Biology subjects

Nicola, P. A.

Publications and source records attributed to Nicola, P. A..

10 recordsLinked to original sources

bioRxiv2026

A comprehensive atlas of somatic mutation rates and mutational signatures in normal human cells

Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune system to cancer. To inform understanding of somatic evolution in the human body we report the mutation rates and mutational signatures of 53 normal cell types. Most show evidence of linear mutation accumulation over time with single base substitution mutation rates ranging from ~3.5/year/diploid genome in spermatogonia and sperm, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in sun-exposed skin epidermal cells and 10-50/year in the remainder. Certain cell types, including skin epidermis, cardiac myocytes, bladder urothelium, kidney proximal tubule cells, and hepatocytes, show substantial variability in mutation burdens around the linear age trend, indicating the influence of additional factors which differ between individuals and modulate mutation accumulation, including exogenous mutagen exposures. At least 18 single-base substitution and nine small insertion and deletion mutational signatures are present, some in all cell types, some in a subset and others in a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures, but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution of human cell populations in health and disease.

genomics↗

bioRxiv2026

Persistence of tobacco-mutated alveolar progenitor cells after smoking cessation mirrors long term risk of lung adenocarcinoma

Tobacco smoke shapes mutations, selection and clonal expansion in lung epithelial cells. Smoking cessation leads to divergent epidemiology in the two most common lung cancers: squamous cell carcinoma risk declines sharply, while adenocarcinoma risk is preserved. To investigate this discrepancy, we analysed 806 genomes of alveolar type II (AT2) cells and found persistently elevated mutation burdens after cessation. In contrast, in the proximal airway, rare basal stem cells with near-normal mutation burden expand after cessation, protecting against squamous cell carcinoma. Targeted single-molecule DNA sequencing of AT2 cells revealed positive selection for TP53 and cell cycle and MAPK genes, supporting continued cancer risk. A multistage carcinogenesis model emphasised the importance of a small population of hypermutated cells in the alveoli and reproduced the divergent epidemiological trajectories following cessation due to distinct regenerative dynamics. Our findings suggest that differences in mutational burden and clonal regeneration explain post-cessation trends in lung cancer subtypes. One sentence summaryCancer risk reflects not only cumulative exposure to toxins, but the capacity of tissues to erase genomic damage through regeneration from protected cells with clonal advantage.

genomics↗

bioRxiv2025

Somatic TYK2 activating mutations in tumor-infiltrating T cells promote anti-cancer immunity

Cancer cells evolve to increase fitness and evade the immune system, but it is not clear if tumor infiltrating lymphocytes (TILs) undergo selection for somatic mutations that augment anti-cancer immunity. Using single molecule whole exome sequencing in TILs, we identified somatic mutations in Tyrosine-protein kinase 2 (TYK2), several of which increased TYK2 phosphorylation, JAK-STAT signaling, and interferon gamma signaling. Among these mutations, TYK2D810V was recurrently observed in patients with diverse cancer types. In vitro, TYK2D810V enhanced T cells effector functions and cytokine production. We generated mice with a germline Tyk2D807V mutation that recapitulated the human TYK2D810Vmutation. These mice were healthy and did not develop autoimmune disorders. However, they possessed enhanced anti-tumor effects in the context of syngeneic and autochthonous cancer models. Adoptive therapy with Tyk2D807V CD8 T cells also decreased cancer growth. Thus, naturally occurring mutations in non-malignant lymphocytes can antagonize cancer and inspire new immunotherapies strategies.

cancer biology↗

bioRxiv2025

Extensive and differential platinum chemotherapy mutagenesis in children

Childhood cancer survivors often develop long-term adverse effects, which may be caused by direct mutagenesis of cytotoxic agents. Some of these agents generate distinctive DNA imprints (mutational signatures), as exemplified by platinum chemotherapeutics. Here, we examined chemotherapy mutagenesis in paediatric tissues by deploying a duplex sequencing method (NanoSeq), which enables mutation calling from single DNA molecules. We surveyed whole genomes of paediatric liver, blood and other tissues, obtained from surgical resections and at post-mortem. Platinum signatures pervaded all tissues extensively, elevating mutation burdens of paediatric tissues to levels seen in adults. Remarkably, we found a tissue-specific mutational signature in the liver. We examined the functional potential of mutations by gene focused NanoSeq, which revealed that platinum agents cause a vast repertoire of cancer causing variants across normal tissues, such as leukaemogenic mutations in blood. This finding may conceivably link cancer treatment in childhood to mutation-driven long term sequelae.

cancer biology↗

bioRxiv2025

Genomic Insights into Derived Dwarfism and Exudivory in a Genus (Callithrix) of the World's Smallest Anthropoid Monkeys

The primate Callitrichidae family represents the smallest anthropoid primates, which are known to possess dietary specializations for eating viscous plant exudates (exudivory), and as callitrichids Callithrix marmosets push these biological traits to extremes. Using low-coverage whole genome sequencing of Callithrix species, we investigated Callithrix evolutionary history, species genetic diversity, and the genomic basis of derived small body size and exudivory. Our phylogenetic species tree shows that Callithrix likely originated in southeastern Brazil and migrated northward to the semi-arid regions of central and northeastern Brazil. We show that there is greater genetic similarity between smaller and more exudivorous Callithrix species relative to larger and less exudivorous species, and that the genus likely experienced extensive past reticulation. Based on these results, we argue that the Callithrix migration from the Atlantic Forest biome to the relatively more extreme environments of Cerrado/Caatinga biomes progressively reduced body size and increased exudivory specialization in Callithrix marmosets. We also identified species-specific candidate genes under putative positive selection for traits that include body growth, bone development, reproduction, fat metabolism, insulin signaling, and liporegulation. In conclusion, we increased genomic resources for understudied Callithrix species, while providing the most comprehensive overview of marmoset genomic diversity to-date, and identify several candidate genes under positive selection for traits related to small body size and exudivory. Future studies should sample wild marmosets more widely and perform higher-coverage genomic sequencing to better understand how specific genomic variants may impact the evolution of key Callithrix biological traits.

evolutionary biology↗

bioRxiv2023

Pelage Variation and Morphometrics of Closely Related Callithrix Marmoset Species and Their Hybrids

BackgroundHybrids are expected to show greater phenotypic variation than their parental species, yet how hybrid phenotype expression varies with genetic distances in closely-related parental species remains surprisingly understudied. Here we study pelage and morphometric trait variation in anthropogenic hybrids vailable at the end of the article between four species of Brazilian Callithrix marmosets, a relatively recent primate radiation. Marmoset species are distinguishable by pelage phenotype and morphological specializations for eating tree exudates. Here, we (1) describe qualitative phenotypic pelage differences between parental species and hybrids; (2) test whether significant quantitative differences exist between parental and hybrid morphometric phenotypes; and (3) determine which hybrid morphometic traits show heterosis, dysgenesis, trangression, or intermediacy relative to the parental trait. For morphometric traits, we investigated both cranial and post-cranial traits, particularly as most hybrid morphological studies focus on the former instead of the latter. Finally, we estimate mitogenomic distances between marmoset species from previously published data. ResultsMarmoset hybrid facial and overall body pelage variation reflected novel combinations of coloration and patterns present in parental species. In morphometric traits, C. jacchus and C. penicillata were the most similar to each other, while C. aurita was the most distinct, and C. geoffroyi trait measures fell between these other species. Only three traits in C. jacchus x C. penicillata hybrids showed heterosis. We observed heterosis and dysgenesis in several traits of C. penicillata x C. geoffroyi hybrids. Transgressive segregation was observed in hybrids of C. aurita and the other species. These hybrids were also C. aurita-like for a number of traits. Genetic distance was closest between C. jacchus and C. penicillata and farthest between C. aurita and the other species. ConclusionWe attributed significant morphometric differences between marmoset species to variable levels of morphological specialization for exudivory in these species. Our results suggest that intermediate or parental species-like hybrid traits relative to the parental trait values are more likely in crosses between species with relatively lesser genetic distance. More extreme phenotypic variation is more likely in parental species with greater genetic distance, with transgressive traits appearing in hybrids of the most genetically distant parental species. We further suggest that less developmental disturbances can be expected in hybrids of more recently diverged parental species, and that future studies of hybrid phenotypic variation should investigate selective pressures on Callithrix cranial and post-cranial morphological traits.

zoology↗

bioRxiv2022

Comparison of Mitogenomic and Mitochondrial Markers for the Phylogenetic and Evolutionary Study of Marmosets, with special focus on captive Callithrix jacchus

Marmosets, especially Callithrix jacchus, are becoming valuable, high-demand biomedical models but their supply outside of their native Brazil is limited. Thus, uncovering the ancestry and biogeographic origins of captive marmosets is an essential task to optimize their biomedical use. Such information facilitates assessing standing levels of captive marmoset genetic diversity, identifying hybrids, and maintaining genetic diversity of captive marmoset populations. Here, we present 16 newly sequenced mitochondrial genomes from marmosets with C. jacchus phenotypes from international biomedical and animal supply facilities. We combine these new data with publicly available sequences to compare usage of mitogenome and the mtDNA control region for determining the ancestry and diversity of captive marmosets. MtDNA control region and mitogenome haplotypes from all 16 newly sequenced marmosets grouped within C. jacchus phylogenetic clades. Overall, phylogenies based on mitogenomes rather than the control region showed better resolved branching patterns with stronger statistical support within C. jacchus clades. However, both mtDNA markers show that C. jacchus is the sister clade to the phylogenetic C. penicillata Caatinga biome clade. Callithrix jacchus mtDNA control region haplotypes showed the highest haplotype and nucleotide diversity, and were intermediate in terms of per sequence theta and polymorphic sites. The larger number of available Callithrix mtDNA control region sequences relative to mitogenomes was used to determine ancestral mtDNA haplotype biogeographic origins. However, biogeographic origins for many C. jacchus haplotypes including those from international captive facilities could not be determined, which we attributed to unknown provenance information from natural C. jacchus populations. Given our results, we encourage increased sampling and genomic sequencing efforts for natural C. jacchus populations in Brazil, and utilizing the mitogenome over other mtDNA markers for phylogenetic-based analyses. Further, combining marmoset mitogenomic data with phenotypic and nuclear genomic data will greatly enhance the biomedical use of marmosets.

genetics↗

bioRxiv2021

Genomic Skimming and Nanopore Sequencing Uncover Cryptic Hybridization in One of World's Most Threatened Primates

The Brazilian buffy-tufted-ear marmoset (Callithrix aurita), one of the worlds most endangered primates, is threatened by anthropogenic hybridization with exotic, invasive marmoset species. As there are few genetic data available for C. aurita, we developed a PCR-free protocol with minimal technical requirements to rapidly generate genomic data with genomic skimming and portable nanopore sequencing. With this direct DNA sequencing approach, we successfully determined the complete mitogenome of a marmoset that we initially identified as C. aurita. The obtained nanopore-assembled sequence was highly concordant with a Sanger sequenced version of the same mitogenome. Phylogenetic analyses unexpectedly revealed that our specimen was a cryptic hybrid, with a C. aurita phenotype and C. penicillata mitogenome lineage. We also used publicly available mitogenome data to determine diversity estimates for C. aurita and three other marmoset species. Mitogenomics holds great potential to address deficiencies in genomic data for endangered, non-model species such as C. aurita. However, we discuss why mitogenomic approaches should be used in conjunction with other data for marmoset species identification. Finally, we discuss the utility and implications of our results and genomic skimming/nanopore approach for conservation and evolutionary studies of C. aurita and other marmosets.

evolutionary biology↗

bioRxiv2020

Mitogenomic Phylogeny of Callithrix with Special Focus on Human Transferred Taxa

Callithrix marmosets are a relatively young primate radiation, whose phylogeny is not yet fully resolved. These primates are naturally para- and allopatric, but three species with highly invasive potential have been introduced into the southeastern Brazilian Atlantic Forest by the pet trade. There, these species hybridize with each other and endangered, native congeners. We aimed here to reconstruct a robust Callithrix phylogeny and divergence time estimates, and identify the biogeographic origins of autochthonous and allochthonous Callithrix mitogenome lineages. We sequenced 49 mitogenomes from four species (C. aurita, C. geoffroyi, C. jacchus, C. penicillata) and anthropogenic hybrids (C. aurita x Callithrix sp., C. penicillata x C. jacchus, Callithrix sp. x Callithrix sp., C. penicillata x C. geoffroyi) via Sanger and whole genome sequencing. We combined these data with previously published Callithrix mitogenomes to analyze five Callithrix species in total. ResultsWe report the complete sequence and organization of the C. aurita mitogenome. Phylogenetic analyses showed that C. aurita was the first to diverge within Callithrix 3.54 million years ago (Ma), while C. jacchus and C. penicillata lineages diverged most recently 0.5 Ma as sister clades. MtDNA clades of C. aurita, C. geoffroyi, and C. penicillata show intraspecific geographic structure, but C. penicillata clades appear polyphyletic. Hybrids, which were identified by phenotype, possessed mainly C. penicillata or C. jacchus mtDNA haplotypes. The biogeographic origins of mtDNA haplotypes from hybrid and allochthonous Callithrix were broadly distributed across natural Callithrix ranges. Our phylogenetic results also evidence introgression of C. jacchus mtDNA into C. aurita. ConclusionOur robust Callithrix mitogenome phylogeny shows C. aurita lineages as basal and C. jacchus lineages among the most recent within Callithrix. We provide the first evidence that parental mtDNA lineages of anthropogenic hybrid and allochthonous marmosets are broadly distributed inside and outside of the Atlantic Forest. We also show evidence of cryptic hybridization between allochthonous Callithrix and autochthonous C. aurita. Our results encouragingly show that further development of genomic resources will allow to more clearly elucidate Callithrix evolutionary relationships and understand the dynamics of Callithrix anthropogenic introductions into the Brazilian Atlantic Forest.

genomics↗

bioRxiv2019

The Effects of Host Taxon, Hybridization, and Environment on the Gut Microbiome of Callithrix Marmosets

Mammalian captive dietary specialists like folivores are prone to gastrointestinal distress and primate dietary specialists suffer the greatest gut microbiome diversity losses in captivity compared to the wild. Marmosets represent another group of dietary specialists, exudivores that eat plant exudates, but whose microbiome remains relatively less studied. The common occurrence of gastrointestinal distress in captive marmosets prompted us to study the Callithrix gut microbiome composition and predictive function through bacterial 16S ribosomal RNA V4 region sequencing. We sampled 59 wild and non-wild Callithrix across four species and their hybrids. Host environment had a stronger effect on the gut microbiome than host taxon. Wild Callithrix gut microbiomes were enriched for Bifidobacterium, which process host-indigestible carbohydrates. Captive marmoset guts were enriched for Enterobacteriaceae, a family containing pathogenic bacteria. While gut microbiome function was similar across marmosets, Enterobacteriaceae seem to carry out most functional activities in captive host guts. More diverse bacterial taxa seem to perform gut functions in wild marmosets, with Bifidobacterium being important for carbohydrate metabolism. Non-wild marmosets showed gut microbiome composition aspects seen in human gastrointestinal diseases. Thus, captivity may perturb the exudivore gut microbiome, which raises implications for captive exudivore welfare and calls for husbandry modifications.

microbiology↗