Biology subjects

Thathiah, A.

Publications and source records attributed to Thathiah, A..

3 recordsLinked to original sources

bioRxiv2026

A Complete Genome for the Common Marmoset

The common marmoset is a New World monkey (NWM) commonly used as a model organism to investigate questions in primate evolution and human disease, including Alzheimers and other neurodegenerative diseases, as well as neuropsychiatric disorders. Here we present the first telomere-to-telomere (T2T) reference genome for the common marmoset, adding over 88 Mb of sequence and resolving challenging genomic regions. An additional near-T2T assembly from a second unrelated individual yields a total of four high-quality haplotypes for analysis. The improved contiguity and accuracy of these assemblies enable unprecedented insights into complex and rapidly evolving genomic regions such as centromeres, sex chromosomes, ribosomal DNA (rDNA) structure, and the major histocompatibility complex (MHC). We fully resolved all marmoset centromeres, uncovering dimeric alpha satellites with chromosomal specificity and stratified inactive layers documenting ancestral centromere turnover. We assembled six acrocentric autosomes with gene-poor, satellite-rich short arms and provide evidence that most of them can harbor rDNA and all of them share large pseudo-homologous regions (PHRs). The Y chromosome, but not the X chromosome, carries active rDNA and PHRs, and the rDNA copy number is sexually dimorphic. Chromosomes that share PHRs also share closely related centromeric satellite DNA, supporting a model of ongoing recombinational exchange between heterologous chromosomes facilitated by rDNA. We discovered multiple novel, marmoset-specific MHC genes that are predicted to protect against pathogens encountered in its environment. Leveraging this complete reference, we further identified over 500 transcribed genes with transcript models or expansions specific to the marmoset lineage. Together with additional long-read marmoset assemblies, these genomes were used to construct a marmoset pangenome, providing a robust reference framework for short-read mapping across diverse individuals. This resource will improve the utility of the common marmoset as a biomedical model organism and fill key gaps in our understanding of primate evolution.

genomics↗

bioRxiv2024

Marmosets as model systems for the study of Alzheimers disease and related dementias: substantiation of physiological Tau 3R and 4R isoform expression and phosphorylation

INTRODUCTIONMarmosets have been shown to spontaneously develop pathological hallmarks of Alzheimers disease (AD) during advanced age, including amyloid-beta plaques, positioning them as a model system to overcome the rodent-to-human translational gap for AD. However, Tau expression in the marmoset brain has been understudied. METHODSTo comprehensively investigate Tau isoform expression in marmosets, brain tissue from eight unrelated marmosets across various ages was evaluated and compared to human postmortem AD tissue. Microtubule-associated protein tau (MAPT) mRNA expression and splicing were confirmed by RT-PCR. Tau isoforms in the marmoset brain were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining. Synaptic Tau expression was analyzed from crude synaptosome extractions. RESULTS3R and 4R Tau isoforms are expressed in marmoset brains at both transcript and protein levels across ages. Results from western blot analysis were confirmed by mass spectrometry, which revealed that Tau peptides in marmoset corresponded to the 3R and 4R peptides in the human AD brain. 3R Tau was primarily enriched in neonate brains, and 4R enhanced in adult and aged brains. Tau was widely distributed in neurons with localization in the soma and synaptic regions. Phosphorylation residues were observed on Thr-181, Thr-217, and Thr-231, Ser202/Thr205, Ser396/Ser404. Paired helical filament (PHF)-like aggregates were also detected in aged marmosets. DISCUSSIONOur results confirm the expression of both 3R and 4R Tau isoforms and important phosphorylation residues in the marmoset brain. These data emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for the study of AD.

systems biology↗

bioRxiv2021

Deletion of Serf2 shifts amyloid conformation in an Aβ amyloid mouse model

In age-related neurodegenerative disease, like Alzheimers and Parkinsons disease, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm- and human cell models for disease. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated SERF2 brain-specific knockout mice which, unlike full body knockout mice, were viable, and showed no major behavioral and cognitive abnormalities. We combined these knockout mice with the APPPS1 mouse model for human amyloid beta aggregation. Using structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in human brain, we show that knockout of SERF2 alters the structure of amyloid fibrils and deposits. Moreover, scanning transmission electron microscopy revealed thicker, shorter and more densely packed amyloid in absence of SERF2. Altogether, our data reveal pleiotropic functions of SERF in development and aging and support a function as a modifier of amyloid aggregation in mammalian brain. Our results indicate that single cellular factors like SERF can determine the structural outcome of amyloid aggregation, offering possibilities for polymorphism-based disease interventions.

molecular biology↗