Biology subjects

Yamamoto, R.

Publications and source records attributed to Yamamoto, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Efficient coding makes and breaks Webers law

Webers law is a rare quantitative regularity in psychology, yet its origins remain debated. Here we provide causal evidence that it arises from the more fundamental principle of efficient coding. This principle posits that representational resources are allocated according to stimulus frequencies: distributions skewed toward smaller stimuli thus result in discriminability decreasing with magnitude, as in Webers law. Skewing frequencies in the other direction--making large magnitudes more frequent than small ones--enabled us to invert this pattern, and to break Webers law. In discrimination tasks with three different sensory modalities, human subjects discriminability across stimuli was sensitive to the stimulus distribution, and this adaptation improved task performance. These findings establish efficient coding as a dynamic, organizing principle, explaining when and why Webers law holds.

neuroscience↗

bioRxiv2026

Spatiotemporal cellular landscape of the human utricle sensory epithelium

Vestibular dysfunction affects individuals of all ages and becomes increasingly common with age. Despite the essential role of the utricle in balance, its molecular states and tissue architecture in humans remain poorly defined. Here, we integrated paired single-nucleus transcriptomic and epigenomic profiling with imaging-based spatial transcriptomics to characterize the human fetal utricle and its spatiotemporal patterning. We resolved transcriptionally heterogeneous, spatially segregated populations of sensory and nonsensory epithelial cells and reconstructed sensory cell differentiation across three gestational ages, showing that these cells acquire region-specific transcriptional signatures before final subtype specification. We further uncover a progressive decline in nonsensory cell proliferation accompanied by chromatin remodelling, as well as transitional epithelial populations with distinct spatial and regulatory programs. Together, these data define the molecular and spatial dynamics of the human fetal utricle and reveal cell states and regulatory pathways that provide a foundation for studying vestibular disorders and regeneration. HIGHLIGHTSO_LISpatial identity of utricular sensory hair cells precedes full subtype specification C_LIO_LIDistinct transcriptional regulators control hair cell fate and regional patterning C_LIO_LISupporting cells remodel chromatin as their proliferative capacity declines C_LIO_LITransitional epithelial cells adopt ordered states along the utricular border C_LIO_LISensory and nonsensory cells show divergent regulatory and signalling programs C_LI

cell biology↗

bioRxiv2026

EVEE: Interpretable variant effect prediction from genomic foundation model embeddings

Scientific foundation models learn high-dimensional representations from diverse data modalities, yet what they encode and how to extract that knowledge remain open questions. Here we show that probing the internal representations of Evo 2, a 7-billion-parameter genomic foundation model, enables accurate and interpretable genetic variant effect prediction. We introduce a covariance-based probe that captures second-order structure from Evo 2 sequence embeddings to predict variant pathogenicity across variant types and functional consequences, matching or exceeding specialized predictors within their domains. To ground these predictions in known biological mechanisms, we train a complementary panel of probes on existing annotations to detect which genomic properties are disrupted by a variant. This categorized evidence is then integrated with each variants genomic context through a language model to generate variant-specific mechanistic hypotheses. Our pathogenicity predictions correlate with experimental measures of variant function, clinical penetrance, and biobank disease associations while the mechanistic hypotheses are consistent with expert reviews, known mechanism classes, and downstream molecular readouts. We release pathogenicity scores, disruption profiles, and contextualized interpretations for 4.2 million variants from the ClinVar database as an open resource through the Evo Variant Effect Explorer (EVEE). More broadly, this structured probing approach offers a general framework for interrogating foundation models across scientific disciplines and grounding their outputs in existing domain concepts.

genomics↗

bioRxiv2026

Ripples precede insight in the right human hippocampus

Insight is a sudden transition from uncertainty to awareness of a solution, often preceded by non-conscious processing. Despite the ubiquity of insights in human cognition, the neural mechanisms underlying this pre-conscious restructuring phase remain largely unknown. Recent theoretical frameworks suggest that the hippocampus, through its capacity for rapid associative retrieval and flexible recombination of stored representations, may facilitate the non-conscious exploration that precedes insight. Hippocampal ripples associated with memory replay and consolidation, represent a promising candidate mechanism for this process. We recorded intracranial local field potentials from depth electrodes in the hippocampus of ten patients with drug-resistant epilepsy while they performed non-verbal reasoning tasks. Participants indicated the moment of solution awareness via button press, enabling precise temporal alignment of neural activity to subjective insight. We observed a significant increase in ripple rate during a pre-response window. Critically, this effect was lateralized to the right hippocampus. These findings provide the first direct human electrophysiological evidence linking right-lateralized hippocampal ripples to the non-conscious phase of insight. We propose that right hippocampal ripples support rapid retrieval and flexible recombination of representations, potentially triggering cortical processes that culminate in conscious solution awareness.

neuroscience↗

bioRxiv2025

Cell-Type-Resolved Isoform Atlas of Human Tissues Reveals Age and Alzheimer's Disease-Associated Splicing Changes

Alternative splicing is a key mechanism for transcriptomic diversity, but how isoforms map to specific cell types in bulk tissues remains unclear. We present Sciege, a multimodal method that integrates bulk short-read RNA-seq with single-cell and long-read data to estimate cell type-specific isoform distributions. Through simulations, we demonstrate that Sciege accurately estimates isoform abundances and identifies differentially abundant transcripts through statistical tests. Applied to seven tissues in GTEx and brain tissue in ROSMAP datasets, Sciege generates a first-to-date multi-tissue isoform atlas and reveals isoform changes linked to cell types, aging, and Alzheimers disease. Validation with external cohorts and experimental data confirms our findings. Notably, we identify upregulation of the MAPT-010 isoform in AD inhibitory neurons, consistent with known methylation signatures. Our approach demonstrates the value of integrating RNA-seq data to study cell type-specific splicing and provides a foundation for further genetic and functional studies of alternative splicing across biological contexts.

bioinformatics↗

bioRxiv2025

Retrospective metabolomics via dual-dimensional deconvolution using ZT Scan DIA 2.0

We present a scanning data-independent acquisition (DIA) strategy, ZT Scan DIA, combined with dual-dimensional tandem mass spectrometry spectral filtering and deconvolution along both the quadrupole and retention time axes to reconstruct compound-specific MS2 spectra from complex mixtures. This approach is particularly effective for hydrophilic metabolomics data, where spectral similarity-based annotation is widely used, increasing annotation rates by 119-193% compared with conventional data-dependent acquisition (DDA) and window-based DIA methods. In lipidomics, deconvolution improved annotation precision by removing contaminant product ions and enabled separate quantification of co-eluting isomers using MS2 chromatograms, although common diagnostic ions could also be erroneously removed. Nevertheless, optimization of analysis parameters minimized this negative effect. Furthermore, we developed a practical data processing pipeline in which raw ZT Scan DIA-MS2 chromatograms are directly used for isomer separation and MS2-based quantification, covering 1,393 and 3,020 molecules for human plasma and mouse liver tissues, respectively. All data processing steps, including direct import of vendor raw data, are supported in MS-DIAL.

bioengineering↗

bioRxiv2025

Mutation of an insulin-sensitive Drosophila insulin-like receptor mutant requires methionine metabolism reprogramming to extend lifespan

Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan across many species. Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, we recently developed a series of Drosophila insulin-like receptor (dInr) mutants with single amino acid substitutions that extend lifespan but differentially affect insulin sensitivity, growth and reproduction. Transheterozygotes of canonical dInr mutants (Type I) extend longevity and are insulin-resistant, small and weakly fecund. In contrast, a dominant mutation (dInr353, Type II) within the Kinase Insert Domain (KID) robustly extends longevity but is insulin-sensitive, full-sized, and highly fecund. We applied transcriptome and metabolome analyses to explore how dInr353 slows aging without insulin resistance. Type I and II mutants overlap in many pathways but also produce distinct transcriptomic profiles that include differences in innate immune and reproductive functions. In metabolomic analyses, the KID mutant dInr353 reprograms methionine metabolism in a way that phenocopies dietary methionine restriction, in contrast to canonical mutants which are characterized by upregulation of the transsulfuration pathway. Because abrogation of S-adenosylhomocysteine hydrolase blocks the longevity benefit conferred by dInr353, we conclude the methionine cycle reprogramming of Type II is sufficient to slow aging. Metabolomic analysis further revealed the Type II mutant is metabolically flexible: unlike aged wildtype, aged dInr353 adults can reroute methionine toward the transsulfuration pathway, while Type I mutant flies upregulate the trassulfuration pathway continuously from young age. Altered insulin/insulin growth factor signaling has the potential to slow aging without the complications of insulin resistance by modulating methionine cycle dynamics. Author SummaryMutations in the invertebrate insulin/IGF signaling system robustly extend lifespan. Yet these interventions often cause insulin resistance, reduce growth, and impair fertility. In contrast, a dominant gain-of-function mutation in the kinase insert domain of the Drosophila insulin/IGF receptor extends lifespan while maintaining insulin sensitivity, growth, or reproduction. Here, we demonstrate this unique mutation reprograms methionine metabolism pathway in a way that mirrors dietary methionine restriction, which is known to extend lifespan in several animals including Drosophila and mice. Genetic epistasis analysis verifies this methionine cycle inhibition is an underlying cause for how the kinase insert domain mutation slows Drosophila aging while maintaining insulin-sensitivity, growth, and fecundity.

physiology↗

bioRxiv2024

A Novel Gene Synthesis Platform for Designing Functional Protein Polymers

Recombinant protein polymers with repeat sequences of specific amino acids can be regarded as sustainable functional materials that can be designed using genetic engineering. However, synthesizing genes encoding these proteins is significantly time-consuming and labor-intensive owing to the difficulty of using common gene synthesis tools, such as restriction enzymes and PCR primers. To overcome these obstacles, we propose a novel method: seamless cloning of rolling-circle amplicons (SCRCA). This method involves one-pot preparation of repetitive-sequence genes with overlapping ends for cloning, facilitating the easy construction of the desired recombinants. Using SCRCA, we synthesized 10 genes encoding hydrophilic resilin-like and hydrophobic elastin-like repeat units that induce liquid-liquid phase separation. SCRCA shows higher transformation efficiency and better workability than conventional methods, and the time and budget required for SCRCA are comparable to those required for non-repetitive-sequence gene synthesis. Additionally, SCRCA allows the construction of a repeat unit library at a low cost. The library shows considerably higher diversity compared with that of the state-of-the-art method. By combining this library construction with the directed evolution concept, we can rapidly develop an elastin-like protein polymer with a desired function. SCRCA can greatly accelerate research on protein polymers.

bioengineering↗

bioRxiv2024

Stable platelet production via the bypass pathway explains the long-term reconstitution capacity of hematopoietic stem cells

Precise understanding how hematopoietic stem cells (HSCs) differentiate in vivo is difficult because we can not trace the in vivo differentiation of HSCs. The single-cell transplantation assay and our own paired daughter cell assay of phenotypic HSCs has revealed the presence of HSCs with reconstitution capacity whose differentiation potential is restricted to the myeloid lineage (MySCs) and the presence of novel direct differentiation pathway form HSCs to MySCs (named myeloid bypass pathway). However, how HSCs differentiate in vivo during hematopoiesis has remained unclear since the paired daughter cell assay was performed partially ex vivo. Aiming to characterize HSCs, including the myeloid bypass pathway, we examined the kinetics of HSC differentiation using a mathematical model. We analyzed data from single-cell transplantation assays in which five blood cell lineages were followed successively after transplantation. An age-related skewing to the myeloid lineage was quantitatively indicated as the production of B cells reduced with age. Dependence on platelet bypass increased with aging and consistently high dependence was associated with long-term reconstitution capacity of the HSCs. Focusing on the ratio of chimerism among cell lineages, the characteristics of dependence on platelet bypass can be accurately determined by the ratio of erythrocyte to platelet chimerism at 8 weeks after transplantation. This new identification criterion is an indicator of long-term reconstitution of HSCs that does not rely on observation of long-term transplantation experiments. These findings reveal the novel characteristics of HSCs related to aging and stemness and highlight the importance of the bypass pathway in HSC differentiation. Significance statementIn vivo differentiation of hematopoietic stem cells (HSCs) is important for understanding blood cell production. Here we investigated the differentiation kinetics of HSCs in single-cell transplantation assays by using a mathematical model. Our findings demonstrate the importance of the bypass pathway in platelet production for the long-term reconstitution capacity of HSCs. These results also suggest the utility of studying time changes in HSC differentiation. The new HSC characteristics and its detection criteria identified in this study are expected to be useful in understanding HSC diversity and aging.

cell biology↗

bioRxiv2024

Overexpression of diglucosyldiacylglycerol synthase leads to daptomycin resistance in Bacillus subtilis

The lipopeptide antibiotic daptomycin exhibits bactericidal activity against gram-positive bacteria by forming a complex with phosphatidylglycerol (PG) and lipid II in the cell membrane, causing membrane perforation. With the emergence of daptomycin-resistant bacteria, understanding the mechanism of bacterial resistance to daptomycin has gained great importance. In the present study, we found that overexpression of ugtP, which encodes a diglucosyldiacylglycerol synthase, resulted in daptomycin resistance in Bacillus subtilis. The amount of diglucosyldiacylglycerol (Glc2DAG) increased in the ugtP-overexpressed strain, whereas the amounts of the acidic phospholipids cardiolipin (CL) and PG and the basic phospholipid lysylphosphatidylglycerol (Lys-PG) decreased. Moreover, ugtP overexpression did not alter the cell surface charge or the susceptibility to the cationic antimicrobial peptide nisin or the cationic surfactant hexadecyltrimethylammonium bromide (CTAB). Furthermore, under daptomycin exposure, we obtained daptomycin-resistant mutants that carried ugtP mutations and showed increased amounts of Glc2DAG and more than 4-fold increase in the MIC of daptomycin. These results suggest that an increase in the amount of Glc2DAG changes the phospholipid composition and leads to daptomycin resistance without altering the bacterial cell surface charge in B. subtilis. ImportanceDaptomycin is one of the last-resort drugs for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, and the emergence of daptomycin-resistant bacteria has become a problem. Understanding the mechanism of daptomycin resistance is important for establishing clinical countermeasures against daptomycin-resistant bacteria. In the present study, we found that overexpression of ugtP, which encodes diglucosyldiacylglycerol synthase, causes daptomycin resistance in B. subtilis, a model organism for gram-positive bacteria. Overexpression of ugtP increased diglucosyldiacylglycerol levels, resulting in altered phospholipid composition and daptomycin resistance. These findings are important for establishing clinical strategies against daptomycin-resistant bacteria, including their detection.

microbiology↗

bioRxiv2024

Atlas of Cynomolgus Macaque Hematopoiesis

Self-renewal and differentiation are inherent properties of hematopoietic stem cells (HSCs) that are necessary to support hematopoiesis; however, the underlying mechanisms, especially in human, remain unclear. Here, using the cynomolgus macaque as a surrogate model, we develop a new gating strategy to isolate with high purity transplantable cynomolgus HSCs and generated a single-cell transcriptomic map of cynomolgus HSCs and progenitor cells -- that covering gestational periods previously not analyzed in human. We show that hematopoietic cells from the late-1st to early-3rd trimester fetal liver and late-2nd trimester and thereafter bone marrow have repopulating potential, closely mimicking humans. Unexpectedly however, we found unlike in human, cynomolgus HSCs express CD38 but not CD33, indicating that these cellular counterparts are molecularly distinct. Our transcriptomic analysis reveals the presence of a direct differentiation pathway from HSCs to megakaryocyte lineages, lineage-primed multipotent progenitors and also identified putative HSC surface markers. Taken together, our comprehensive dataset highlights not only the utility of cynomolgus monkeys as model systems to study hematopoiesis but also their potential for translational applications.

cell biology↗

bioRxiv2024

Molecular differences between neonatal and adult stria vascularis from organotypic explants and transcriptomics

SummaryThe stria vascularis (SV), part of the blood-labyrinth barrier, is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and adult mice to create a robust platform for SV research. We validated our model by demonstrating that the proliferative behaviour of the SV in vitro mimics SV in vivo, providing a representative model and advancing high-throughput SV research. We also provided evidence for pharmacological intervention in our system by investigating the role of Wnt/{beta}-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing from in vivo neonatal and adult mouse SV and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss. SignificanceHearing loss impairs our ability to communicate with people and interact with our environment. This can lead to social isolation, depression, cognitive deficits, and dementia. Inner ear degeneration is a primary cause of hearing loss, and our study provides an in depth look at one of the major sites of inner ear degeneration: the stria vascularis. The stria vascularis and associated blood-labyrinth barrier maintain the functional integrity of the auditory system, yet it is relatively understudied. By developing a new in vitro model for the young and adult stria vascularis and using single cell RNA sequencing, our study provides a novel approach to studying this tissue, contributing new insights and widespread implications for auditory neuroscience and regenerative medicine. Highlights- We established an organotypic explant system of the neonatal and adult stria vascularis with an intact blood-labyrinth barrier. - Proliferation of the stria vascularis decreases with age in vitro, modelling its proliferative behaviour in vivo. - Pharmacological studies using our in vitro SV model open possibilities for testing injury paradigms and therapeutic interventions. - Inhibition of Wnt signalling decreases proliferation in neonatal stria vascularis. - We identified key genes and transcription factors unique to developing and mature SV cell types using single cell RNA sequencing.

molecular biology↗

bioRxiv2023

dsRID: Editing-free in silico identification of dsRNA region using long-read RNA-seq data

Double-stranded RNAs (dsRNAs) are potent triggers of innate immune responses upon recognition by cytosolic dsRNA sensor proteins. Identification of endogenous dsRNAs helps to better understand the dsRNAome and its relevance to innate immunity related to human diseases. Here, we report dsRID (double-stranded RNA identifier), a machine learning-based method to predict dsRNA regions in silico, leveraging the power of long-read RNA-sequencing (RNA-seq) and molecular traits of dsRNAs. Using models trained with PacBio long-read RNA-seq data derived from Alzheimers disease (AD) brain, we show that our approach is highly accurate in predicting dsRNA regions in multiple datasets. Applied to an AD cohort sequenced by the ENCODE consortium, we characterize the global dsRNA profile with potentially distinct expression patterns between AD and controls. Together, we show that dsRID provides an effective approach to capture global dsRNA profiles using long-read RNA-seq data.

bioinformatics↗

bioRxiv2023

EBF1 limits the numbers of cochlear hair and supporting cells and forms the scala tympani and spiral limbus during the development of the inner ear

Early B-cell factor 1 (EBF1) is a basic helix-loop-helix transcription factor essential for the differentiation of various tissues. Our single-cell RNA sequencing data suggest that Ebf1 is expressed in the sensory epithelium of the inner ear. Here, we found that the Ebf1 gene and its protein are expressed in the prosensory domain of the inner ear, medial region of the cochlear floor, inner ear mesenchyme, and cochleo-vestibular ganglion. Ebf1 deletion results in incomplete formation of the spiral limbus and scala tympani, increased number of cells in the organ of Corti and Kollikers organ, and aberrant course of the spiral ganglion axons. The inner ear-specific deletion of Ebf1 revealed that scala tympani formation depended on Ebf1 expressed in the otic mesenchyme. Ebf1 deletion in the cochlear epithelia caused the proliferation of SOX2-positive cochlear cells at E13.5, indicating that EBF1 suppresses the proliferation of the prosensory domain and cells of Kollikers organ to facilitate the development of appropriate numbers of hair and supporting cells. Furthermore, mice with deletion of cochlear epithelium-specific Ebf1 showed poor postnatal hearing function. Our results suggest that Ebf1 is essential for normal auditory function in mammals.

developmental biology↗

bioRxiv2023

Reconstructing cellular differentiation networks and identifying cell fate-determining features with CIBER

Trajectory inference methods are frequently used for cell fate analysis, however, most of them are similarity-based and lack an understanding of the causality underlying differentiation processes. Here, we present CIBER, a Causal Inference-Based framework for the Evaluation of feature effects and the Reconstruction of cellular differentiation networks. CIBER provides a novel paradigm for dissecting cell state transitions other than trajectory inference and differential analysis. It is a versatile framework that can be applied to various types of data, including transcriptomic, epigenomic and microarray data. It can identify both known and potential cell-lineage structures with minimal prior knowledge. By integrating the CIBER-learned network with structural causal model and applying in silico perturbation as inventions, we generated an effect matrix that quantifies the impact of different features on each differentiation branch. Using this effect matrix, CIBER can identify crucial features involved in haematopoiesis, even if these features show no significant difference in expression between lineages. Moreover, CIBER can predict novel regulation associations and provide insight into the potential mechanism underlying the influence of transcription factors on biological processes. To validate CIBERs capabilities, we conducted in vivo experiments on Bcl11b, a non-differentially expressed transcription factor identified by CIBER. Our results demonstrate that dysfunction of Bcl11b leads to a bias towards myeloid lineage differentiation at the expense of lymphoid lineage, which is consistent with our predictions.

systems biology↗

bioRxiv2022

Estimation of crossbridge-state during cardiomyocyte beating using second harmonic generation

Estimation of dynamic change of crossbridge formation in living cardiomyocytes is expected to provide crucial information for elucidating cardiomyopathy mechanisms, efficacy of an intervention, and other parameters. Here, we developed an assay system to dynamically measure second harmonic generation (SHG) polarization in pulsating cardiomyocyte and proved that the SHG anisotropy derived from myosin filaments in disease-model cardiomyocytes depended on their crossbridge status, providing an evaluation method for myosin force generation. Experiments utilizing an inheritable mutation that induces excessive myosin-actin interactions revealed that the correlation between sarcomere length and SHG anisotropy represents crossbridge formation ratio during pulsation. Furthermore, the present method found that ultraviolet irradiation induced an increased population of attached crossbridges that lost force-generating ability upon myocardial differentiation, causing acquired dysfunction. Taking an advantage of infrared two-photon excitation in SHG microscopy, myocardial dysfunction could be intravitally evaluated in a Drosophila disease model. Thus, along with the establishment of the methodology, we successfully demonstrated the applicability and effectiveness of the present method to evaluate the actomyosin activity of a drug or genetic defect on living cardiomyocytes.

biophysics↗

bioRxiv2022

Single-cell RNA-seq reveals stepwise fate conversion of supporting cells to hair cells in the chick auditory epithelium

In contrast to mammals, the avian cochlea, specifically the basilar papilla, can regenerate sensory hair cells, which involves fate conversion of supporting cells to hair cells. To determine the mechanisms for converting supporting cells to hair cells, we used single-cell RNA sequencing during hair cell regeneration in explant cultures of chick basilar papillae. We identified dynamic changes in the gene expression of supporting cells, and the pseudotime trajectory analysis demonstrated the stepwise fate conversion from supporting cells to hair cells. Initially, supporting cell identity was erased and transition to the precursor state occurred. A subsequent gain in hair cell identity progressed together with downregulation of precursor-state genes. Transforming growth factor beta receptor 1-mediated signaling was involved in induction of the initial step, and its inhibition resulted in suppression of hair cell regeneration. Our data provide new insights for understanding fate conversion from supporting cells to hair cells in avian basilar papillae.

neuroscience↗

bioRxiv2021

Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Age is the primary risk factor for many common human diseases including heart disease, Alzheimers dementias, cancers, and diabetes. Determining how and why tissues age differently is key to understanding the onset and progression of such pathologies. Here, we set out to quantify the relative contributions of genetics and aging to gene expression patterns from data collected across 27 tissues from 948 humans. We show that age impacts the predictive power of expression quantitative trait loci across several tissues. Jointly modelling the contributions of age and genetics to transcript level variation we find that the heritability (h2) of gene expression is largely consistent among tissues. In contrast, the average contribution of aging to gene expression variance varied by more than 20-fold among tissues with [Formula] in 5 tissues. We find that the coordinated decline of mitochondrial and translation factors is a widespread signature of aging across tissues. Finally, we show that while in general the force of purifying selection is stronger on genes expressed early in life compared to late in life as predicted by Medawars hypothesis, a handful of highly proliferative tissues exhibit the opposite pattern. These non-Medawarian tissues exhibit high rates of cancer and age-of-expression associated somatic mutations in cancer. In contrast, gene expression variation that is under genetic control is strongly enriched for genes under relaxed constraint. Together we present a novel framework for predicting gene expression phenotypes from genetics and age and provide insights into the tissue-specific relative contributions of genes and the environment to phenotypes of aging.

genetics↗