Biology subjects

Velazquez-Arcelay, K.

Publications and source records attributed to Velazquez-Arcelay, K..

4 recordsLinked to original sources

bioRxiv2026

A single-cell and spatial atlas of prostate cancer reveals the combinatorial nature of gene modules underlying lineage plasticity and metastasis

Prostate cancer encompasses a spectrum of disease states driven by complex cellular heterogeneity. To delineate the transcriptional programs underlying lineage plasticity and metastasis, we constructed a comprehensive single-cell atlas of 128 patients, spanning localized, castration-resistant, and metastatic disease. Lineage plasticity was prevalent in localized disease, with subsets of tumor cells adopting distinct basal-like and club-like states. Luminal-like cancer cells also displayed extensive lineage infidelity, defined not by a binary loss of identity but by the combinatorial erosion of luminal gene modules associated with higher grade and stage. In the metastatic setting, gene program association analysis (GPAS) identified a broad induction of cell-cycle gene modules across organ sites as well as an induction of organ-specific gene modules, including osteomimetic signaling in bone, neuro-migratory genes in brain, and erythroid-like transitions in liver. Neuroendocrine prostate cancers (NEPCs) were not monolithic but defined by combinations of NE-associated gene modules including a novel HES6 program. Notably, these modules were detected at intermediate levels in localized samples, suggesting molecular plasticity precedes histological transformation. We also developed a refined NE signature that could distinguish NEPC tumors more accurately than previously published signatures. Within the tumor microenvironment (TME), we observed an elevation of pro-inflammatory Th17 T-cells in African American patients and identified a rare Schwann cell population. Finally, we present PCformer, a transformer-based foundation model trained on >500,000 cells to automate cell-state classification. Together, this comprehensive atlas demonstrates the complex nature of gene modules underlying lineage infidelity and plasticity in cancer cells and highlights distinct immune and stromal populations within the tumor ecosystem.

genomics↗

bioRxiv2025

Comparing Neanderthal introgression maps reveals core agreement but substantial heterogeneity

Statistical methods to identify Neanderthal ancestry in modern human genomes rest on varying assumptions and inputs. Nonetheless, most studies of introgression use only a single method to define Neanderthal ancestry. Due to a lack of "ground truth," we have a limited understanding of the accuracy, comparative strengths and weaknesses, and the sensitivity of downstream conclusions for these methods. Here, we performed large-scale comparisons of genome-wide introgression maps from 12 representative Neanderthal introgression detection algorithms. These span methods that consider archaic and human reference genomes not from Africa (ArchaicSeeker2, CRF, DICAL-ADMIX), only archaic genomes (S*, Sprime, HMM, SARGE, ARGWeaver-D), only human reference genomes, including from Africa (IBDmix), or simulated data (ArchIE). Our results highlight a core set of regions predicted by nearly all methods, as well as substantial heterogeneity in commonly used Neanderthal introgression maps. Furthermore, we find that downstream analyses may result in different conclusions depending on the map used. Thus, we recommend careful consideration of map(s) chosen for an analysis and support the use of multiple maps to ensure robustness of conclusions. We make integrated prediction sets available, enabling further understanding of Neanderthal introgressions legacy on modern humans.

evolutionary biology↗

bioRxiv2023

Neanderthal Introgression Shaped Human Circadian Traits

IntroductionWhen the ancestors of modern Eurasians migrated out of Africa and interbred with Eurasian archaic hominins, namely Neanderthals and Denisovans, DNA of archaic ancestry integrated into the genomes of anatomically modern humans. This process potentially accelerated adaptation to Eurasian environmental factors, including reduced ultra-violet radiation and increased variation in seasonal dynamics. However, whether these groups differed substantially in circadian biology, and whether archaic introgression adaptively contributed to human chronotypes remains unknown. ResultsHere we traced the evolution of chronotype based on genomes from archaic hominins and present-day humans. First, we inferred differences in circadian gene sequences, splicing, and regulation between archaic hominins and modern humans. We identified 28 circadian genes containing variants with potential to alter splicing in archaics (e.g., CLOCK, PER2, RORB, RORC), and 16 circadian genes likely divergently regulated between present-day humans and archaic hominins, including RORA. These differences suggest the potential for introgression to modify circadian gene expression. Testing this hypothesis, we found that introgressed variants are enriched among eQTLs for circadian genes. Supporting the functional relevance of these regulatory effects, we found that many introgressed alleles have associations with chronotype. Strikingly, the strongest introgressed effects on chronotype increase morningness, consistent with adaptations to high latitude in other species. Finally, we identified several circadian loci with evidence of adaptive introgression or latitudinal clines in allele frequency. ConclusionsThese findings identify differences in circadian gene regulation between modern humans and archaic hominins and support the contribution of introgression via coordinated effects on variation in human chronotype. SIGNIFICANCE STATEMENTInterbreeding between humans and Neanderthals created the potential for adaptive introgression as humans moved into environments that had been populated by Neanderthals for hundreds of thousands of years. Here we discover lineage-specific genetic differences in circadian genes and their regulatory elements between humans and Neanderthals. We show that introgressed alleles are enriched for effects on circadian gene regulation, consistently increase propensity for morningness in Europeans, and show evidence of adaptive introgression or associations between latitude and frequency. These results expand our understanding of how the genomes of humans and our closest relatives responded to environments with different light/dark cycles, and demonstrate a coordinated contribution of admixture to human chronotype in a direction that is consistent with adaptation to higher latitudes.

evolutionary biology↗

bioRxiv2021

Diverse functions associate with trans-species polymorphisms in humans

Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter "trans-species polymorphisms" (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. We integrated diverse genomic annotations to explore the functions of 125 previously identified non-coding TSPs that are likely under LTBS since the common ancestor of humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. The diversity of traits associated with non-coding human TSPs suggest that functions beyond the immune system are often subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity. Significance statementMost genetic variants present in human populations are young (<100,000 years old); however, a few hundred are millions of years old with origins before the divergence of humans and chimpanzees. These trans-species polymorphisms (TSPs) were likely maintained by balancing selection--evolutionary pressure to maintain genetic diversity at a locus. However, the functions driving this selection, especially for non-coding TSPs, are largely unknown. We integrate genome-wide annotation strategies to demonstrate TSP associations with immune system function, behavior (addition, cognition, risky behavior), uric acid metabolism, and many other phenotypes. These results substantially expand our understanding of functions TSPs and suggest a substantial role for balancing selection beyond the immune system.

evolutionary biology↗