The TATA-box binding protein (TBP) is a highly conserved basal transcription factor and a core component of the pre-initiation complex (PIC) for all three eukaryotic RNA polymerases (RNA Pols). Despit...

Hybridization and polyploidization influence gene expression with several prominent trends. This study uses a thermodynamic model to show that many observed gene expression patterns in hybrids and all...

The genome-wide burdens of deletions, loss-of-function mutations, and duplications correlate with many traits. Curiously, for most of these traits, variants that decrease expression have the same genome-wide average direction of effect as variants that increase expression. This seemingly contradicts the intuition that, at individual genes, reducing expression should have the opposite effect on a phenotype as increasing expression. To understand this paradox, we introduce a concept called the gene dosage response curve (GDRC) that relates changes in gene expression to expected changes in phenotype. We show that, for many traits, GDRCs are systematically biased in one trait direction relative to the other and, surprisingly, that as many as 40% of GDRCs are non-monotone, with large increases and decreases in expression affecting the trait in the same direction. We develop a simple theoretical model that explains this bias in trait direction. Our results have broad implications for complex traits, drug discovery, and statistical genetics. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement N.M. was supported by a National Science Foundation Graduate Research Fellowship and Stanford's Knight-Hennessy Scholars Program. C.J.S. was supported by Stanford's Knight-Hennessy Scholars Program and the Stanford Center for Computational, Evolutionary and Human Genomics. H.Z. was supported by Stanford Biology Department's graduate student assistantship. This work was supported by the National Institutes of Health (R01HG011432 and R01HG008140 to J.K.P.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. This approval means that researchers do not require separate ethical clearance and can operate under the RTB approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All genetic and health data was acquired from the UK Biobank, a biomedical database containing information from half a million UK participants. Data for genetic association analysis of continuous traits was acquired under application 52374. Data for genetic association analysis of metabolite traits was acquired under application 30418. These data are available upon application to the UK Biobank. All summary statistics generated from genetic association analysis and other processed data files are deposited in Zenodo. <https://doi.org/10.5281/zenodo.13852455> <https://www.ukbiobank.ac.uk/>

2-6 December 2024

Nature Ecology & Evolution - Snail venom glands