Manolis Kellis

Massachusetts Institute of Technology | MIT · Computer Science and Artificial Intelligence Laboratory

Background: A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular s...

GENCODE produces comprehensive reference gene annotation for human and mouse. Entering its twentieth year, the project remains highly active as new technologies and methodologies allow us to catalog the genome at ever-increasing granularity. In particular, long-read transcriptome sequencing enables us to identify large numbers of missing transcript...

Background A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer’s disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD. Method We integrated multi‐modal data from the Religious Order...

Single-nuclei RNA sequencing remains a challenge for many human tissues, as incomplete removal of background signal masks cell-type-specific signals and interferes with downstream analyses. Here, we present Quality Clustering (QClus), a droplet filtering algorithm targeted toward challenging samples. QClus uses additional metrics, such as cell-type...

Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between...

Accurate and complete gene annotations are indispensable for understanding how genome sequences encode biological functions. For twenty years, the GENCODE consortium has developed reference annotations for the human and mouse genomes, becoming a foundation for biomedical and genomics communities worldwide. Nevertheless, collections of important yet...

Gene expression involves transcription and translation. Despite large datasets and increasingly powerful methods devoted to calculating genetic variants’ effects on transcription, discrepancy between messenger RNA and protein levels hinders the systematic interpretation of the regulatory effects of disease-associated variants. Accurate models of th...

Down syndrome (DS) has been linked with deficits in hippocampal dependent cognitive tasks and adult neurogenesis, yet treatment options are still very limited. We and others previously showed that a non-invasive multisensory gamma stimulation using light and sound at 40 Hz ameliorated Alzheimer’s disease pathology and symptoms in mouse models. In t...

Balancing the tradeoff between quantity and quality of phenotypic data is critical in omics studies. Measurements below the limit of quantification (BLQ) are often tagged in quality control fields, but these flags are currently underutilized in human genetics studies. Extreme phenotype sampling is advantageous for mapping rare variant effects. We h...

Programmed ribosomal frameshifting is a translational recoding phenomenon in which a proportion of ribosomes are stimulated to slip backwards or forwards on an mRNA, rephasing the ribosome relative to the mRNA. While frameshifting is often employed by viruses, very few phylogenetically conserved examples are known in vertebrate genes and the eviden...

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4 ⁺ FOXP3 ⁺ regulatory T cells (T regs ) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic p...

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1–3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain s...

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orche...

Crosstalk between N⁶-methyladenosine (m⁶A) and epigenomes is crucial for gene regulation, but its regulatory directionality and disease significance remain unclear. Here, we utilize quantitative trait loci (QTLs) as genetic instruments to delineate directional maps of crosstalk between m⁶A and two epigenomic traits, DNA methylation (DNAme) and H3K2...

Immune checkpoint inhibitors (ICIs) have heralded a remarkable shift in cancer care, significantly extending survival for advanced cancer patients. However, despite their remarkable clinical successes, a substantial majority of patients fail to achieve a lasting response to ICIs. To address this challenge and gain insights into the complex landscap...

Significant efforts have been made to characterize the biophysical properties of proteins. Small proteins have received less attention because their annotation has historically been less reliable. However, recent improvements in sequencing, proteomics, and bioinformatics techniques have led to the high-confidence annotation of small open reading fr...

Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier (BBB), immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. By engineering a novel brain-mimicking 3D hydrogel and co-culturing all six m...

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an inc...

Dominance heritability in complex traits has received increasing recognition. However, most polygenic score (PGS) approaches do not incorporate non-additive effects. Here, we present GenoBoost, a flexible PGS modeling framework capable of considering both additive and non-additive effects, specifically focusing on genetic dominance. Building on sta...

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affec...

In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and...

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose o...

Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial flu...

Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we developed a zebrafish model in which all melanocytes experienced CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only developed from melanocytes lining internal organs, analogous to the location of patient MM. We...

Significant efforts have been made to characterize the biophysical properties of proteins. Small proteins have received less attention because their annotation has historically been less reliable. However, recent improvements in sequencing, proteomics, and bioinformatics techniques have led to the high-confidence annotation of small open reading fr...

MicroRNAs (miRNAs) are crucial for the regulation of gene expression and are promising biomarkers and therapeutic targets. miRNA isoforms (isomiRs) differ in their start/end offsets, which can impact the target gene selection and non-canonical function of the miRNA species. In addition, isomiRs frequently differ in their expression patterns from th...

Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or “chemobrain,” which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent fi...

Gene expression involves transcription and translation. Despite large datasets and increasingly powerful methods devoted to calculating genetic variants' effects on transcription, discrepancy between mRNA and protein levels hinders the systematic interpretation of the regulatory effects of disease-associated variants. Accurate models of the sequenc...

The glymphatic movement of fluid through the brain removes metabolic waste1–4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease5–8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of inters...

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in...

Antigen-presenting cells (APCs) are pivotal mediators of immune responses. Their role has increasingly been spotlighted in the realm of cancer immunology, particularly as our understanding of immunotherapy continues to evolve and improve. There is growing evidence that these cells play a non-trivial role in cancer immunity and have roles dependent...

Prioritizing disease-critical cell types by integrating genome-wide association studies (GWAS) with functional data is a fundamental goal. Single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) have characterized cell types at high resolution, and studies integrating GWAS with scRNA-seq have shown promise, but studies inte...

Background Alzheimer’s Disease (AD) is a polygenic and multifaceted disease with many implicated biological pathways across diverse cell types. The heterogeneous phenotypic manifestation, beyond the common characteristic signature of Amyloid beta plaque, across cognition, pathology, and treatment response is well recognized. However, how the polyge...

Background APOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD), yet the cellular and molecular mechanisms by which APOE4 contributes to AD risk remain largely unknown Method We performed single‐nuclear RNAsequencing from the prefrontal cortex (Brodmann’s Area 10) of thirty‐two individuals, 12 APOE3/3 and 12 APOE3/4 c...

Cancer is a disease that undergoes selective pressure to evolve during its progression, becoming increasingly heterogeneous. Tumoral heterogeneity can dictate therapeutic response. Transcriptomics can be used to uncover complexities in cancer and reveal phenotypic heterogeneity that affects disease response. This is especially pertinent in the immu...

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin s...

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease which lacks efficacious standard-of-care treatments. Molecular studies of skin lesions revealed that IL-1β is central to the pathogenesis of PRP. Treatment of three patients with the IL-1-targeting biologics anakinra and canakinumab resulted in rapid clinical improvement and reversa...

Admixed individuals offer unique opportunities for addressing limited transferability in polygenic scores (PGSs), given the substantial trans-ancestry genetic correlation in many complex traits. However, they are rarely considered in PGS training, given the challenges in representing ancestry-matched linkage-disequilibrium reference panels for admi...

Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory e...

ABCA7 loss-of-function (LoF) variants dramatically increase the risk of Alzheimer’s disease (AD), yet the pathogenic mechanisms and the cell types affected by this loss remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex (PFC) of ABCA7 LoF carriers and matched control i...

Patient-specific, human-based cellular models that integrate biomimetic BBB, immune, and myelinated neuron components are critically needed to enable translationally relevant and accelerated discovery of neurological disease mechanisms and interventions. By engineering a brain-mimicking 3D hydrogel and co-culturing all six major brain cell types de...

Objective: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mech...

Background: Recent advances in xenotransplantation in living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use and first in human trials. Major obstacles remain though, including a lack of knowledge of the genetic incompatibilities between pig donors and human recipients which may led to harmful im...

Cerebrovascular dysregulation is a hallmark of Alzheimer’s disease (AD), but the changes that occur in specific cell types have not been fully characterized. Here, we profile single-nucleus transcriptomes in the human cerebrovasculature in six brain regions from 220 individuals with AD and 208 age-matched controls. We annotate 22,514 cerebrovascula...

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in t...

A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analy...

Background: While CTLA-4 and PD-1 immune-checkpoint blockade (ICB) have revolutionized melanoma treatment, these treatments have different mechanisms, response rates, and toxicities. Differential predictors of response are poorly characterized. Combination ICB has the highest response rates but also much higher toxicity, and which patients to treat...

Immune checkpoint blockade (ICB) therapy has improved long-term survival for patients with advanced melanoma. However, there is critical need to identify potential biomarkers of response and actionable strategies to improve response rates. Through generation and analysis of over 200 chromatin modification maps for ICB-treated melanoma patient sampl...

Immune checkpoint inhibitors (ICIs) have revolutionized the care for cancer and extended survival for advanced cancer patients. While ICIs have shown astonishing clinical benefits, less than 50% of patients experience a durable response. To find better biomarkers for ICI response and understand the diverse cellular players in the tumor microenviron...

Inguinal white adipose tissue (iWAT) is essential for the beneficial effects of exercise training on metabolic health. The underlying mechanisms for these effects are not fully understood, and here, we test the hypothesis that exercise training results in a more favorable iWAT structural phenotype. Using biochemical, imaging, and multi-omics analys...

Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington’s disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic di...

GENCODE produces high quality gene and transcript annotation for the human and mouse genomes. All GENCODE annotation is supported by experimental data and serves as a reference for genome biology and clinical genomics. The GENCODE consortium generates targeted experimental data, develops bioinformatic tools and carries out analyses that, along with...

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. While CD4 ⁺ Foxp3 ⁺ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profil...

APOE4 is the strongest genetic risk factor for Alzheimer’s disease1, 2–3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4, 5, 6, 7–8. Here, to gain more comprehensive insights into the imp...

Background The vast majority of immunotherapy resistant tumors do not harbor obvious resistance mutations and little remains known about alternative mechanisms of adaptive resistance. Methods We present a patient with Stage III melanoma treated with adjuvant Pembrolizumab (Pembro) who developed progressive disease three months after starting thera...

Single nuclei RNA sequencing (snRNA-seq) is widely used to study tissues and diseases. However, the technique remains challenging, as cytoplasmic RNA often contaminates nuclei-containing droplets and may even complicate the removal of empty droplets. Incomplete removal of contaminated background signal masks cell type-specific signal and interferes...

A series of SARS-CoV-2 variants of concern (VOCs) have evolved in humans during the COVID-19 pandemic—Alpha, Beta, Gamma, Delta, and Omicron. Here, we used global proteomic and genomic analyses during infection to understand the molecular responses driving VOC evolution. We discovered VOC-specific differences in viral RNA and protein expression lev...

Precise, scalable, and sustainable control of genetic and cellular activities in mammalian cells is key to developing precision therapeutics and smart biomanufacturing. Here we create a highly tunable, modular, versatile CRISPR-based synthetic transcription system for the programmable control of gene expression and cellular phenotypes in mammalian...

Exercise training is critical for the prevention and treatment of obesity, but its underlying mechanisms remain incompletely understood given the challenge of profiling heterogeneous effects across multiple tissues and cell types. Here, we address this challenge and opposing effects of exercise and high-fat diet (HFD)-induced obesity at single-cell...