Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues

Fusion transcripts can contribute to diversity of molecular networks in the human cortex. In this study, we explored the occurrence of fusion transcripts in normal human cortex along with single neurons and astrocytes. We identified 1305 non-redundant fusion events from 388 transcriptomes representing 59 human cortices and 329 single cells. Our results indicate while the majority of fusion transcripts in human cortex are intra-chromosomal (85%), events found in single neurons and astrocytes were primarily inter-chromosomal (80%). The number of fusions in single neurons was significantly higher than that in single astrocytes (p <0.05), indicating fusion as a possible contributor towards transcriptome diversity in neuronal cells. The identified fusions were largely private and 4 specific recurring events were found both in cortex and in single neurons but not in astrocytes. We found a significant increase in the number of fusion transcripts in human brain with increasing age both in single cells and whole cortex (p <0.0005 and <0.005, respectively). This is likely one of the many possible contributors for the inherent plasticity of the adult brain. The fusion transcripts in fetal brain were enriched for genes for long-term depression; while those in adult brain involved genes enriched for long-term potentiation pathways. Our findings demonstrate fusion transcripts are naturally occurring phenomenon spanning across the health-disease continuum, and likely contribute to the diverse molecular network of human brain

Whole exome sequencing reveals novel candidate genes in familial forms of Glaucomatous Neurodegeneration

Glaucoma is the largest cause of irreversible blindness with a multifactorial genetic etiology. This study explores novel genes and gene networks in familial forms of primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) to identify rare mutations with high penetrance. Thirty-one samples from nine MYOC-negative families (five POAG and four PACG) underwent whole-exome sequencing and analysis. A set of prioritized genes and variations were screened in an independent validation cohort of 1536 samples and the whole-exome data from 20 sporadic patients. The expression profiles of the candidate genes were analyzed in 17 publicly available expression datasets from ocular tissues and single cells. Rare, deleterious SNVs in AQP5, SRFBP1, CDH6 and FOXM1 from POAG families and in ACACB, RGL3 and LAMA2 from PACG families were found exclusively in glaucoma cases. AQP5, SRFBP1 and CDH6 also revealed significant altered expression in glaucoma in expression datasets. Single-cell expression analysis revealed enrichment of identified candidate genes in retinal ganglion cells and corneal epithelial cells in POAG; whereas for PACG families, retinal ganglion cells and Schwalbe’s Line showed enriched expression. Through an unbiased exome-wide search followed by validation, we identified novel candidate genes for familial cases of POAG and PACG. The SRFBP1 gene found in a POAG family is located within the GLC1M locus on Chr5q. Pathway analysis of candidate genes revealed enrichment of extracellular matrix organization in both POAG and PACG

Whole exome-sequencing of vitiligo lesions indicate lower burden of somatic variations: implications in risk for non-melanoma skin cancers

Genetic depigmentary conditions such as albinism with complete loss of epidermal pigmentation pose a higher risk for cutaneous malignancies ( Lekalakala et al., 2015 ). By analogy, clinical management for photoprotection of the acquired depigmented skin in vitiligo is of serious concern. It is believed that vitiligo would pose a similar, elevated risk. Systematic evaluation of a large cohort of vitiligo subjects indicated a decreased risk for both melanoma and non-melanoma skin cancers ( Hexsel et al., 2009 ; Kim et al., 2020 ; Paradisi et al., 2014 ; Rodrigues, 2017 ; Schallreuter et al., 2002 ; Teulings et al., 2013 ; Weng et al., 2021 ). Extrapolating from demographic studies, it is tempting to speculate that vitiligo could negatively influence either initiation or progression of cutaneous malignancies ( Rodrigues, 2017 ). Given the autoimmune etiology that targets melanocyte destruction, protection against melanoma could be rationalized, however a similar protection from non-melanoma skin cancer is perplexing. Therefore, these observations need to be substantiated with evidence at the tissue level. Recent advancements in genomics enables to map the somatic variations which would act as molecular correlate for cancer. In normal, seemingly healthy skin deep-sequencing of selected panel of cancer associated genes suggests pervasive positive selection of somatic variations that provides valuable insights into the origin of mutations and map their progression to skin cancers ( Martincorena et al., 2015 ; Zheng et al., 2021 )