Biology subjects

Shetty, A. C.

Publications and source records attributed to Shetty, A. C..

16 recordsLinked to original sources

bioRxiv2026

TLR7 inhibition limits cardiac ischemic injury by disrupting ITGAM-dependent immune-endothelial interaction

Percutaneous coronary intervention (PCI) limits ischemic myocardial infarction but also triggers ischemia-reperfusion (I/R) injury in part driven by innate immune activation. Here, we identify Toll-like receptor 7 (TLR7), an endosomal sensor of single-stranded RNA, as a mediator of post-ischemic inflammation and myocardial damage. Pharmacological inhibition of TLR7 with enpatoran reduced myocardial inflammation and infarct size and improved cardiac function in a mouse model of I/R injury when administered before, during, or shortly after ischemia. Single-nucleus RNA sequencing revealed coordinated post-I/R expansion of myeloid cells and distinct inflammatory endothelial subsets enriched for leukocyte-interaction programs, with marked upregulation of Itgam in cardiac leukocytes and endothelial cells and in circulating monocytes. Circulating ITGAM+ monocytes were similarly increased in patients with ST-segment elevation myocardial infarction 24 hours after coronary stenting. Mechanistically, TLR7 activation induced Itgam expression in endothelial cells and leukocytes and promoted their adhesion via ITGAM-ICAM1 interaction under physiological shear stress, whereas ITGAM neutralization disrupted this interaction, reduced immune cell infiltration, and limited ischemic injury. These findings define a TLR7-ITGAM signaling axis as a key driver of endothelial-leukocyte crosstalk in myocardial I/R injury and support TLR7 inhibition as a promising therapeutic strategy to mitigate acute myocardial infarction.

immunology↗

bioRxiv2025

Peripheral blood cell-type and sex-specific signatures of alcohol misuse revealed by single-cell transcriptomics

Alcohol use disorder (AUD) is a complex condition with diverse molecular underpinnings. Chronic alcohol exposure is associated with alterations in both innate and adaptive immune cell populations that in turn contribute to AUD susceptibility and severity, suggesting a bidirectional gene-environment relationship. Yet, most clinical AUD studies of this system have relied on indirect measurement of immune function and/or assessment of only a small number of cell types or immune markers, approaches which cannot capture the immune systems inherent complexity and cellular heterogeneity. Therefore, in order to better characterize immune dysregulation in AUD, the goal of this study was to use single cell RNA sequencing (scRNA-seq) in peripheral blood mononuclear cells (PBMCs) to compare immune cell proportions and differential gene expression between individuals with AUD and healthy controls. Our findings highlight a distinct disproportionality of lymphocytes and monocytes in individuals with AUD and healthy controls as well as sex and dose-dependent alterations immune cell functional characteristics. These peripheral blood cell-type proportions and dose-dependent signatures of alcohol exposure may aid in developing more targeted and effective pharmacological interventions for AUD. Results also highlight the importance in including sex as a biological variable in AUD research, particularly when examining immune function.

genomics↗

bioRxiv2025

Epithelial-Immune-Stromal Interactions Define Divergent Repair and Fibrosis Pathways After Acute Kidney Injury in Human Renal Transplants

Acute kidney injury (AKI) is a major cause of early graft dysfunction after kidney transplantation, particularly in recipients of high-risk donor kidneys prone to ischemia-reperfusion injury. However, the cellular mechanisms dictating whether injury resolves or progresses to fibrosis remain unclear. This study combines single-nucleus RNA sequencing and imaging mass cytometry (IMC) analysis of human kidney allograft biopsies collected within eight weeks posttransplant, stratified by long-term functional outcomes. Grafts that recovered function were enriched in regenerative proximal tubular (PT) cells co-expressing PROM1, CD24, and injury markers, consistent with scattered tubular cells (STCs). In contrast, non-recovering grafts contained a unique subpopulation of transitional proximal tubule cells (tPT4) characterized by dedifferentiation, loss of epithelial identity, and acquisition of fibroblast-like features. Fibroblast trajectory analysis revealed a profibrotic lineage, progressing from stromal progenitors to myofibroblasts, exclusive to nonrecovery grafts. Immune profiling showed divergent macrophage (M{Phi}) polarization, with reparative M{Phi}2 cells and regulatory dendritic cell (DC)-like signatures in recovering grafts, versus inflammatory M{Phi}1 and pro-fibrotic DCs in non-recovery. IMC confirmed spatial colocalization of injured tubules, activated fibroblasts, and immune cells in fibrotic regions, validated in an independent cohort. Functional assays demonstrated that ischemic epithelial injury activated monocyte-derived M{Phi}s with mixed inflammatory/reparative profiles and induced fibroblast-related gene expression, while PAX8 knockdown impaired epithelial proliferation and promoted pro-inflammatory signaling. These findings reveal epithelial cell plasticity as a central driver of divergent repair outcomes following renal transplant AKI and highlight epithelial-immune-stromal crosstalk as a therapeutic target to promote recovery and prevent chronic graft injury. One Sentence SummarySingle-cell and spatial mapping of human kidney transplants reveal regenerative and fibrotic cell programs across tubular, immune, and stromal compartments that determine whether acute injury resolves or progresses to chronic allograft injury.

biochemistry↗

bioRxiv2025

Cellular and Molecular Resolution of Focal Segmental Glomerulosclerosis Recurrence in Human Allografts

Primary Focal Segmental Glomerulosclerosis (FSGS) is an important cause of end-stage renal disease (ESRD). Primary FSGS recurrence rates in transplanted kidneys are high, with 25-50% in first transplants and up to 80% in second transplants, often leading to graft loss. To investigate the molecular and cellular events underlying recurrent primary FSGS (reFSGS), we performed single-nucleus RNA sequencing (snRNA-seq) on kidney transplant biopsies from patients with reFSGS and controls with normal allograft function. Our analysis revealed that podocyte loss in reFSGS is driven by metabolic and structural dysregulation rather than apoptosis. Overexpression of vascular endothelial growth factor (VEGF)-A by podocytes was observed, potentially disrupting glomerular endothelial cell growth and permeability. Parietal epithelial cells (PECs) exhibited dedifferentiation towards a podocyte-like state, potentially compensating for podocyte loss, but this was associated with increased collagen deposition and glomerular sclerosis. Ligand-receptor interactions between glomerular cells and B cells further promoted extracellular matrix deposition and fibrosis. Additionally, tubular cells demonstrated evidence of tubular sclerosis and impaired regenerative potential, accompanied by increased interactions with T cells. These findings provide novel insights into the pathogenesis of reFSGS and identify potential therapeutic targets. This study establishes a foundation for future research to further investigate cell-type-specific interventions in recurrent FSGS.

molecular biology↗

bioRxiv2024

Regulatory T cells crosstalk with tumor and endothelium through lymphotoxin signaling

Regulatory T cells (Tregs) are suppressors of anti-tumor immunity that exert multifaceted functions by signaling surrounding cells. We revealed Tregs use their high-level surface lymphotoxin (LT)1{beta}2 to preferentially stimulate LT{beta} receptor (LT{beta}R) nonclassical NF{kappa}B signaling on both tumor and lymphatic endothelial cells (LECs) to accelerate tumor growth and metastasis. Selectively targeting LT{beta}R nonclassical NF{kappa}B pathways on both tumors and LECs cocultured with Tregs, inhibited tumor growth and migration in vitro. Further, we identified protumorigenic chemokines and interferon-stimulated response genes selectively driven by LT{beta}R nonclassical NF{kappa}B in melanoma cells. Endothelial specific genes related to oncogenic process such as SOX18 and FLRT2 were identified to be driven under LT{beta}R nonclassical NF{kappa}B in LECs. Leveraging in vivo Treg LT1{beta}2 interactions with LT{beta}R on tumor and LECs, transfer of WT but not LT-deficient Tregs promoted transplanted WT B16F10 growth and tumor cell-derived CXCL1 and CXCL10 secretion in LT{beta}R-deficient host mice, and increased endothelial specific genes related to tumor angiogenesis and lymphangiogenesis, in WT mice bearing LT{beta}R-depleted melanoma. Selectively blocking LT{beta}R nonclassical NF{kappa}B pathways remarkably suppressed tumor growth and lymphatic metastasis by reducing tumor cell and LEC-derived CXCL1 and CXCL10 production, restricting Treg and myeloid-derived suppressor cell (MDSC) recruitment to tumor. It also retained intratumoral effector T cells, especially IFN{gamma}+ CD8 T cells by restraining Treg facilitated lymphatic vessel permeability. Our data revealed that Treg LT1{beta}2 promotes LT{beta}R nonclassical NF{kappa}B signaling in tumor cells and LECs providing a rational strategy to modulate Treg-mediated protumorigenic molecules to prevent tumor growth and metastasis.

cancer biology↗

bioRxiv2023

Single neuron analysis of aging associated changes in learning reveals progressive impairmentsin transcriptional plasticity

Molecular mechanisms underlying aging associated impairments in learning and long-term memory storage are poorly understood. Here we leveraged the single identified motor neuron L7 in Aplysia, which mediates a form of non-associative learning, sensitization of the siphon-withdraw reflex, to assess the transcriptomic correlates of aging associated changes in learning. RNAseq analysis of the single L7 motor neuron isolated following short-term or long-term sensitization training of 8,10 and 12 months old Aplysia, corresponding to mature, late mature and senescent stages, has revealed progressive impairments in transcriptional plasticity during aging. Specifically, we observed modulation of the expression of multiple lncRNAs and mRNAs encoding transcription factors, regulators of translation, RNA methylation, and cytoskeletal rearrangements during learning and their deficits during aging. Our comparative gene expression analysis also revealed the recruitment of specific transcriptional changes in two other neurons, the motor neuron L11 and the giant cholinergic neuron R2 whose roles in long-term sensitization were previously not known. Taken together, our analyses establish cell type specific progressive impairments in the expression of learning- and memory-related components of the transcriptome during aging.

neuroscience↗

bioRxiv2022

Dual species transcriptomics reveals core metabolic and immunologic processes in the interaction between primary human neutrophils and Neisseria gonorrhoeae strains

Neisseria gonorrhoeae (the gonococcus, Gc) is the causative agent of the sexually transmitted infection gonorrhea. Gc is a prominent threat to human health by causing severe and lifelong clinical sequelae, including infertility and chronic pelvic pain, which is amplified by the emergence of "superbug" strains that are resistant to all current antibiotics. Gc is highly adapted to colonize human mucosal surfaces, where it survives despite initiating a robust inflammatory response and influx of polymorphonuclear leukocytes (PMNs or neutrophils) that typically clear bacteria. Here, dual-species RNA-sequencing (RNA-seq) was used to define Gc and PMN transcriptional profiles alone and after infection. Three strains of Gc and three human donors transcriptional responses were assessed to characterize core host and bacterial responses. Comparative analysis of Gc transcripts revealed major overlap between the Gc response to PMNs, iron, and hydrogen peroxide; specifically, the TonB system and TonB dependent transporters (TDT) were upregulated in response to PMNs. We experimentally confirmed that induction of the iron-dependent TDT TbpB is responsive to the presence of PMNs and that tonB is required for Gc survival from PMNs. Pathway analysis of PMN transcripts induced by Gc infection revealed differential expression of genes driving pathways involved in cell adhesion and migration, inflammatory responses, and inflammation resolution. Production of pro-inflammatory cytokines, including IL1B and IL8, the adhesion factor ICAM1, and the anti-inflammatory prostaglandin PGE2 was confirmed to be induced in PMNs in response to Gc. Together, this study represents a comprehensive and experimentally validated dual-species transcriptomic analysis of three isolates of Gc and primary human PMNs that gives insight into how this bacterium survives innate immune onslaught to cause disease in humans.

genomics↗

bioRxiv2021

Cochlear organoids reveal epigenetic and transcriptional programs of postnatal hair cell differentiation from supporting cells

We explored the transcriptional and epigenetic programs underlying the differentiation of hair cells from postnatal progenitor cells in cochlear organoids. Heterogeneity in the cells including cells with the transcriptional signatures of mature hair cells allowed a full picture of possible cell fates. Construction of trajectories identified Lgr5+ cells as progenitors for hair cells and the genomic data revealed gene regulatory networks leading to hair cells. We validated these networks, demonstrating dynamic changes both in expression and predicted binding sites of these transcription factors during organoid differentiation. We identified known regulators of hair cell development, Atoh1, Pou4f3, and Gfi1, and predicted novel regulatory factors, Tcf4, an E-protein and heterodimerization partner of Atoh1, and Ddit3, a CCAAT/enhancer-binding protein (C/EBP) that represses Hes1 and activates transcription of Wnt signaling-related genes. Deciphering the signals for hair cell regeneration from mammalian cochlear supporting cells reveals candidates for HC regeneration which is limited in the adult.

developmental biology↗

bioRxiv2020

Determining Aspergillus fumigatus transcription factor expression and function during invasion of the mammalian lung

To gain a better understanding of the transcriptional response of Aspergillus fumigatus during invasive pulmonary infection, we used a NanoString nCounter to assess the transcript levels of 467 A. fumigatus genes during growth in the lungs of immunosuppressed mice. These genes included ones known to respond to diverse environmental conditions and those encoding most transcription factors in the A. fumigatus genome. We found that invasive growth in vivo induces a unique transcriptional profile as the organism responds to nutrient limitation and attack by host phagocytes. This in vivo transcriptional response is largely mimicked by in vitro growth in Aspergillus minimal medium that is deficient in nitrogen, iron, and/or zinc. From the transcriptional profiling data, we selected 9 transcription factor genes that were either highly expressed or strongly up-regulated during in vivo growth. Deletion mutants were constructed for each of these genes and assessed for virulence in mice. Two transcription factor genes were found to be required for maximal virulence. One was rlmA, which governs the ability of the organism to proliferate in the lung. The other was ace1, which regulates of the expression of multiple secondary metabolite gene clusters and mycotoxin genes independently of laeA. Using deletion and overexpression mutants, we determined that the attenuated virulence of the {Delta}ace1 mutant is due to decreased expression aspf1, which specifies a ribotoxin, but is not mediated by reduced expression of the fumigaclavine gene cluster or the fumagillin-pseruotin supercluster. Thus, in vivo transcriptional profiling focused on transcription factors genes provides a facile approach to identifying novel virulence regulators. Author summaryAlthough A. fumigatus causes the majority of cases of invasive aspergillosis, the function of most of the genes in its genome remains unknown. To identify genes encoding transcription factors that may be important for virulence, we used a NanoString nCounter to measure the mRNA levels of A. fumigatus transcription factor genes in the lungs of mice with invasive aspergillosis. The transcriptional profiling data indicate that the organism is exposed to nutrient limitation and stress during growth in the lungs, and that it responds by up-regulating genes that encode mycotoxins and secondary metabolites. In vitro, this response was most closely mimicked by growth in medium that was deficient in nitrogen, iron and/or zinc. Using the transcriptional profiling data, we identified two transcription factors that govern A. fumigatus virulence. These were RlmA, which is governs proliferation in the lung and Ace1, which controls the production of mycotoxins and secondary metabolites.

microbiology↗

bioRxiv2020

Altered Huntingtin-Chromatin Interactions Predict Transcriptional and Epigenetic Changes in Huntingtons Disease

Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntingtons disease (HD), but the mechanistic basis remains poorly understood. Using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that the huntingtin protein (HTT) reproducibly occupies specific locations in the mouse genome. Moreover, many genomic loci were differentially occupied by HTT in striatal tissue from a homozygous knock-in mouse model of HD (B6.HttQ111/Q111) when compared to wildtype controls. Huntingtin ChIP-seq peaks were enriched in the coding regions of cell identity genes important for striatal function, with many of these genes found to have reduced expression in the striata of HD patients and mouse models, as well as reduced HTT occupancy in HttQ111/Q111mice compared to controls. Conversely, HTT ChIP-seq peaks were depleted near genes that are up-regulated in HD. ChIP-seq of bulk striatal histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with active chromatin marks (H3K4me3 and H3K27ac), and with enhancer of zeste homolog 2 (EZH2), a key enzymatic component of the PRC2 complex. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/Q111 vs. wildtype mice was associated with increased EZH2 binding, increased histone H3 lysine 4 (H3K4me3), and decreased histone H3 lysine 27 (H3K27me3). Our study suggests that huntingtin-chromatin interactions may play a direct role in organizing chromatin and promoting cell type-specific gene expression, with loss of HTT occupancy predicting decreased gene expression in HD.

neuroscience↗

bioRxiv2020

Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Osteoclasts (OCs) are bone resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type mice, Ly6Chi and Ly6Cint monocytes are the primary source of OC formation when compared to Ly6C- monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of pre-established transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of IRF8, a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8 deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation.

immunology↗

bioRxiv2020

Rare variant enriched identity-by-descent enables the detection of distant relatedness and older divergence between populations

MotivationThe global human population has experienced an explosive growth from a few million to roughly 7 billion people in the last 10,000 years. Accompanying this growth has been the accumulation of rare variants that can inform our understanding of human evolutionary history. Common variants have primarily been used to infer the structure of the human population and relatedness between two individuals. However, with the increasing abundance of rare variants observed in large-scale projects, such as Trans-Omics for Precision Medicine (TOPMed), the use of rare variants to decipher cryptic relatedness and fine-scale population structure can be beneficial to the study of population demographics and association studies. Identity-by-descent (IBD) is an important framework used for identifying these relationships. IBD segments are broken down by recombination over time, such that longer shared haplotypes give strong evidence of recent relatedness while shorter shared haplotypes are indicative of more distant relationships. Current methods to identify IBD accurately detect only long segments (> 2cM) found in related individuals. AlgorithmWe describe a metric that leverages rare-variants shared between individuals to improve the detection of short IBD segments. We computed IBD segments using existing methods implemented in Refined IBD where we enrich the signal using our metric that facilitates the detection of short IBD segments (<2cM) by explicitly incorporating rare variants. ResultsTo test our new metric, we simulated datasets involving populations with varying divergent time-scales. We show that rare-variant IBD identifies shorter segments with greater confidence and enables the detection of older divergence between populations. As an example, we applied our metric to the Old-Order Amish cohort with known genealogies dating 14 generations back to validate its ability to detect genetic relatedness between distant relatives. This analysis shows that our method increases the accuracy of identifying shorter segments that in turn capture distant relationships. ConclusionsWe describe a method to enrich the detection of short IBD segments using rare-variant sharing within IBD segments. Leveraging rare-variant sharing improves the information content of short IBD segments better than common variants alone. We validated the method in both simulated and empirical datasets. This method can benefit association analyses, IBD mapping analyses, and demographic inferences.

genomics↗

bioRxiv2020

Tornadic shear stress induces a transient, calcineurin-dependent hyper-virulent phenotype in Mucorales molds

Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geo-meteorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g. during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in a Drosophila melanogaster infection model. In contrast to other experimental procedures to exert mechanical stress, tornadic shear challenge (TSC) by magnetic stirring induced a hyper-virulent phenotype in several clinically relevant Mucorales species but not in Aspergillus or Fusarium. Whereas fungal growth rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, soluble factors released in the supernatant of shear-challenged R. arrhizus spores rendered static spores hyper-virulent. Consistent with a rapid decay of TSC-induced hyper-virulence, minimal transcriptional changes were revealed by comparative RNA sequencing analysis of static and shear-challenged Rhizopus arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by cyclosporine A (CsA) and tanespimycin abrogated the increased pathogenicity of R. arrhizus spores following TSC. Similarly, calcineurin loss-of-function mutants of Mucor circinelloides displayed no increased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC induces hyper-virulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment of wounds as an adjunct mitigation strategy for NMM following high-energy trauma. SignificanceGiven the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strategies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear stress challenge transiently induces a hyper-virulent phenotype in various pathogenic Mucorales species but not in other molds known to cause wound infections. Our data support a model whereby shear stress-induced hyper-virulence is primarily driven by soluble factors and orchestrated by the calcineurin/hsp90 pathway. Importantly, pharmacological and genetic inhibition of calcineurin signaling abrogated hyper-virulence in shear stress-challenged Mucorales, encouraging further evaluation of (topical) calcineurin inhibitors to improve therapeutic outcomes of NMM after combat-related blast injuries or violent storms.

microbiology↗

bioRxiv2019

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

genomics↗

bioRxiv2018

FADU: A Feature Counting Tool for Prokaryotic RNA-Seq Analysis

MotivationThe major algorithms for quantifying transcriptomics data for differential gene expression analysis were designed for analyzing data from human or human-like genomes, specifically those with single gene transcripts and distinct transcriptional boundaries that extend beyond the coding sequence (CDS) as identified through expressed sequence tags (ESTs) or EST-like sequence data. Some eukaryotic genomes and all, or nearly all, bacterial genomes require alternate methods of quantification since they lack annotation of transcriptional boundaries with EST or EST-like data, have overlapping transcriptional boundaries, and/or have polycistronic transcripts.\n\nResultsAn algorithm was developed and tested that better quantifies transcriptomics data for differential gene expression analysis in organisms with overlapping transcriptional units and polycistronic transcripts. Using data from standard libraries originating from Escherichia coli and Ehrlichia chaffeensis, and strand-specific libraries from the Wolbachia endosymbiont wBm, FADU can derive counts for genes that are missed by HTSeq and featurecounts. Using the default parameters with the E. coli data, FADU can detect transcription of 51 more genes than HTSeq in union mode and 21 genes more than featurecounts, with 42 and 18 of these features being <300 bp, respectively. Due to its ability to derive counts for otherwise unrepresented genes without overstating their abundance, we believe FADU to be an improved tool for quantifying transcripts in prokaryotic systems for RNA-Seq analyses.\n\nAvailability and implementationFADU is available at https://github.com/adkinsrs/FADU. FADU was implemented using Python3 and requires the PySAM module (version 0.12.0.1 or later).\n\nContactjdhotopp@som.umaryland.edu

genomics↗

bioRxiv2017

The Evolutionary Genomic Dynamics of Peruvians Before, During, and After the Inca Empire

Native Americans from the Amazon, Andes, and coast regions of South America have a rich cultural heritage, but have been genetically understudied leading to gaps in our knowledge of their genomic architecture and demographic history. Here, we sequenced 150 high-coverage and genotyped 130 genomes from Native American and mestizo populations in Peru. A majority of our samples possess greater than 90% Native American ancestry and demographic modeling reveals, consistent with a rapid peopling model of the Americas, that most of Peru was peopled approximately 12,000 years ago. While the Native American populations possessed distinct ancestral divisions, the mestizo groups were admixtures of multiple Native American communities which occurred before and during the Inca Empire. The mestizo communities also show Spanish introgression only after Peruvian Independence. Thus, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern day Peruvians.

genomics↗