Hereditary fusion genes are identified as genetic factors associated with monozygotic twins
A fusion gene is a hybrid gene that juxtaposes two previously independent genes. It is a consequence of somatic genomic alterations, including reversion, deletion, and translocation. The first fusion gene was reported in the early 1980s. It showed that a translocation between chromosomes 9 and 22 led to producing the BCR-ABL1 fusion gene with the capacity to induce chronic myeloid leukemia. Since then, fusion genes have been generally thought to be somatic and cancerous. However, fusion genes have been found to be present in both cancer and healthy samples and contradicted long-held notions, suggesting that there are some untold stories.
Scientists from SplicingCodes are the first to define the hereditary fusion genes as the fusion genes that offspring inherit from their parents and exclude read-through fusion genes generated via transcriptional termination failures of two same-strand neighbor genes. Hence, read-through fusion genes are also defined as epigenetic fusion genes. They have used monozygotic (identical) twins who share identical genetic materials as the simplest genetic model to investigate the human hereditary fusion genes. Since previous family studies have shown that monozygotic inheritance is family-inherited, but no genetic factors have been found, they want to use monozygotic twins to discover potential hereditary fusion genes. Their discovery has been posted on bioRxiv: https://biorxiv.org/cgi/content/short/2022.05.06.490969v1. The scientists have used SCIF (SplicingCodes Identify Fusion Transcripts) to analyze RNA-Seq data from 37 pairs of monozygotic twins and 427 GTEx blood samples as a control. They have identified 1,180 hereditary fusion genes, from which fifty-one hereditary fusion genes have been found to be associated with monozygotic inheritance, ranging from 25.7% to 67.7%. The maximum hereditary fusion genes encoded by monozygotic twins is 608 per genome. Potential fifty-one hereditary fusion genes suggest that monozygotic inheritance is a complex trait dominated by eight genes. In addition, the hereditary fusion genes from the SCO2 gene locus (Figure below) include PLXNB2-SCO2, PPP6R2-SCO2, TRABD-SCO2, and PIM3-SCO2, which are detected in 67.6%, 41.9%, 28.4%, and 52.7% of the monozygotic twin siblings, respectively. The most exciting finding is that many of the top monozygotic hereditary fusion genes are previously-discovered cancer fusion genes, suggesting that many cancer fusion genes are not somatic but hereditary.
Figure 4 Potential genomic alterations on chromosome 22q13.33 generate SCO2-fused hereditary fusion genes. a). The schematic diagram showed the 22q13.33 genomic structure. b). SCO2 was translocated downstream of PLXNB2 to generate PLXNB2-SCO2; c) SCO2 was translocated downstream of PPP6R2 to produce PPP6R2-SCO2; d) SCO2 was translocated downstream of TRABD to form TRABD-SCO2; e) SCO2 was translocated to downstream of PIM3 to generate PIM3-SCO2. Solid red arrows were SCO2 genes. Solid black and gray arrows represented 5′ genes and the genes surrounding the SCO2 and 5′ genes. White arrows indicated genomic alterations to generate the SCO2-fused fusion genes.
Degen Zhuo (2022) The first glimpse of Homo sapiens hereditary fusion genes DOI: https://doi.org/10.1101/2022.05.06.490969
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