Biology subjects

Schroeder, M.

Publications and source records attributed to Schroeder, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Genetic Diversity and Population Structure of the Black-Footed Cat: Insights into Felis's Deadliest Predator

BackgroundBlack-footed cats (Felis nigripes) are one of Africas least studied felines. The population dynamics and demographic history of this solitary species have not been well-described. Reports of ongoing decline of present-day populations resulted in the IUCN Red List categorizing the species as vulnerable to extinction. As populations decline and become isolated from each other, they become susceptible to strong genetic drift and inbreeding, which can lead to the accumulation of deleterious alleles and increased sextinction risk. However, the IUCN cited data deficiencies across the species range as a limitation in this categorization for black-footed cats. In cases where ecological surveys are lacking, range-wide population genomic surveys can improve our understanding of population dynamics. ResultsIn the first genomic study of free-roaming individuals, we sequenced whole genomes of black-footed cats (N=44) from across their distribution. To do so, we incorporated whole genome sequences generated from both modern biological samples and century-old museum specimens. We assembled a highly contiguous reference genome using a combination of PacBio HiFi data and publicly available Hi-C data and investigated the demographic history, population structure, and genetic diversity of wild black-footed cats. We found evidence of historical effective population sizes of [~]11,500 individuals, which is lower than estimates reported in other felid species. Consistent with modest historical population sizes, we found that present-day genome-wide diversity was low ({pi} {approx} 0.0004). However, despite low genetic diversity, we find that black-footed cat genomes do not harbor long runs of homozygosity. Simulation results indicate that low present-day genetic diversity may simply result from modest historical population size. However, other analyses point to evidence of a population contraction in the last 50 generations, which could contribute to future genomic erosion. We also compared genomic variation in populations across the range to evaluate patterns of population structure, finding evidence of higher genetic similarity between individuals in closer geographic proximity. ConclusionOverall, these results provide range-wide information about the demographic history and present-day genetic diversity of an understudied species. Together with analyses of population structure, we speculate that there may be greater connectivity between populations of black-footed cats than previously assumed. Our study underscores the utility of genomic data in providing insights into population dynamics for better conservation management.

evolutionary biology↗

bioRxiv2026

Structural alphabets approach performance of structural alignment in remote homology detection

MotivationRemote homology detection (RHD) is central to fold recognition and protein function annotation. While structural alignments provide a gold standard, they are computationally expensive. Encoding protein structures as sequences over structural alphabets offers a scalable alternative, but the relative performance of simple secondary-structure alphabets versus higher-resolution representations remains unclear. ResultsWe systematically compare 20-letter (3Di), 8-letter (Q8), and 3-letter (Q3) structural alphabets across three large-scale fold recognition benchmarks of increasing difficulty, using both advanced and basic sequence alignment algorithms. All three alphabets perform close to structural alignment gold standards and substantially outperform sequence-based methods. Remarkably, the minimal Q3 alphabet, distinguishing only helices, strands, and loops, achieves robust performance. We further demonstrate the practical utility of this finding in a protein function annotation task for a newly sequenced genome. Data AvailabilityBenchmark data are freely available at https://doi.org/10.6084/m9.figshare.c.8208161. Contactmichael.schroeder@tu-dresden.de Supplementary InformationSupplementary data are available online at the journal website.

bioinformatics↗

bioRxiv2025

Much ado about nothing: Modelling amino acid replacement with predicted protein structures

Substitution matrices like BLOSUM62 model the likelihood of replacement of amino acids in evolution. Substitution matrices are used in protein sequence alignment tasks. Since the introduction of BLOSUM62 over three decades ago, many matrices have been released. Yet, to date, no effort uses large amounts of 3D structures predicted by AlphaFold. Here, we define AFSM, the AlphaFold Substitution Matrix derived from over 20,000 predicted 3D structures following the BLOSUM methodology. We benchmark AFSM against BLOSUM62 and 16 other matrices on five tasks in multiple sequence alignment (MSA) and protein homology search. Our analysis surprisingly reveals that all matrices perform similarly. Only when there are few sequences in an MSA, then BLOSUM62 and AFSM perform better than using no matrix. This suggests that substitution matrices were most beneficial when there was little sequence data. We corroborate this argument by showing that embeddings, which are computed from billions of sequences, perform better than substitution matrices, when sequence data is sparse. Taken together, this suggests that structural data does not improve BLOSUM62. But increased sequence data makes extrapolation with substitution matrices obsolete. Nonetheless, BLOSUM62 continues to capture chemists intuition on amino acids by providing numerical values implicitly reflecting physicochemical properties, and it remains indispensable for direct comparison of two sequences.

bioinformatics↗

bioRxiv2025

Un-LOK-ing a new approach for conformational selective targeting of STK10 (LOK)

STK10 (serine/threonine kinase 10, LOK), is an important regulator of diverse cellular processes, such as cell cycle progression or lymphocyte migration. STK10 has emerged as a potential therapeutic target for diseases associated with impaired cell migration and cell division. Here we present a late-stage optimization of a macrocyclic pyrazolo[1,5-a]pyrimidine scaffold that led to a urea-based lead series targeting the back-pocket of STK10. Co-crystal structure analysis of 23 revealed that the optimized macrocycles adopted a unique binding mode that protrudes deep into the back pocket of STK10. Compound 23 exhibited potent on-target activity in biophysical and activity assays and displayed nanomolar activity for STK10 in cells. In addition, 23 shows good selectivity against the kinome and remarkably also against the closely related kinase SLK (STE20-like kinase). Therefore, we propose that targeting the unique and largely extended pocket in STK10 represents an opportunity to develop highly selective STK10 inhibitors. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/666149v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@36f039org.highwire.dtl.DTLVardef@d55025org.highwire.dtl.DTLVardef@80c007org.highwire.dtl.DTLVardef@bf2471_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Sustaining the cell energy in dynamic environments requires photosynthetic electron flows with diverse bandwidths

All living cells depend on the dynamic balance between their energy supply and demand to survive and thrive in dynamic environments. In extreme cases, like for photosynthetic organisms, their energy source, light, can fluctuate dramatically in intensity over timescales of seconds to hours. While various photosynthetic electron flows (EF) are crucial for maintaining bioenergetic homeostasis, how EFs are modulated to respond to dynamic energy intake remains unclear. Here, we show in the model green alga Chlamydomonas reinhardtii that each EF is best suited to a specific domain of energetic fluctuation periodicity for which it can support the cells energetic needs, which we term bandwidth. By systematically exposing cells to a range of light periodicities, we show that while cyclic EF has a large bandwidth, pseudo-cyclic EF (PCEF) can only sustain the cells energetic needs for fast light fluctuations, and that the interplay between the chloroplast and the mitochondria (CMEF) has a limited bandwidth. We further show that the bandwidths of PCEF and CMEF, specialized for dynamic lights, are related to their capacity to generate ATP and protect the photosynthetic apparatus. Finally, we show that in wild-type cells, the activity level of PCEF matches its bandwidth, and we propose that cells tune the relative activity of AEFs depending on the light fluctuation frequency. Our work opens an avenue of research to characterize the molecular mechanisms that can sustain phototrophic growth in complex and dynamic energetic landscapes. It further provides a generalizable framework for understanding the physiological importance of molecular mechanisms in a dynamic environment.

plant biology↗

bioRxiv2025

The structural basis of drugs targeting protein-protein interactions uncovered with the protein-ligand interaction profiler PLIP

Promiscuity of drugs and targets plays an important role in drug-target prediction, ranging from the explanation of side effects to their exploitation in drug repositioning. A specific form of promiscuity concerns drugs, which interfere with protein-protein interactions. With the rising importance of such drugs in drug discovery and with the large-scale availability of structural data, the question arises on the structural basis of this form of promiscuity and the commonalities of the underlying protein-ligand (PLI) and protein-protein interactions (PPI). To this end, we employ the protein-ligand interaction profiler, PLIP, to characterize the PLI and PPI of MDM2/p53, Bcl-2/BAX, XIAP/Casp9, CCR5/gp120, and BRD/H4. We show that the wealth of existing complexes in PDB, of predicted protein structures, and of molecular docking results gives deep insights into the design principles for drugs targeting protein interactions. Drugs targeting protein interaction interfaces are a promising avenue in drug discovery. Understanding drug and target promiscuity at a structural level will pave the way to deliver on this promise.

bioinformatics↗

bioRxiv2025

Proximity determines donor candidacy during DNA double-stranded break homology directed repair

DNA double-stranded breaks (DSBs) are especially toxic events that can be reversed by homology-directed repair (HDR), wherein information is copied from an intact template molecule. RAD51 mediates initial DSB/template pairing during homology search. A major challenge in understanding homology search in cells is the lack of tools to monitor this process. We developed RAD51 proximity identification sequencing (RaPID-seq), a sensitive method that marks all candidate templates searched by RAD51. We find that HDR is hierarchical, such that DSB proximity determines template candidacy and subsequent recombination is unlocked by DSB/template homology. Sequences that lie outside the proximal window are not efficiently searched, even if identical in sequence. Our data reveal the invisible process of homology search and shed new light on fundamental mechanisms underlying genome editing.

molecular biology↗

bioRxiv2024

A cereblon (CRBN) molecular glue degrader of NIMA-related kinase 7 (NEK7) reveals a context-dependent role in NLRP3 inflammasome activation

The NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome is a cytoplasmic signaling complex that promotes inflammation in response to signals from infection and cellular damage. Increased activation of the NLRP3 inflammasome is linked to numerous diseases including gout, osteoarthritis, cardiovascular disease, neuroinflammatory diseases and cancer, which has prompted the search for therapeutics that can inhibit the NLRP3 pathway. Recent work suggested that NIMA-related kinase 7 (NEK7) may be required for proper assembly and activation of the NLRP3 inflammasome independent of its kinase activity, and that hence reduction of NEK7 protein levels may block NLRP3 activation. Since NEK7 contains a glycine beta hairpin loop structural degron found in many targets of cereblon (CRBN) molecular glue degraders, we used this strategy to degrade NEK7 and inhibit the NLRP3 inflammasome. We identified NK7-902, a CRBN glue degrader of NEK7. NK7-902 potently and selectively degraded NEK7 in human primary monocytes, peripheral blood mononuclear cells (PBMCs) and whole blood. Unexpectedly, full NEK7 degradation led to only partial blockade of NLRP3-dependent interleukin-1{beta} (IL-1{beta}) release in these cells under different stimulation conditions, with the extent of IL-1{beta} inhibition varying greatly across donors. Unlike most CRBN glue degraders, NK7-902 degraded NEK7 in mouse cells and efficiently inhibited NLRP3-dependent IL-1{beta} release in a mouse cryopyrin-associated syndrome (CAPS) model. By contrast, oral administration of NK7-902 in non-human primates led to profound and long lasting NEK7 degradation but only transiently blocked IL-1{beta} production in blood. Collectively, our data suggest that NEK7 is involved but may not be strictly required for NLRP3 activation in primates and humans. HighlightsO_LIIdentification of NK7-902, a CRBN molecular glue degrader of NEK7 C_LIO_LINK7-902 fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3-dependent IL-1{beta} production C_LIO_LIUnlike most CRBN glue degraders, NK7-902 shows activity in murine systems C_LIO_LIIn vivo oral administration of NK7-902 in non-human primates leads to profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation C_LI

immunology↗

bioRxiv2024

Effect of digital noise-reduction processing on subcortical speech encoding and relationship to behavioral outcomes

Perceptual benefits from digital noise reduction (NR) vary among individuals with different noise tolerance and sensitivity to distortions introduced in NR-processed speech; however, the physiological bases of the variance are understudied. Here, we developed objective measures of speech encoding in the ascending pathway as candidate measures of individual noise tolerance and sensitivity to NR-processed speech using the brainstem responses to speech syllable /da/. The speech-evoked brainstem response was found to be sensitive to the addition of noise and NR processing. The NR effects on the consonant and vowel portion of the responses were robustly quantified using response-to-response correlation metrics and spectral amplitude ratios, respectively. Further, the f0 amplitude ratios between conditions correlated with behavioral accuracy with NR. These findings suggest that investigating the NR effects on bottom-up speech encoding using brainstem measures is feasible and that individual subcortical encoding of NR-processed speech may relate to individual behavioral outcomes with NR.

neuroscience↗

bioRxiv2024

pr-independent biogenesis of infectious mature Zika virus particles

Flavivirus assembly at the endoplasmic reticulum is driven by the structural proteins envelope (E) and premembrane (prM). Here, contrary to the established paradigm for flavivirus assembly, we demonstrate that the biogenesis of flavivirus particles does not require an intact prM nor proteolytic activation. The expression of E preceded by a truncated version of prM (M-E) was sufficient for the formation of non-infectious Zika virus subviral particles and pseudo-infectious reporter virions. Subviral particles encoded by a ZIKV M-E DNA vaccine elicited a neutralizing antibody response that was insensitive to the virion maturation state, a feature of flavivirus humoral immunity shown to correlate with protection. M-E vaccines that uniformly present structural features shared with mature virions offer a higher quality and broadly applicable approach to flavivirus vaccination.

microbiology↗

bioRxiv2024

Protein secondary structure and remote homology detection

1A protein can be represented by its primary, secondary, or tertiary structure. With recent advances in AI, there is now as much tertiary as primary structural data available. Fast and accurate search methods exist for both types of data, with searches over both representations being highly precise. However, primary structure data can sometimes be incomplete. As a result, tertiary structure has become the gold standard for remote homology detection. How does secondary structure perform in remote homology detection? Secondary structure interprets proteins as a sequence using an alphabet representing helices, strands, or loops. It shares its sequential nature with primary structure while retaining topological information similar to tertiary structure. To assess the effectiveness of secondary structure in remote homology detection, we devised a challenging classification task aimed at determining the superfamily membership of very distantly related protein domains. We used benchmarks from the CATH and SCOP databases and evaluated sequence and structure alignment algorithms on primary, secondary, and tertiary structures. As expected, both basic and advanced sequence alignment algorithms applied to primary structure achieved high precision, but their overall area under the curve was lower compared to the gold standard of structural alignment using tertiary structure. Surprisingly, a simple string comparison algorithm applied to secondary structure performed close to the gold standard. This result supports the hypothesis that key structural information is already encoded in secondary structure and suggests that secondary structure may be a promising representation to use when high-confidence structural data is unavailable, such as in cases involving protein flexibility and disorder.

bioinformatics↗

bioRxiv2024

The Rad52 superfamily as seen by AlphaFold

1Rad52, a highly conserved eukaryotic protein, plays a crucial role in DNA repair, especially in double-strand break repair. Recent findings reveal that its distinct structural features, including a characteristic {beta}-sheet and {beta}-hairpin motif, are shared with the lambda phage single-strand annealing proteins, Red{beta}, indicating a common superfamily. Our analysis of over 10,000 single-strand annealing proteins (SSAPs) across all kingdoms of life supports this hypothesis, confirming their possession of the characteristic motif despite variations in size and composition. We found that archaea, representing only 1% of the studied proteins, exhibit most of these variations. Through the examination of four representative archaeal SSAPs, we elucidate the structural relationship between eukaryotic and bacterial SSAPs, highlighting differences in {beta}-sheet size and {beta}-hairpin complexity. Furthermore, we identify an archaeal SSAP with a structure nearly identical to the human variant and screen over 100 million unannotated proteins for potential SSAP candidates. Our computational analysis complements existing sequence with structural evidence supporting the suggested orthology among five SSAP families across all kingdoms: Rad52, Red{beta}, RecT, Erf, and Sak3.

bioinformatics↗

bioRxiv2023

Comprehensive Interrogation of Synthetic Relationships in the Human DNA Damage Response

The DNA damage response (DDR) is a multi-faceted network of pathways that preserves genome stability. Unraveling the complementary interplay between these pathways remains a challenge. Here, we comprehensively mapped genetic interactions for all core DDR genes using combinatorial CRISPRi screening. We discovered myriad new connections, including interactions between cancer genes and small molecule targets. We focused on two of the strongest interactions: FEN1/LIG1:WDR48 and FANCM:SMARCAL1. First, we found that WDR48 works with USP1 to restrain overactive translesion synthesis in FEN1/LIG1-deficient cells, and that a preclinical inhibitor of USP1 specifically kills FEN1-deficient cells. Second, we found that SMARCAL1 and FANCM suppress DNA double-strand break (DSB) formation at TA-rich repeats in late replicating regions that otherwise escape into mitosis and cause nuclear fragmentation. We present fundamental insights into genome maintenance processes and our dataset provides a springboard for mechanistic investigations into connections between DDR factors and suggests multiple interactions that could be exploited in cancer therapy.

cell biology↗

bioRxiv2023

Epitope Engineered Human Haematopoietic Stem Cells are Shielded from CD123-targeted Immunotherapy

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE) or chimeric antigen receptor (CAR) cells is very effective for haematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for immunotherapy of myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various haematological malignancies, including acute myeloid leukaemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). However, shared expression of CD123 on healthy haematopoietic stem and progenitor cells (HSPCs) bears the risk for extensive myelotoxicity upon targeted depletion. Here, we demonstrate that rationally designed, epitope-engineered HSPCs were completely shielded from CD123-targeted immunotherapy but remained fully functional while CD123-deficient HSPCs displayed a competitive disadvantage. Thus, molecularly shielded HSPCs could allow tumor-selective targeted immunotherapy and in parallel enable rebuilding a fully functional haematopoietic system. We envision that this approach is broadly applicable to many targets and cells, could render hitherto undruggable targets accessible to immunotherapy and will allow continued posttransplant immunotherapy, for instance to treat minimal residual disease (MRD) or be used as a salvage therapy. Since the function of the engineered targets is preserved, multiplexed molecular shielding could also enable targeted combination immunotherapies to address tumor heterogeneity. More generally, epitope shielding will be applicable for replacement of other cell types including the many immune cells which are currently being considered for engineered cellular therapies.

bioengineering↗

bioRxiv2023

Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings

Targeted protein degradation (TPD) of neo-substrates with proteolysis targeting chimeras (PROTACs) or molecular glues has emerged as a key modality in exploring new biology as well as designing new drug candidates where catalytic inhibition is neither efficacious nor an option. TPD is mediated through harnessing E3 ligases and redirecting them to ubiquitinate de novo target proteins for subsequent proteasomal degradation. Until recently, E3 ligase chemical matter available for mediating TPD has been limited to a relatively low number of ligases, considering that over 600 E3 ligases are encoded by the human genome. In addition, the most utilized ligase for TPD approaches, CRBN, has been observed to be downregulated in settings of acquired resistance to immunomodulatory inhibitory drugs (IMiDs). IMiDs are molecular glues that target IKZF transcription factors to CRBN for degradation. Resistance is potentially accelerated by non-essentiality of CRBN for cell viability. Here we investigated if the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a potent, non-covalent DCAF1 binder. We show that this binder, selective for the CRL4DCAF1 E3 ligase complex, can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirm specific degradation via the CRL4DCAF1 E3 ligase. We further highlight the versatility of DCAF1 for TPD by developing a DCAF1-dasatininb PROTAC targeting multiple cytosolic and membrane bound tyrosine kinases. We expand these findings towards Brutons tyrosine kinase (BTK) selective PROTACs and through extensive optimization and characterization efforts share key observations that led to a potent and selective DCAF1-BTK PROTAC (DBt-10). Finally, with this PROTAC DBt-10, we show rescue of BTK degradation in a BTK-dependent, CRBN-degradation-resistant cell line and provide a rationale for E3 ligase swap to overcome CRBN mediated resistance.

biochemistry↗

bioRxiv2023

The BOD1L subunit of the mammalian SETD1A complex sustains the expression of DNA damage repair genes despite restraining H3K4 trimethylation

SETD1A is the histone 3 lysine 4 (H3K4) methyltransferase central to the mammalian version of the highly conserved eight subunit Set1 complex (Set1C) that apparently conveys H3K4 trimethylation (H3K4me3) onto all active Pol II promoters. Accordingly, the Setd1a mouse knock-out dies in early embryogenesis at the epiblast stage and mouse embryonic stem cells (ESCs) die when SETD1A is removed. We report that ESC death is accompanied by loss of expression of DNA repair genes and accumulating DNA damage. BOD1L and BOD1 are homologs of the yeast Set1C subunit, Shg1, and subunits of the mammalian SETD1A and B complexes. We show that the Shg1 homology region binds to a highly conserved central alpha-helix in SETD1A and B. Like mutagenesis of Shg1 in yeast, conditional mutagenesis of Bod1l in ESCs promoted increased H3K4 di- and tri-methylation but also, like loss of SETD1A, loss of expression of DNA repair genes, increased DNA damage and cell death. In contrast to similar losses of DNA repair gene expression, the converse changes in H3K4 methylation after loss of SETD1A or BOD1L implies that H3K4 methylation is not essential for expression of the target DNA repair genes. Because BOD1L becomes highly phosphorylated after DNA damage and acts to protect damaged replication forks, the SETD1A complex, and BOD1L in particular, are key nodes for the DNA damage repair network.

cell biology↗

bioRxiv2023

Diatom adhesive trail proteins acquired by horizontal gene transfer from bacteria serve as primers for marine biofilm formation

O_LIBiofilm-forming benthic diatoms are key primary producers in coastal habitats, where they frequently dominate sunlit submerged and intertidal substrata. The development of a unique form of gliding motility in raphid diatoms was a key molecular adaptation that contributed to their evolutionary success. Gliding motility is hypothesized to be driven by an intracellular actin-myosin motor and requires the secretion of polysaccharide- and protein-based adhesive materials. To date, the structure-function correlation between diatom adhesives utilized for gliding and their relationship to the extracellular matrix that constitutes the diatom biofilm is unknown. C_LIO_LIProteomics analysis of the adhesive material from Craspedostauros australis revealed eight novel, diatom-specific proteins. Four of them constitute a new family of proteins, named Trailins, which contain an enigmatic domain termed Choice-of-Anchor-A (CAA). Immunostaining demonstrated that Trailins are only present in the adhesive trails required to generate traction on native substrata, but are absent from the extracellular matrix of biofilms. Phylogenetic analysis and Protein 3D structure prediction suggests that the CAA-domains in Trailins were obtained from bacteria by horizontal gene transfer, and exhibit a striking structural similarity to ice-binding proteins. C_LIO_LIOur work advances the understanding of the molecular basis for diatom underwater adhesion and biofilm formation providing evidence that there is a molecular switch between proteins required for initial surface colonization and those required for 3D biofilm matrix formation. C_LI

plant biology↗

bioRxiv2022

Global analysis of the yeast knock-out phenome

Genome-wide phenotypic screens in the budding yeast Saccharomyces cerevisiae have produced the largest, richest and most systematic phenotypic description of any organism. Such an achievement was enabled by the development of highly scalable phenotypic assays and construction of the yeast knock-out (YKO) collection, comprising ~5,000 isogenic strains each deleted for exactly one open reading frame. Systematic screening of the YKO collection led to ~500 publications describing ~14,500 phenotypes capturing nearly every aspect of yeast biology. Yet, integrative analyses of this rich data source have been virtually impossible due to the lack of a central repository and consistent meta-data annotations. Here, we describe the aggregation, harmonization and analysis of all published phenotypic screens of the YKO collection, which we refer to as the Yeast Phenome (www.yeastphenome.org). To demonstrate the power of data integration and illustrate how much it facilitates the generation of testable hypotheses, we present three discoveries uniquely enabled by Yeast Phenome. First, we use the variation in the number of phenotypes per gene to identify tryptophan homeostasis as a central point of vulnerability to a wide range of chemical compounds, including FDA-approved drugs. Second, using phenotypic profiles as a tool for predicting gene function, we identify and validate the role of YHR045W as a novel regulator of ergosterol biosynthesis and DNA damage response, and YGL117W as a new member of the aromatic amino acid biosynthesis pathway. Finally, we describe a surprising exponential relationship between phenotypic similarity and intergenic distance in both yeast and human genomes. This relationship, which stretches as far as 380 kb in yeast and 100 Mb in humans, suggests that gene positions are optimized for function to a much greater extent than appreciated previously. Overall, we show that Yeast Phenome enables systematic enquiries into the nature of gene-gene and gene-phenotype relationships and is an important new resource for systems biology.

systems biology↗