of wild-type rhodopsin, a finding consistent with the rapid degradation of the mutant protein. Immunofluorescence microscopy indicates that RHOQ344X is mislocalized to the inner segment and outer nuclear layers of rod photoreceptors in both RhoQ344X/+ and RhoQ344X/Q344X mice, confirming the essential role of the C-terminal VxPx motif in promoting OS delivery of rhodopsin. The mislocalization of RHOQ344X is associated with the concurrent mislocalization of wild-type rhodopsin in RhoQ344X/+ mice. To understand the global changes in proteostasis, we conducted quantitative proteomics analysis and found attenuated expression of rod-specific OS membrane proteins accompanying reduced expression of ciliopathy causative gene products, including constituents of BBSome and axonemal dynein subunit. Those studies unveil a novel negative feedback regulation involving ciliopathy-associated proteins. In this process, a defect in the trafficking signal leads to a reduced quantity of the trafficking apparatus, culminating in a widespread reduction in the transport of ciliary proteins.