About

Aakrosh Ratan is an Associate Professor in the Department of Genome Sciences at the University of Virginia. His research disciplines include Bioinformatics and Genomics, Cancer Biology, Computational Biology, Genetics, and Molecular Biology. His research interests focus on genomics, molecular evolution, and algorithm design and analysis. Ratan has developed methods for detecting and mapping genomic variation from large-scale sequencing datasets, including variants such as SNPs, indels, and large-scale rearrangements, utilizing graph frameworks to represent genome variation and sequence uncertainty. He has contributed to large-scale analyses of cancer genomic datasets, aiming to understand the changes driving tumorigenesis and the influence of genomic variation on clinical prognosis. His work includes leading studies on the role of germline variation in cancer outcomes and analyzing the mutational landscape of rare lymphoproliferative disorders such as Large Granular Lymphocyte (LGL) Leukemia. Additionally, Ratan's research encompasses studies of genetic diversity across species, applying genome-wide assessments to understand evolutionary history, population differentiation, and adaptation. His collaborative efforts have resulted in significant publications on the genomic landscape of various diseases and species, emphasizing his expertise in bioinformatics, genomics, and cancer biology.

Research topics

• Genetics
• Biology
• Computational biology
• Computer Science
• Molecular biology
• Internal medicine
• Evolutionary biology
• Bioinformatics
• Medicine
• Cancer research
• Immunology
• Endocrinology
• Demography

Selected publications

• Patient-informed CRISPR screen identifies FLNB as a congenital heart disease and ciliopathy gene

  Human Genetics and Genomics Advances · 2026-02-11

  articleOpen access

  Heterotaxy (HTX) is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart disease (CHD). Despite advances in sequencing, many CHD and HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR-Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD and HTX, 3 with recessive and 2 with damaging heterozygous variants in FLNB. Disrupting flnb in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD and HTX.

  PublisherDOI

• Abstract 7305: Evaluating the unfolded protein response as a therapeutic target in clear cell renal cell carcinoma patients

  Cancer Research · 2026-04-03

  article

  Abstract Metastatic clear cell renal cell carcinoma (ccRCC) is an incurable and lethal disease. While treatment of ccRCC has shifted toward antiangiogenic and immunotherapy combinations, long-term response is rare, underscoring the urgent need for novel therapeutic targets. We previously demonstrated in a murine model that therapeutic targeting of the unfolded protein response (UPR) via the mediator PKR-like ER kinase (PERK) can reverse tumor progression, immune suppression, and resistance to immune checkpoint blockade (ICB) (Mandula et al. Cancer Cell. 2022). Early-phase clinical studies are now evaluating PERK inhibition as a therapeutic strategy in solid tumors, including ccRCC. Here, we performed a retrospective analysis of patients with ccRCC using an analytical framework to estimate PERK activity from transcriptome data. We evaluated three independent ccRCC patient data sets - iATLAS patients treated with ICB (n = 296), ORIEN AVATAR patients treated with ICB (n = 85), and a TCGA treatment-naive cohort (n = 534). Across these datasets, PERK expression was associated with increased progression risk and worse overall survival. To evaluate the role of PERK in the context of endoplasmic reticulum (ER) stress, we generated a PERK knockout model using CRISPR gRNA in ccRCC cell lines and then challenged the cells with an ER stressor, thapsigargin. Interestingly, we found cytoplasmic vacuolization reminiscent of an unresolved unfolded protein response, ER swelling, and proteostasis disruption. Moreover, joint treatment with the PERK inhibitor AMG44 and thapsigargin significantly reduced viability in ccRCC cells. To further assess the therapeutic potential of PERK inhibition during standard-of-care therapy, we evaluated its impact during VEGF blockade. We observed decreased cell viability in PERK-silenced cells following cabozantinib (VEGF inhibitor) exposure, either through drug inhibition or genetic deletion. In summary, as clinical interest in PERK inhibition (PERKi) grows across multiple solid tumors, our findings highlight PERK as a potential therapeutic target in ccRCC and identify associated biomarkers that may inform future clinical strategies. Citation Format: Timothy Shaw, Thushara Madanayake, Darwin Chang, Jay Mandula, Alyssa Obermayer, George J. Weiner, Dan Spakowicz, Bodour Salhia, Martin McCarter, Susanne Arnold, Aakrosh Ratan, Sheri L. Holmen, Stephen B. Edge, Julian Acevedo, Ayanambakkam Attanathi, Robert J. Rounbehler, Michelle Churchman, Ahmad Tarhini, Jose R. Conejo-Garcia, Brandon J. Manley, Paulo C. Rodriguez. Evaluating the unfolded protein response as a therapeutic target in clear cell renal cell carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7305.

  PublisherDOI

• From North Asia to South America: Tracing the longest human migration through genomic sequencing

  Science · 2025-05-15 · 13 citations

  article

  Genome sequencing of 1537 individuals from 139 ethnic groups reveals the genetic characteristics of understudied populations in North Asia and South America. Our analysis demonstrates that West Siberian ancestry, represented by the Kets and Nenets, contributed to the genetic ancestry of most Siberian populations. West Beringians, including the Koryaks, Inuit, and Luoravetlans, exhibit genetic adaptation to Arctic climate, including medically relevant variants. In South America, early migrants split into four groups-Amazonians, Andeans, Chaco Amerindians, and Patagonians-~13,900 years ago. Their longest migration led to population decline, whereas settlement in South America's diverse environments caused instant spatial isolation, reducing genetic and immunogenic diversity. These findings highlight how population history and environmental pressures shaped the genetic architecture of human populations across North Asia and South America.

  PublisherDOI

• Characterizing the clinical and genomic features of androgen indifferent prostate cancer.

  Journal of Clinical Oncology · 2025-02-10

  article

  222 Background: Androgen indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse and AIPC remains a poorly understood malignancy. This study aims to characterize the clinical and genomic features of AIPC. Our work ultimately seeks to identify biomarkers with diagnostic and therapeutic potential. Methods: Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we queried all prostate cancer (PC) patients, identified metastatic castrate resistant prostate cancer (MCRPC) samples, and aimed to enrich for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC) defined as having alterations in at least two of TP53, RB1, PTEN; neuroendocrine PC (NEPC) defined as small cell histology or NEPC signature score ≥ 0.25 (1); and double-negative PC (DNPC), defined as non-NEPC patients with low AR expression/AR signaling score. We compared clinical characteristics and genomic analysis of AIPC vs non-AIPC samples in patients who developed MCRPC. Clinical analysis was done using Wilcoxon rank sum test or Fisher's exact test. Gene expression analysis was performed using DESeq2 and GSEA. Results: Of 1,496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Median age at diagnosis for AIPC was 62 years and 85% were white, compared to 62 years and 87% for non-AIPC. Fifty-seven percent of AIPC patients had ECOG ≥1 at diagnosis vs 16% of non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs 15% for non-AIPC (p=0.003). TMPRSS2-ERG gene fusions were found in a significantly higher proportion of AIPC samples vs non-AIPC (38.5% vs 16%, p=0.014). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p=0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial mesenchymal transition (EMT), interferon response, and angiogenesis were significantly upregulated in AIPC vs non-AIPC samples. Conclusions: There was a significantly higher rate of de novo metastasis in the AIPC cohort. The downregulated androgen response and upregulated EMT pathways in AIPC suggest enrichment for androgen indifference with our methodology. Upregulated immune signaling and angiogenesis as well as higher MSI suggest opportunities for therapeutic investigation. Future directions include more focused in vitro and in vivo analysis to identify actionable targets. 1. Beltran H, et al. Nat Med . 2016;22(3):298-305. doi:10.1038/nm.4045.

  PublisherDOI

• Patient-informed CRISPR Screen Identifies FLNB as a Novel Congenital Heart Disease and Ciliopathy Gene

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15

  preprintOpen access

  ABSTRACT Heterotaxy (HTX) syndrome is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart defects (CHD). Despite advances in sequencing, many CHD/HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR/Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD/HTX, 3 with recessive, and 2 with damaging heterozygous mutations in FLNB. Disrupting FLNB in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD/HTX.

  PublisherOA PDFDOI

• Chromosome-length genome assembly of the critically endangered Mountain bongo (<i>Tragelaphus eurycerus isaaci):</i> a resource for conservation and comparative genomics

  G3 Genes Genomes Genetics · 2025-05-15 · 1 citations

  articleOpen access

  The Mountain bongo (Tragelaphus eurycerus isaaci), a critically endangered tragelaphine antelope native to the montane forests of Kenya, faces significant threats from habitat loss and hunting. Although the Mountain bongo is a flagship species in Kenya, the majority are found in small, isolated populations of less than 100 animals total, making it a species of high conservation concern. In this report, we present a chromosome-length draft genome assembly for the Mountain bongo, generated using a combination of linked-read and proximity ligation (Hi-C) sequencing techniques. The assembly resulted in a 2.96 Gb sized genome with a contig N50 of 79.5 kb and a scaffold N50 of 192 Mb. Assembly completeness was 95.1% based on 12,234 Benchmarking Universal Single-Copy Orthologs (BUSCO) and annotation revealed 29,820 protein-coding genes, of which 27,761 were functionally annotated, and a repetitive content of 47.31%. Synteny analysis against the domestic cattle (Bos taurus) genome assembly revealed numerous chromosomal rearrangements between the 2 species. Our analysis also revealed insights into the evolutionary and demographic history of the Mountain bongo, offering valuable information for conservation management. We also assembled and annotated the mitochondrial genome which showed <1% differences from the Lowland bongo subspecies, T. e. eurycerus. By integrating genomic data with traditional conservation methods, this reference lays the foundation to evaluate and preserve genetic diversity of both in situ and ex situ populations of the Mountain bongo amidst growing environmental pressures.

  PublisherOA PDFDOI

• Loss of DHX36/G4R1, a G4 resolvase, drives genome instability and regulates innate immune gene expression in cancer cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-03 · 1 citations

  preprintOpen access

  SUMMARY G-quadruplexes (G4s) are four-stranded alternative secondary structures formed by guanine-rich nucleic acids and are prevalent across the human genome. G4s are enzymatically resolved using specialized helicases. Previous in vitro studies showed that DEAH-box Helicase 36 (DHX36/G4R1/RHAU), has the highest specificity and affinity for G4 structures. Here, by mapping genome-wide DNA double-strand breaks (DSBs), we demonstrate that knockout (KO) of DHX36 helicase increases DSB enrichment at G4 sites and that the presence of the G4 motif is a significant mediator of genome instability at regulatory regions. The loss of DHX36 corresponds with the significant upregulation of NF-κB transcriptional programs, culminating in the production and secretion of proinflammatory cytokines. Loss of DHX36 expression results in an increase in the innate immune signaling stimulator of interferon response cGAMP interactor 1 ( STING1 ) expression and activation of genes involved in immune response pathways. Importantly, higher levels of DHX36 mRNA expression in human B-cell acute lymphoblastic leukemia correlate with improved overall survival relative to lower expression of DHX36 , highlighting its critical role in preserving genome integrity at a cellular level and in the context of cancer.

  PublisherOA PDFDOI

• Historic manioc genomes illuminate maintenance of diversity under long-lived clonal cultivation

  Science · 2025-03-06 · 11 citations

  article

  Manioc-also called cassava and yuca-is among the world's most important crops, originating in South America in the early Holocene. Domestication for its starchy roots involved a near-total shift from sexual to clonal propagation, and almost all manioc worldwide is now grown from stem cuttings. In this work, we analyze 573 new and published genomes, focusing on traditional varieties from the Americas and wild relatives from herbaria, to reveal the effects of this shift to clonality. We observe kinship over large distances, maintenance of high genetic diversity, intergenerational heterozygosity enrichment, and genomic mosaics of identity-by-descent haploblocks that connect all manioc worldwide. Interviews with Indigenous traditional farmers in the Brazilian Cerrado illuminate how traditional management strategies for sustaining, diversifying, and sharing the gene pool have shaped manioc diversity.

  PublisherDOI

• Loss of DHX36/G4R1, a G4 resolvase, drives genome instability and regulates innate immune gene expression in cancer cells

  Nucleic Acids Research · 2025-06-14 · 2 citations

  articleOpen access

  G-quadruplexes (G4s) are four-stranded alternative secondary structures formed by guanine-rich nucleic acids and are prevalent across the human genome. G4s are enzymatically resolved by specialized helicases. Previous in vitro studies showed that DEAH-box helicase 36 (DHX36/G4R1/RHAU) has the highest specificity and affinity for G4 structures. Here, by mapping genome-wide DNA double-strand breaks (DSBs), we demonstrate that knockout of DHX36 helicase increases DSB enrichment at G4 sites and that the presence of the G4 motif is a significant mediator of genome instability at regulatory regions. The loss of DHX36 corresponds with the significant upregulation of NF-κB transcriptional programs, culminating in the production and secretion of proinflammatory cytokines. Loss of DHX36 expression results in the accumulation of cytoplasmic DNA fragments, an increase in the innate immune signaling stimulator of interferon response cGAMP interactor 1 (STING1) expression, and activation of genes involved in immune response pathways. Importantly, higher levels of DHX36 messenger RNA expression in human B-cell acute lymphoblastic leukemia correlate with improved overall survival relative to lower expression of DHX36, highlighting its critical role in preserving genome integrity at a cellular level and in the context of cancer.

  PublisherOA PDFDOI

• Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function

  Blood Advances · 2025-12-10 · 2 citations

  articleOpen access

  ABSTRACT: Toll-like receptor 8 (TLR8) gain-of-function (GOF) somatic variants were recently identified as causing severe neutropenia, lymphoproliferation, and immune dysregulation. We report the expanded clinical and laboratory phenotype and management of 10 patients, including the original cohort of 6 male patients. We identify the first female patient with TLR8 GOF who presented during infancy with pure red cell aplasia due to a germ line TLR8 variant, and 2 new disease-causing somatic variants in male patients. Eight patients had somatic mosaicism with peripheral blood variant allele fractions of 7% to 26%, and age of disease onset of 9 months to 28 years. All patients had neutropenia, most with severe neutropenia refractory to medical therapy. Anemia and thrombocytopenia were common. Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates. An increased number of large granular lymphocytes (LGLs) was identified in 5 patients. Seven patients underwent allogeneic hematopoietic cell transplant (HCT). High rates of post-HCT cytopenia of unclear etiology and graft-versus-host disease were observed. Five patients are surviving at 1 to 3 years after HCT with full donor myeloid and T-cell chimerism, and resolution of disease phenotype. The 2 patients who presented during childhood and did not undergo HCT ultimately died from disease. In conclusion, TLR8 GOF is an X-linked dominant disorder that should be considered in male and female patients with cytopenia, particularly severe neutropenia, lymphoproliferation with immune dysregulation, increased LGLs, and new to this cohort, red cell aplasia. Disease is refractory to medical management, and curative, allogeneic HCT should be considered early after diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT04339777.

  PublisherOA PDFDOI

Recent grants

• Genomic Architecture of LGL Leukemia

  NIH · $4.4M · 2015–2029

Frequent coauthors

• Stephan C. Schuster

  Singapore Centre for Environmental Life Sciences Engineering

  65 shared

• Jerome I. Rotter

  UCLA Medical Center

  62 shared

• Laura Almasy

  University of Pennsylvania

  54 shared

• Susan Redline

  Massachusetts General Hospital

  51 shared

• Rasika A. Mathias

  National Institute of Allergy and Infectious Diseases

  48 shared

• Lisa R. Yanek

  47 shared

• Ramachandran S. Vasan

  National Heart Lung and Blood Institute

  46 shared

• Stephen S. Rich

  46 shared

Education

• Ph.D., Department of Computer Science and Engineering

  Pennsylvania State University University Park

  2009

• S.M., Department of Computer Science

  National University of Singapore

  2004

• Bachelor of Technology, Department of Electrical Engineering

  Indian Institute of Technology Roorkee

  2003