Biology subjects

Spina, L.

Publications and source records attributed to Spina, L..

4 recordsLinked to original sources

bioRxiv2026

Inter-individual variation of cellular and gene-expression properties of the human striatum

The human brain varies from person to person in ways that shape behaviors and vulnerabilities, yet the cellular and molecular bases for inter-individual variation are largely unknown. Here we describe an analysis of cellular and gene-expression variation in four key structures of the striatum complex - the caudate, putamen, nucleus accumbens, and internal capsule - as well as the prefrontal cortex, from single-nucleus RNA-seq analysis of 3.9 million nuclei from 178 adult brain donors. We found that people with more astrocytes in any one brain region tended to have this property in all brain regions sampled; the same was true of striatal interneurons, microglia, and oligodendrocyte precursor cells (OPCs). OPCs showed attrition with age, declining in numbers by approximately 40% between age 30 and age 80 in both gray matter and white matter regions. We identified thousands of age-associated (but few sex-associated) variations in gene expression; the vast majority of these effects of age were cell-type-specific. Aging most strongly affected gene expression in projection neurons - especially striatal medium spiny neurons (MSNs/SPNs) - and had a much smaller effect on gene expression in interneurons. Individuals ages could be predicted to within about five years based on RNA-expression patterns from any of the striatal cell types. Common genetic variants detectably affected the expression levels of some ten thousand genes; the great majority of these effects were cell-type-specific. These data will provide a foundation for exploring natural inter-individual variation, aging, and tissue-based studies of human brain vulnerabilities.

neuroscience↗

bioRxiv2026

Haplotype specific analyses in the phased genomes era: the case of apple cv "Golden Delicious"

Apple is one of the major cultivated fruit crops in temperate regions. To better support breeding programs and facilitate the development of improved cultivars, we generated a new haplotype-resolved version of the Golden Delicious genome, one of the major founders of many modern apple lineages. The assembly features the separation of the two haplotypes, with a total size of 647.3 Mb and 649.2 Mb, respectively. The phasing was accurately validated with 10,321 curated SNPs. Telomere-to-telomere continuity was verified by the analysis of telomeric sequence composition at the end of each chromosome. Gene prediction identified a total of 45,116 genes in haplotype 1 and 45,063 genes in haplotype 2. A pangenome analysis employing 6 haplotype resolved genomes identified both common and unique gene families. The availability of a phased genome enabled the assessment of genome-wide allelic specific expression. Our case study, focusing on Md-PG1 (a key regulator of fruit softening), revealed that the allelic form on haplotype 2 (GDH2-10g24673) was the dominant contributor to total gene expression. In addition, the phased genome also showed specific miRNA chromosomal distribution patterns, as well as a distinct methylation profile. Altogether, these genomic resources provide new insights into the allelic regulation of key agronomic traits and represent a valuable tool to accelerate apple breeding.

genomics↗

bioRxiv2025

A shared DNA-repeat toxicity threshold, reached somatically at cell-type-specific rates, unites cortical and striatal neurodegeneration in Huntingtons disease

Huntingtons disease (HD) affects two major brain areas - the striatum and cerebral cortex - in ways that differ in timing, severity, and gene-expression changes. For these reasons, and because many cortical neurons project axons to the affected striatal neurons, striatal and cortical atrophy have long been proposed to have distinct mechanisms, with one potentially a secondary consequence of the other. In the striatum, we recently found that neurons degenerate asynchronously as their own huntingtin (HTT) gene CAG-repeat tracts, typically inherited at 40-50 CAGs, expand somatically beyond 150 CAGs. To ask whether a similar or different dynamic affects the cerebral cortex, we analyzed HTT CAG repeats and genome-wide RNA expression together in more than 130,000 nuclei from 12 cortical areas of brain donors with HD. The resulting data revealed that cortical and striatal neurodegeneration in fact result from analogous sequences of cell-autonomous events, each instructed by somatic expansion of a neurons own HTT CAG repeat. Analyses revealed that somatic expansion beyond a high toxicity threshold (of about 150 CAGs) is necessary and sufficient to initiate pathological changes; that this pathogenicity length threshold is shared by striatal and cortical projection neurons of all types; and that cortical area, cortical layer, and axonal projections play only incidental roles, as proxies for the true driver: profound (up to 50-fold) variation among types and subtypes of pyramidal neurons in the likelihood of reaching the 150-CAG toxicity threshold in a human lifetime. These results also suggest that containing somatic DNA-repeat expansion below this high toxicity threshold would protect both brain areas in HD.

genetics↗

bioRxiv2024

Concerted neuron-astrocyte gene expression declines in aging and schizophrenia

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a striking relationship between peoples cortical neurons and cortical astrocytes. We used single-nucleus RNA-seq to analyze the prefrontal cortex of 191 human donors ages 22-97 years, including healthy individuals and persons with schizophrenia. Latent-factor analysis of these data revealed that in persons whose cortical neurons more strongly expressed genes for synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the Synaptic Neuron- and-Astrocyte Program (SNAP). In schizophrenia and aging - two conditions that involve declines in cognitive flexibility and plasticity 1,2 - cells had divested from SNAP: astrocytes, glutamatergic (excitatory) neurons, and GABAergic (inhibitory) neurons all reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy persons of similar age, may underlie many aspects of normal human interindividual differences and be an important point of convergence for multiple kinds of pathophysiology.

neuroscience↗