Thiessen, N. | bioRxiv Science

bioRxiv2022

Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma

Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either TERT activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are key drivers of ALT but only present in [~]50% of ALT tumors. To identify potential new pathways to telomere maintenance, we investigate allele-specific gene dosage effects from whole genomes and transcriptomes in 115 primary neuroblastomas. We show that copy-number dosage deregulates telomere maintenance, genomic stability, and neuronal pathways and identify upregulation of variants of histone H3 and H2A as a potential alternative pathway to ALT. We investigate the interplay between TERT activation, overexpression and copy-number dosage and reveal loss of imprinting at the RTL1 gene associated with poor clinical outcome. These results highlight the importance of gene dosage in key oncogenic mechanisms in neuroblastoma.

genomics↗

bioRxiv2019

Allele-specific transcript abundance: A pilot study in healthy centenarians

The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in non-coding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression towards major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

genetics↗