Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study long-read whole-genome sequencing and repeat-primed polymerase chain reaction were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyGlycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.

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Cucurbitaceae plants are of considerable biological and economic importance, and genomes of cucumber, watermelon, and melon have been sequenced. However, a comparative genomics exploration of their genome structures and evolution has not been available. Here, we aimed at performing a hierarchical inference of genomic homology resulted from recursive paleopolyploidizations. Unexpectedly, we found that, shortly after a core-eudicot-common hexaploidy, a cucurbit-common tetraploidization (CCT) occurred, overlooked by previous reports. Moreover, we characterized gene loss (and retention) after these respective events, which were significantly unbalanced between inferred subgenomes, and between plants after their split. The inference of a dominant subgenome and a sensitive one suggested an allotetraploid nature of the CCT. Besides, we found divergent evolutionary rates among cucurbits, and after doing rate correction, we dated the CCT to be 90–102 Ma, likely common to all Cucurbitaceae plants, showing its important role in the establishment of the plant family.

Cold stress profoundly affects plant growth and development and is a key factor affecting the geographic distribution and evolution of plants. Plants have evolved adaptive mechanisms to cope with cold stress. Here, through the genomic analysis of Arabidopsis, three Brassica species and 17 other representative species, we found that both cold-related genes (CRGs) and their collinearity were preferentially retained after polyploidization followed by genome instability, while genome-wide gene sets exhibited a variety of other expansion mechanisms. The coldrelated regulatory network was increased in Brassicaceae genomes, which were recursively affected by polyploidization. By combining our findings regarding the selective retention of CRGs from this ecological genomics study with the available knowledge of cold-induced chromosome doubling, we hypothesize that cold stress may have contributed to the success of polyploid plants through both increasing polyploidization and selectively maintaining CRGs during evolution. This hypothesis requires further biological and ecological exploration to obtain solid supporting evidence, which will potentially contribute to understanding the generation of polyploids and to the field of ecological genomics.