Biology subjects

Cockell, S. J.

Publications and source records attributed to Cockell, S. J..

3 recordsLinked to original sources

bioRxiv2021

Integration of probabilistic functional networks without an external Gold Standard

BackgroundProbabilistic functional integrated networks (PFINs) are designed to aid our understanding of cellular biology and can be used to generate testable hypotheses about protein function. PFINs are generally created by scoring the quality of interaction datasets against a Gold Standard dataset, usually chosen from a separate high-quality data source, prior to their integration. Use of an external Gold Standard has several drawbacks, including data redundancy, data loss and the need for identifier mapping, which can complicate the network build and impact on PFIN performance. ResultsWe describe the development of an integration technique, ssNet, that scores and integrates both high-throughput and low-throughout data from a single source database in a consistent manner without the need for an external Gold Standard dataset. Using data from Saccharomyces cerevisiae we show that ssNet is easier and faster, overcoming the challenges of data redundancy, Gold Standard bias and ID mapping, while producing comparable performance. In addition ssNet results in less loss of data and produces a more complete network. ConclusionsThe ssNet method allows PFINs to be built successfully from a single database, while producing comparable network performance to networks scored using an external Gold Standard source.

bioinformatics↗

bioRxiv2021

A de novo paradigm for male infertility

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

genetics↗

bioRxiv2020

RBMX enables productive RNA processing of ultra-long exons important for genome stability

Previously we showed that the germline-specific RNA binding protein RBMXL2 is essential for male meiosis where it represses cryptic splicing patterns (1). Here we find that its ubiquitously expressed paralog RBMX helps underpin human genome stability by preventing non-productive splicing. In particular, RBMX blocks selection of aberrant splice and polyadenylation sites within some ultra-long exons that would interfere with genes needed for normal replication fork activity. Target exons include within the ETAA1 (Ewings Tumour Associated 1) gene, where RBMX collaborates with its interaction partner Tra2{beta} to enable full-length exon inclusion by blocking selection of an aberrant 3 splice site. Our data reveal a novel group of RNA processing targets potently repressed by RBMX, and help explain why RBMX is associated with gene expression networks in cancer, replication and sensitivity to genotoxic drugs.

molecular biology↗