Biology subjects

Lima, A. C.

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

3 recordsLinked to original sources

bioRxiv2023

A naturally occurring variant of MBD4 causes maternal germline hypermutation in primates

As part of an ongoing genome sequencing project at the Oregon National Primate Research Center, we identified a rhesus macaque with a rare homozygous frameshift mutation in the gene Methyl-CpG binding domain 4 (MBD4). MBD4 is responsible for the repair of C>T deamination mutations at CpG locations and has been linked to somatic hypermutation and cancer predisposition in humans. We show here that MBD4-associated hypermutation also affects the germline: the 6 offspring of the MBD4-null dam have a 4-6 fold increase in de novo mutation burden. This excess burden was predominantly C>T mutations at CpG locations consistent with MBD4 loss-of-function in the dam. There was also a significant excess of C>T at CpA sites, indicating an important, underappreciated role for MBD4 to repair deamination in CpA contexts. The MBD4-null dam developed sustained eosinophilia later in life, but we saw no other signs of neoplastic processes associated with MBD4 loss-of-function in humans, nor any obvious disease in the hypermutated offspring. This work provides what is likely the first evidence for a genetic factor causing hypermutation in the maternal germline of a mammal, and adds to the very small list of naturally occurring variants known to modulate germline mutation rates in mammals.

genetics↗

bioRxiv2023

TAD Evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function

Topological associating domains (TADs) are self-interacting genomic units crucial for shaping gene regulation patterns. Despite their importance, the extent of their evolutionary conservation and its functional implications remain largely unknown. In this study, we generate Hi-C and ChIP-seq data and compare TAD organization across four primate and four rodent species, and characterize the genetic and epigenetic properties of TAD boundaries in correspondence to their evolutionary conservation. We find that only 14% of all human TAD boundaries are shared among all eight species (ultraconserved), while 15% are human-specific. Ultraconserved TAD boundaries have stronger insulation strength, CTCF binding, and enrichment of older retrotransposons, compared to species-specific boundaries. CRISPR-Cas9 knockouts of two ultraconserved boundaries in mouse models leads to tissue-specific gene expression changes and morphological phenotypes. Deletion of a human-specific boundary near the autism-related AUTS2 gene results in upregulation of this gene in neurons. Overall, our study provides pertinent TAD boundary evolutionary conservation annotations, and showcase the functional importance of TAD evolution.

evolutionary biology↗

bioRxiv2021

Optimizing EEG source reconstruction with concurrent fMRI-derived spatial priors

Reconstructing EEG sources involves a complex pipeline, with the inverse problem being the most challenging. Multiple inversion algorithms are being continuously developed, aiming to tackle the non-uniqueness of this problem, which has been shown to be partially circumvented by also including fMRI-derived spatial priors in the inverse models. However, only task activation maps and resting-state networks (RSNs) have been explored so far, overlooking the recent, but already accepted, notion that brain networks exhibit dynamic functional connectivity (dFC) fluctuations. Moreover, there is no consensus regarding the inversion algorithm of choice, nor a systematic comparison between different sets of spatial priors. Using simultaneous EEG-fMRI data, here we compared four different inversion algorithms (MN, LORETA, EBB and MSP) under a Bayesian framework, each with three different sets of priors consisting of: 1) those specific to the algorithm (S1); 2) S1 plus fMRI task activation maps and RSNs (S2); and 3) S2 plus network modules of task-related dFC states estimated from the dFC fluctuations (S3). The quality of the reconstructed EEG sources was quantified in terms of model-based metrics, namely the free-energy and variance explained of the inversion models, and the overlap/proportion of brain regions known to be involved in the visual perception tasks that the participants were submitted to, and RSN templates, with/within EEG source components. Model-based metrics suggested that model parsimony is preferred, with the combination MSP+S1 exhibiting the best performance. However, optimal overlap/proportion values were found using EBB+S2 or MSP+S3, respectively, indicating that fMRI spatial priors, including dFC state modules, are crucial for the EEG source components to reflect neuronal activity of interest. Our results pave the way towards a more informative selection of the optimal EEG source reconstruction approach, which may be crucial in future studies.

neuroscience↗