Doerfel, M. | Search bioRxiv

bioRxiv2023

Evaluating possible maternal effect lethality of Naa10 knockout mice, and modulation of phenotypes for embryonic and neonatal lethality by genetic background and environment

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/ymale mice on the inbred genetic background in this different animal facility.

genetics↗

bioRxiv2017

Not by systems alone: identifying functional outliers in rare disease pedigrees

In characterizing a disease, it is common to search for dysfunctional genes by assaying the transcriptome. The resulting differentially expressed genes are typically assessed for shared features, such as functional annotation or co-expression. While useful, the reliability of these systems methods is hard to evaluate. To better understand shared disease signals, we assess their replicability by first looking at gene-level recurrence and then pathway-level recurrence along with co-expression signals across six pedigrees of a rare homogeneous X-linked disorder, TAF1 syndrome. We find most differentially expressed genes are not recurrent between pedigrees, making functional enrichment largely distinct in each pedigree. However, we find two highly recurrent \"functional outliers\" (CACNA1I and IGFBP3), genes acting atypically with respect to co-expression and therefore absent from a systems-level assessment. We show this occurs in re-analysis of Huntingtons disease, Parkinsons disease and schizophrenia. Our results suggest a significant role for genes easily missed in systems approaches.

systems biology↗