A de novo evolved gene in the house mouse regulates female pregnancy cycles

The de novo emergence of new genes has been well documented through genomic analyses. However, a functional analysis, especially of very young protein-coding genes, is still largely lacking. Here, we identify a set of house mouse-specific protein-coding genes and assess their translation by ribosome profiling and mass spectrometry data. We functionally analyze one of them, ̑extitGm13030}, which is specifically expressed in females in the oviduct. The interruption of the reading frame affects the transcriptional network in the oviducts at a specific stage of the estrous cycle. This includes the upregulation of ̑extit{Dcpp} genes, which are known to stimulate the growth of preimplantation embryos. As a consequence, knockout females have their second litters after shorter times and have a higher infanticide rate. Given that ̑extit{Gm13030 shows no signs of positive selection, our findings support the hypothesis that a de novo evolved gene can directly adopt a function without much sequence adaptation

Dedicated transcriptomics combined with power analysis lead to functional understanding of genes with weak phenotypic changes in knockout lines

Author summary Knockout mice benefit the understanding of gene functions in mammals. However, it has proven difficult for many genes to identify clear phenotypes, related due to lack of sufficient assays. As Lewis Wolpert put it in a famous quote “But did you take them to the opera?”, thus metaphorically alluding to the need to extend phenotyping efforts. This insight led to the establishment of phenotyping pipelines that are nowadays routinely used to characterize knock-out lines. However, transcriptomic approaches based on RNA-Seq have been much less explored for such deep-level studies. We conducted here both, a theoretical power analysis and practical RNA-Seq experiments on two knockout lines with small phenotypic effects to investigate the parameters including sample size, sequencing depth, fold change, and dispersion. Our dedicated RNA-Seq studies discovered thousands of genes with small transcriptional changes and enriched in specific functions in both knockout lines. We find that it is more important to increase the number of samples than to increase the sequencing depth. Our work shows that a deep RNA-Seq study on knockouts is powerful for understanding gene functions in cases of weak phenotypic effects, and provides a guideline for the experimental design of such studies

Copy number variation in small nucleolar RNAs regulates personality behavior

Animals show behavioral traits that can collectively be called personality. We focus here on the role of the Prader-Willi Syndrom gene region in regulating personality behavior. It includes two clusters of tandem repeats coding for small nucleolar RNAs, SNORD115 and SNORD116. SNORD115 is known to regulate splicing of the serotonin receptor Ht2cr and SNORD116 is predicted to interact with the transcript of the chromatin regulator Ankrd11. We show that both snoRNA clusters display major copy number variation within and between populations, as well as in an inbred mouse strain and that this affects the expression of their specific target genes. Using a set of behavioral scores related to personality in populations of two species of wild mice, guinea pigs and humans, we find a strong correlation between the snoRNA copy number and these scores. Our results suggest that the SNORD clusters are major regulators of personality and correlated traits

An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors