Population-scale Ancestral Recombination Graphs with tskit 1.0

arXiv (Cornell University) · 2026-02-10

Ancestral recombination graphs (ARGs) are an increasingly important component of population and statistical genetics. The tskit library has become key infrastructure for the field, providing an expressive and general representation of ARGs together with a suite of efficient fundamental operations. In this note, we announce tskit version 1.0, describe its underlying rationale, and document its stability guarantees. These guarantees provide a foundation for durable computational artefacts and support long-term reproducibility of code and analyses.

Population-scale Ancestral Recombination Graphs with tskit 1.0

Open MIND · 2026-02-10

Ancestral recombination graphs (ARGs) are an increasingly important component of population and statistical genetics. The tskit library has become key infrastructure for the field, providing an expressive and general representation of ARGs together with a suite of efficient fundamental operations. In this note, we announce tskit version 1.0, describe its underlying rationale, and document its stability guarantees. These guarantees provide a foundation for durable computational artefacts and support long-term reproducibility of code and analyses.

Senolytic treatment attenuates immune cell infiltration without improving <scp>IAV</scp> outcomes in aged mice

Aging Cell · 2025-01-03 · 6 citations

Aging is a major risk factor for poor outcomes following respiratory infections. In animal models, the most severe outcomes of respiratory infections in older hosts have been associated with an increased burden of senescent cells that accumulate over time with age and create a hyperinflammatory response. Although studies using coronavirus animal models have demonstrated that removal of senescent cells with senolytics, a class of drugs that selectively kills senescent cells, resulted in reduced lung damage and increased survival, little is known about the role that senescent cells play in the outcome of influenza A viral (IAV) infections in aged mice. Here, we tested if the aged mice survival or weight loss IAV infections could be improved using three different senolytic regimens. We found that neither dasatinib plus quercetin, fisetin, nor ABT-263 improved outcomes. Furthermore, both dasatanib plus quercetin and fisetin treatments further suppressed immune infiltration than aging alone. Additionally, our data show that the short-term senolytic agents do not reduce senescent markers in our aged mouse model. These findings suggest that acute senolytic treatments do not universally reverse aging related immune phenotype against all respiratory viral infections.

Paradoxical SERCA2a Dysregulation Contributes to Atrial Fibrillation in a Model of Diet-Induced Obesity

International Journal of Molecular Sciences · 2025-06-11 · 2 citations

Obesity is a major risk factor for atrial fibrillation (AF), the most common serious cardiac arrhythmia, but the molecular mechanisms underlying obesity-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation to investigate how obesity promotes AF. Surface electrocardiography revealed that obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF. At the cellular level, this combination facilitated delayed afterdepolarizations in atrial myocytes, implicating altered Ca2+ dynamics. Interestingly, obesity did not affect the expression of key atrial Ca2+-handling proteins, including the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a). However, obesity increases the proportion of inhibitory phospholamban (PLN) monomers and decreases PLN phosphorylation, suggesting reduced SERCA2a activity. Paradoxically, Ca2+ reuptake in atrial myocytes from obese mice was similar to that achieved by potent small-molecule SERCA2a activators. We found that adrenergic stimulation increased Ca2+ transient amplitude without altering Ca2+ reuptake in myocytes from obese mice. Transcriptomic analysis revealed that a high-fat diet upregulated neuronatin, a protein involved in obesity that enhances SERCA2-mediated Ca2+ reuptake in neurons. We propose that obesity enables SERCA2a activation independently of PLN regulation, while adrenergic stimulation triggers arrhythmogenic Ca2+-induced Ca2+ release, promoting AF. In conclusion, this study demonstrates that obesity causes a paradoxical dysregulation of SERCA2a in atrial myocytes, with increased activity despite higher levels of inhibitory PLN monomers and reduced PLN phosphorylation. These findings offer new insights into the cellular mechanisms of obesity-induced AF and suggest potential therapeutic targets.

Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm

bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-01 · 1 citations

Abdominal aortic aneurysms (AAAs) are a degenerative aortic disease and associated with hallmarks of aging, such as mitophagy. Despite this, the exact associations among mitophagy, aging, and AAA progression remain unknown. In our study, gene expression analysis of human AAA tissue revealed downregulation of mitophagy pathways, mitochondrial structure, and function-related proteins. Human proteomic analyses identified decreased levels of mitophagy mediators PINK1 and Parkin. Aged mice and, separately, a murine AAA model showed reduced mitophagy in aortic vascular smooth muscle cells (VSMCs) and PINK1 and Parkin expression. Parkin knockdown in VSMCs aggravated AAA dilation in murine models, with elevated mitochondrial ROS and impaired mitochondrial function. Importantly, inhibiting USP30, an antagonist of the PINK1/Parkin pathway, increased mitophagy in VSMCs, improved mitochondrial function, and reduced AAA incidence and growth. Our study elucidates a critical mechanism that proposes AAAs as an age-associated disease with altered mitophagy, introducing new potential therapeutic approaches.

Deficiency in the mitophagy mediator Parkin accelerates murine skin allograft rejection

American Journal of Transplantation · 2024-08-12 · 3 citations

Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity

bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-06 · 1 citations

Abstract Obesity is a major risk factor for atrial fibrillation (AF) the most common serious cardiac arrhythmia, but the molecular mechanisms underlying diet-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation (‘two-hit’ model) to study the mechanisms by which diet-induced obesity promotes AF. Surface electrocardiography revealed that diet-induced obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF. At the cellular level, diet-induced obesity and acute adrenergic stimulation facilitate the formation of delayed afterdepolarizations in atrial myocytes, implicating altered Ca 2+ dynamics as the underlying cause of AF. We found that diet-induced obesity does not alter the expression of major Ca 2+ -handling proteins in atria, including the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), a major component of beat-to-beat Ca 2+ cycling in the heart. Paradoxically, obesity reduces phospholamban phosphorylation, suggesting decreased SERCA activity, yet atrial myocytes from obese mice showed a significantly increased Ca 2+ transient amplitude and SERCA-mediated Ca 2+ uptake. Adrenergic stimulation further increases the Ca 2+ transient amplitude but does not affect Ca 2+ reuptake in atrial myocytes from obese mice. Transcriptomics analysis showed that a high-fat diet prompts upregulation of neuronatin, a protein that has been implicated in obesity and is known to stimulate SERCA activity. We propose a mechanism in which obesity primes SERCA for paradoxical activation, and adrenergic stimulation facilitates AF conversion through a Ca 2+ -induced Ca 2+ release gain in atrial myocytes. Overall, this study links obesity, altered Ca 2+ signaling, and AF, and targeting this mechanism may prove effective for treating obesity-induced AF.

Abstract 3011: Parkin Mediated Mitophagy Deficiency In VSMCs Exacerbates Abdominal Aortic Aneurysm

Arteriosclerosis Thrombosis and Vascular Biology · 2024-05-01

Background: Parkin-mediated mitophagy eliminates dysfunctional mitochondria to reduce inflammatory responses caused by mtDAMPs. Given that reduced mitophagy is a hallmark of aging and AAA is an aging-associated disease, we sought to investigate the role of Parkin-mediated mitophagy in the development of AAAs. Methods: Groups of young (8-10 wks, n= 6/group) and aged (18-20 months, n=6/group) male Mito-QC mice either without intervention or underwent AAV.mPCSK9 D377Y infection and western diet feeding followed by Angiotensin II (AngII) or saline pump infusion for 28 days. Separately, young male Myh11-creER T2 Parkin fl/fl mice underwent tamoxifen (Parkin SMCKO) or vehicle injections (n=35-39/group), AAV.mPCSK9 D377Y infection, western diet feeding and AngII infusion. In vitro , MOVAs were treated with AngII and the USP30 inhibitor, a mitophagy enhancer, or vehicle followed by assessment of Parkin and mtROS. Results: VSMCs in aged Mito-QC mice, identified by a CD45 - CD90 - α-actin + profile, exhibit diminished mitophagy activity (p=0.017) and decreased Parkin expression (p=0.029). In young AAAs, VSMCs characterized as CD45 - CD90 - α-actin high and α-actin low also demonstrated decreased mitophagy (p=0.0017, p=0.0020), decreased Parkin(p=0.029), and a decreased trend in SDHB in Complex II (p=0.103) and NDUFB8 in Complex I (p=0.040) of the electron transport chain. Parkin SMCKO mice demonstrated increased AAA rupture (p=0.038), greater aneurysm size (p=0.044), reduced mtDNA copy numbers (p=0.026) and elevated mtROS compared to their controls. Parkin SMCKO mice demonstrated trends of diminished expression of respiratory complexes (p=0.070) and an exacerbated decrease in the maximal OCR involving both coupled and uncoupled activities of Complex I plus II (p=0.045, 0.028). In vitro experiments demonstrated treatment with the USP30 inhibitor reversed the reduction in mitophagy activity and mtROS increasement induced by AngII in MOVAS. Conclusions: In conclusion, mitophagy activity in aortic VSMCs and Parkin decreased with aging and separately, in AAAs and Parkin SMCKO mice, associated with exacerbation of AAA progression. These studies suggest stabilization of Parkin-dependent mitophagy could represent a novel AAA therapeutic target.

Publisher Correction: Clonally expanded memory CD8+ T cells accumulate in atherosclerotic plaques and are pro-atherogenic in aged mice

Nature Aging · 2024-05-24 · 1 citations

Genetic and Epigenetic Signatures for Cognitive Resilience in Neuropathologically Defined Alzheimer’s Disease Brains

Alzheimer s & Dementia · 2024-12-01

Abstract Background Not all people with neuropathological evidence of Alzheimer’s disease (AD) manifest clinical symptoms in life (cognitive resilience). We aimed to identify genetic and epigenetic signatures of cognitive resilience, utilizing data from brain donors with neuropathological evidence of AD who were either symptomatic or asymptomatic in life. Method Among brain donors with neuropathologically‐confirmed AD (364 asymptomatic/cognitively resilient and 490 symptomatic) from the Boston University AD Research Center, Framingham Heart Study—where we generated our own data—as well as the Religious Orders Study and Rush Memory and Aging Project, we utilized genome‐wide genetic array data, genome‐wide DNA methylation array data and RNA sequencing data. We conducted a genome‐wide association study (GWAS) and a methylation‐wide association study (MWAS) in each dataset and meta‐analyzed. Relationships between top‐ranked CpG sites, SNPs, and expression levels of the selected genes/isoforms were further evaluated. Result Meta‐analysis of genome‐wide significant MWAS results revealed 3 CpG sites from 3 genes, ARHGAP22, UBAC2, and KANSL1 (top‐ranked= cg19832721: Log2 fold change [Log2FC]=‐0.12, P=2.5x10 ‐8 ). Meta‐analysis of GWAS findings identified significant ((P&lt;1x10 ‐5 ) associations with 9 single nucleotide polymorphisms (SNPs) located in 9 different loci including APOE (top‐ranked=rs6917901 in TNFAIP3: odds ratio [OR]=0.53, 95% confidence interval [CI]=0.41‐0.67, P=3.8x10 ‐7 ). Expression of KANSL1 and its isoform ENST00000638269 were increased in symptomatic compared with cognitive resilient AD subjects (gene: Log2FC=0.082, P=5.95x10 ‐6 ; isoform: Log2FC=0.325, P=5.95x10 ‐4 ). The methylation level of cg19832721 was negatively correlated with expression of the KANSL1 isoform (Beta=‐27.13, P=0.002) but not with the gene (P&gt;0.05). SNP rs4586175 located in the ROBO3‐ROBO4 locus was significantly associated with symptomatic AD (OR=0.58, CI=0.45‐0.74, P=9.89x10 ‐6 ) and increased expression of the ROBO3 isoform ENST00000543966 (Beta=2.72, P=0.03). A CpG site cg08770647 located 773 bp from rs4586175 was nominally associated with symptomatic AD (Log2FC=0.06, P=1.52x10 ‐4 ) and its methylation level was correlated with increased expression of the ROBO3 isoform (Beta=83.26, P=0.01). Conclusion Our study suggests that interactions between genetic and epigenetic signatures contribute to cognitive resilience in persons with pathologically confirmed AD. Our findings also provide insight about genetic mechanisms that could be targeted to retard or prevent onset of AD clinical symptoms.