Biology subjects

Bon, C.

Publications and source records attributed to Bon, C..

7 recordsLinked to original sources

bioRxiv2026

The genetic legacy of archaic hominins in Central and Southeast Asia uncovers three distinct Denisovan populations

The sequencing of Neanderthal and Denisovan genomes has provided new insights into human evolution. Today, interactions between Neanderthals, Denisovans, and populations of European, East Asian, and Oceanian descent are well documented. However, neighboring regions such as Central and Southeast Asia remain understudied for archaic admixture despite their key geographic location and complex migration histories. To fill this gap, we investigate archaic ancestry in 16 populations from Central Asia and 14 from mainland Southeast Asia. Our results show that Neanderthal and Denisovan ancestry in these populations is of the same order of magnitude as in other Eurasian populations. However, although Denisovan ancestry accounts for less than 1% in mainland Asian populations, it originates from several admixture events involving different Denisovan populations. In particular, we find in Southeast Asia that Denisovan ancestry results from three distinct admixture events with three different Denisovan populations, highlighting the complexity of Denisovan contact with the ancestors of present-day Southeast Asian populations and providing new insights into the extensive geographic distribution of Denisovan populations.

evolutionary biology↗

bioRxiv2023

Internal Ribosome Entry Sites act as Effector Domain in linear and circular antisense long non-coding SINEUP RNAs

SINEUPs are antisense long non-coding RNAs that enhance translation of overlapping sense mRNAs through the activity of two domains: a SINEB2 sequence UP-regulating translation (Effector Domain, ED) and an antisense region providing target specificity (Binding Domain, BD). In this study, we demonstrate that the invSINEB2 sequence from the natural SINEUP AS Uchl1 RNA is an Internal Ribosomal Entry Site (IRES) when acting in cis and that known viral and cellular IRES sequences can act as Effector Domain in synthetic SINEUPs. To identify natural IRES-containing, non-coding RNAs with SINEUP-like activity, we focused on circular RNAs showing that the non-coding circ5533, transcribed from the c-myc locus, enhances endogenous protein expression of its target PX Domain Containing Serine/Threonine Kinase Like (Pxk) by increasing mRNA association to polysomes. In summary, this study shows that natural and synthetic SINEUPs include linear and circular transcripts with an embedded IRES sequence as ED.

molecular biology↗

bioRxiv2022

Angelman syndrome patient neuron screen identifies a potent and selective clinical ASO targeting UBE3A-ATS with long lasting effect in cynomolgus monkey

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of neuronal E3 ligase UBE3A with no available treatment. Restoring UBE3A levels via downregulation of the paternally cis-acting long non-coding antisense transcript (UBE3A-ATS) is a potential disease modifying. Developing molecules targeting human UBE3A-ATS is challenging because it is expressed only in neurons and lacks animal species sequence conservation. To overcome this, we performed a library screen of locked-nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) on AS patient-derived neurons, identifying initial sequences. Further optimization led to the identification of the ASO, RO7248824, which selectively and potently reduces UBE3A-ATS, while concomitantly upregulating the UBE3A mRNA and protein. These properties held true in both human AS patient- and neurotypical-, as well as cynomolgus monkey-derived neurons. In vivo use of tool molecules in wild-type (WT) and AS Ube3am-/p+ mice, revealed a steep relationship between UBE3A-ATS knock-down and UBE3A mRNA/protein upregulation, whereby an almost 90% downregulation was needed to achieve a 50% upregulation, respectively. This relationship was confirmed in cynomolgus monkeys. Whereby, repeated lumbar intrathecal administrations of RO7248824 was well tolerated without adverse in-life effects or tissue pathology and produced a robust, long lasting (up to 3 months) paternal reactivation of UBE3A mRNA/protein across key monkey brain regions. Our results demonstrate that AS human pluripotent stem cell neurons serve as an excellent translational tool and furthermore LNA-modified ASOs exhibit excellent drug-like properties. Sustained efficacy translated to infrequent, intrathecal dosing and serves as the basis for the ongoing clinical development of RO7248824 for AS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/495066v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1c2a97eorg.highwire.dtl.DTLVardef@1059954org.highwire.dtl.DTLVardef@95835aorg.highwire.dtl.DTLVardef@1e2adea_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO From AS patient blood to a neuronal screen, identifies clinical ASO with excellent in vivo properties. (1) Patients were recruited. (2) Whereby blood was reprogrammed into hIPSC and subsequently differentiated into neurons. (3) ASOs were designed and screened on human neurons to downregulate the UBE3A-ATS likely via directed RNase H Cleavage of Nascent Transcripts. (4a) RO7248824 was identified that potently and selective reduces UBE3A-ATS, concomitantly with upregulating the UBE3A sense transcript and protein which was used for in vitro pk/pd. (4b) In parallel tool murine ASO were used demonstrate in vivo POC.(5) Pivotal nonhuman primate studies to monitor safety and predict the human dose. (6) RO7248824 is in AS clinical trial. C_FIG One Sentence SummaryFrom angelman syndrome human neuron screen to cynomolgus monkey proof of concept identifies the clinical molecule RO7248824

neuroscience↗

bioRxiv2021

Genetic continuity of Indo-Iranian speakers since the Iron Age in southern Central Asia.

Since prehistoric times, South Central Asia has been at the crossroads of the movement of people, culture, and goods. Today, the Central Asias populations are divided into two cultural and linguistic groups: the Indo-Iranian and the Turko-Mongolian groups. Previous genetic studies unveiled that migrations from East Asia contributed to the spread of Turko-Mongolian populations in Central Asia and the partial replacement of the Indo-Iranian population. However, little is known about the origin of the latter. To shed light on this, we compare the genetic data on two current-day populations- Yaghnobis and Tajiks - with genome-wide data from published ancient individuals. The present Indo-Iranian populations from Central Asia display a strong genetic continuity with Iron Age samples from Turkmenistan and Tajikistan. We model Yaghnobis as a mixture of 93% Iron Age individual from Turkmenistan and 7% from Baikal. For the Tajiks, we observe a higher Baikal ancestry and an additional admixture event with a South Asian population. Our results, therefore, suggest that in addition to a complex history, Central Asia shows a remarkable genetic continuity since the Iron Age, with only limited gene flow.

genomics↗

bioRxiv2021

Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons

BackgroudParkinsons disease (PD) presents the selective loss of A9 dopaminergic (DA) neurons of Substantia Nigra pars compacta (SNpc) and the presence of intracellular aggregates called Lewy bodies. -synuclein (-syn) species truncated at the carboxy terminal (C-terminal) accumulate in pathological inclusions and promote -syn aggregation and toxicity. Hemoglobin (Hb) is the major oxygen carrier protein in erythrocytes. In addition, Hb is expressed in A9 DA neurons where it influences mitochondrial activity. Hb overexpression increases cells vulnerability in a neurochemical model of PD in vitro and forms cytoplasmic and nucleolar aggregates upon short-term overexpression in mouse SNpc. Methods and {beta}-globin chains were co-expressed in DA cells of SNpc in vivo upon stereotaxic injections of an Adeno-Associated Virus isotype 9 (AAV9) and in DA iMN9D cells in vitro. ResultsLong-term Hb over-expression in SNpc induced the loss of about 50% of DA neurons, a mild motor impairment and deficits in recognition and spatial working memory. Hb triggered the formation of endogenous -synuclein C-terminal truncated species. Similar -syn fragments were found in vitro in DA iMN9D cells over-expressing and {beta}-globins when treated with pre-formed -syn fibrils. ConclusionOur study positions Hb as a relevant player in PD pathogenesis for its ability to trigger DA cells loss in vivo and the formation of C-terminal -synuclein fragments.

neuroscience↗

bioRxiv2019

Metagenomic analysis of a blood stain from the French revolutionary Jean-Paul Marat (1743-1793)

The French revolutionary Jean-Paul Marat (1743-1793) was assassinated in 1793 in his bathtub, where he was trying to find relief from the debilitating skin disease he was suffering from. At the time of his death, Marat was annotating newspapers, which got stained with his blood and were subsequently preserved by his sister. We extracted and sequenced DNA from the blood stain and also from another section of the newspaper, which we used for comparison. Results from the human DNA sequence analyses were compatible with a heterogeneous ancestry of Marat, with his mother being of French origin and his father born in Sardinia. Metagenomic analyses of the non-human reads uncovered the presence of fungal, bacterial and low levels of viral DNA. Relying on the presence/absence of microbial species in the samples, we could cast doubt on several putative infectious agents that have been previously hypothesised as the cause of his condition but for which we detect not a single sequencing read. Conversely, some of the species we detect are uncommon as environmental contaminants and may represent plausible infective agents. Based on all the available evidence, we hypothesize that Marat may have suffered from a fungal infection (seborrheic dermatitis), possibly superinfected with bacterial opportunistic pathogens.

genetics↗

bioRxiv2018

Chromosome evolution at the origin of the ancestral vertebrate genome

About 450 million years ago, a marine chordate was subject to two successive whole genome duplications (WGDs) before becoming the common ancestor of vertebrates and diversifying into the more than 60,000 species found today. Here, we reconstruct in details the evolution of chromosomes of this early vertebrate along successive steps of the two WGD. We first compared 61 extant animal genomes to build a highly contiguous order of genes in a 326 million years old ancestral Amniota genome. In this genome, we established a well-supported list of duplicated genes originating from the WGDs to link chromosomes in tetrads, a telltale signature of these events. This enabled us to reconstruct a scenario where a pre-vertebrate genome composed of 17 chromosomes duplicated into 34 chromosomes, and was subject to 7 chromosome fusions before duplicating again into 54 chromosomes. After the separation of Agnatha (jawless fish) and Gnathostomata, four more fusions took place to form the ancestral Euteleostomi genome of 50 chromosomes. These results firmly establish the occurrence of the two WGD, resolving in particular the ambiguity raised by the analysis of the lamprey genetic map. In addition, we provide insight into the origin of homologous micro-chromosomes found in the chicken and the gar genomes. This work provides a foundation for studying the evolution of vertebrate chromosomes from the standpoint of a common ancestor, and particularly the pattern of duplicate gene retention and loss that resulted in the gene composition of extant genomes.

genomics↗