Biology subjects

Robb, J. E.

Publications and source records attributed to Robb, J. E..

10 recordsLinked to original sources

bioRxiv2026

The BAF complex works with FOS to regulate human neuronal activity-dependent ASD-associated gene programs

The BAF chromatin remodeling complex is critical to normal brain development, and rare variants within genes encoding BAF subunits are a common genetic cause of neurodevelopmental disorders, including autism spectrum disorder (ASD). Yet the factors that direct BAF binding across the neuronal genome, the human neuronal gene programs that are regulated by BAF, and the mechanisms whereby BAF subunit perturbation leads to ASD are not known. We find that BAF binds with the activity-dependent transcription factor FOS to distal regulatory regions that, in response to neuronal activity, undergo chromatin opening and show evidence of enhancer activation. Knock-out of ARID1A, a BAF subunit implicated in ASD, leads to decreased chromatin accessibility at FOS/BAF binding sites concomitant with decreased expression of nearby activity-regulated ASD-associated genes. Additionally, we find that the FOS binding motif in FOS/BAF-bound regions is highly constrained in the human population, and that rare variants in this motif in ASD-affected individuals disrupt stimulus-dependent enhancer activation. This suggests that genetic variation in FOS/BAF-bound regions contributes to ASD pathogenesis, due to an inability to recruit FOS and BAF to enhancers to promote gene expression. Together, our findings highlight a role for BAF in mediating neuronal transcriptional programs downstream of FOS and reveal a mechanism by which non-coding variants may impact BAF function and contribute to risk for ASD.

neuroscience↗

bioRxiv2025

ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program

Mutations in the chromatin reader and tumor suppressor ZMYND11 are the cause of ZMYND11-related syndromic intellectual disability (ZRSID), a disorder characterized by symptoms such as language and motor delay, behavioral disruptions, and seizures. We find that neuronal deletion of ZMYND11 in mice causes aberrant upregulation of non-neuronal gene programs, leading to reduced dendritic branching and spine density, as well as hyperactivity and abnormal motor behavior. We investigated the mechanism by which ZMYND11 regulates gene expression and discovered that ZMYND11 interacts with and inhibits the histone methyltransferase KMT2A (MLL1), a transcriptional co-activator which contributes to oncogenic and developmental gene programs. We find that a ZRSID-associated ZMYND11 point mutation abrogates ZMYND11 interaction with KMT2A, suggesting that this interaction is critical for the function of ZMYND11 in regulating brain development. Using a degron-tagged ZMYND11 mouse model to enable the rapid degradation of ZMYND11 in primary cortical neurons, we show that gene expression changes induced by ZMYND11 loss are attenuated by treatment with the KMT2A inhibitor revumenib, a drug which has recently been approved for the treatment of KMT2A-rearranged leukemia. Our findings shed light on the convergence of chromatin mechanisms regulating neuronal gene expression and raise the possibility that modulation of KMT2A activity may be a useful therapeutic avenue for ZRSID.

neuroscience↗

bioRxiv2025

FOS binding sites are a hub for the evolution of activity-dependent gene regulatory programs in human neurons

After birth, sensory inputs to neurons trigger the induction of activity-dependent genes (ADGs) that mediate many aspects of neuronal maturation and plasticity. To identify human-specific ADGs, we characterized these genes in human-chimpanzee tetraploid neurons. We identified 235 ADGs that are differentially expressed between human and chimpanzee neurons and found that their nearby regulatory sites are species-biased in their binding of the transcription factor FOS. An assessment of these sites revealed that many are enriched for single nucleotide variants that promote or eliminate FOS binding in human neurons. Disrupting the function of individual species-biased FOS-bound enhancers diminishes expression of nearby genes and affects the firing dynamics of human neurons. Our findings indicate that FOS-bound enhancers are frequent sites of evolution and that they regulate human-specific ADGs that may contribute to the unusually protracted and complex process of postnatal human brain development.

evolutionary biology↗

bioRxiv2024

Bone adhered soil as a source of target and environmental DNA and proteins

In recent years, sediments from cave environments have provided invaluable insights into ancient hominids, as well as past fauna and flora. Unfortunately, locations with favourable conditions for ancient DNA (aDNA) preservation in sediments are scarce. In this study we analysed a set of samples obtained from soil adhered to different human skeletal elements, originating from Neolithic to Medieval sites in England, and performed metagenomics and metaproteomics analysis. From them, we were able to recover aDNA sequences matching the genomes of endogenous gut and oral microbiome bacteria. We also found the presence of genetic data corresponding to animals and plants. In particular we managed to retrieve the partial genome and proteome of a Black Rat (Rattus rattus), sharing close genetic affinities to other medieval Rattus rattus. Furthermore, we have also been able to reconstruct a partial human genome. The genetic profile of those human sequences matches the one recovered from the original skeletal element. Our results demonstrate that material usually discarded, as it is soil adhering to human remains, can be used to get a glimpse of the environmental conditions at the time of the death of an individual, even in contexts where due to harsh environmental conditions, the skeletal remains themselves are not preserved.

genomics↗

bioRxiv2024

2500 Years of Human Betaherpesvirus 6A and 6B Evolution Revealed by Ancient DNA

Human betaherpesviruses 6A and 6B are double-stranded DNA viruses, specialised in infecting humans and are best known as the main causative pathogens of the common childhood infection "sixth disease". Despite only being discovered in the 1980s, these viruses are speculated to have a much longer and more complex history within the human population than available modern data make clear. The viruses are carried by large fractions of the human population and can integrate into the human genome, leading to a wide range of clinical manifestations of varied severity. Here, we present the first nine full and two partial ancient genomes of HHV-6A and 6B, dating as far back as the Italian Iron Age (ca. 1100-600 BCE). We demonstrate that large fractions of the current HHV-6 diversity were already well established in the human population by the 14th century CE. Our data suggests that HHV-6B integrated into the human genome at the latest before the 1st-6th century CE, with two integrated clades being populated by ancient DNA genomes in our phylogeny, which further supports that they originated from likely much older ancient founder events. Additionally, we show that all known inherited chromosomally integrated (ici-)HHV-6A clades were already represented in European historical populations, confirming that ici-HHV-6A no longer integrates into the human germline within populations of European ancestry and likely endogenized in early human history. Finally, our results demonstrate the unique suitability of archaeological remains and ancient DNA for the study of the evolution of integrated viruses in human populations.

evolutionary biology↗

bioRxiv2023

Local population structure in Cambridgeshire during the Roman occupation

The Roman period saw the empire expand across Europe and the Mediterranean, including much of what is today the United Kingdom. While there is written evidence of high mobility into and out of Britain for administrators, traders and the military, the impact of imperialism on local population structure is invisible in the textual record. The extent of genetic change that occurred in Britain before the Early Medieval Period and how closely linked by genetic kinship the local populations were, remains underexplored. Here, using genome-wide data from 52 ancient individuals from Cambridgeshire, we show low levels of genetic ancestry differentiation between Romano-British sites and lower levels of runs of homozygosity over 4 centimorgans (cM than in the Bronze Age and Neolithic. We find fourteen cases of genetic relatedness within and one between sites without evidence of patrilineal dominance and one case of temporary mobility within a family unit during the Late Romano-British period. We also show that the modern patterns of genetic ancestry composition in Modern Britain emerged after the Roman period.

genetics↗

bioRxiv2023

A Refined Phylochronology of the Second Plague Pandemic in Western Eurasia

Although dozens of ancient Yersinia pestis genomes and a vast corpus of documentary data are available, the origin and spread of consecutive outbreaks of the Second Plague Pandemic in Europe (14th-18th c.) are still poorly understood. For the majority of ancient genomes, only radiocarbon dates spanning several decades are available, hampering an association with historically recorded plague outbreaks. Here, we present new genomic evidence of the Second Pandemic from 11 sites in England, Estonia, the Netherlands, Russia, and Switzerland yielding 11 Y. pestis genomes with >4-fold mean coverage dating to between 1349 and 1710. In addition, we present a novel approach for integrating the chronological information retrieved from phylogenetic analysis with their respective radiocarbon dates, based on a novel methodology offering more precise dating intervals. Together with a fine-grained analysis of documentarily recorded plague outbreaks, this allows us to tentatively associate all available Y. pestis genomes of the Second Pandemic with historically documented plague outbreaks. Through these combined multidisciplinary analytical efforts, our newly sequenced genomes can be attributed to the Black Death in Cambridge (England), the pestis tertia or pestis quarta in the late 14th century (Estonia), previously unknown branches emerging in the 15th century (Estonia, the Netherlands and England), and a widespread pandemic in Eastern Europe around 1500 (western Russia), which all seem to have originated from one or multiple reservoirs located in Central Europe. While the latter continued to harbour a major Y. pestis lineage at least until the 1630s, represented by new genomes of the Thirty Years War plague (Switzerland), another lineage consecutively spread into Europe between the 17th and 18th century from the Ottoman Empire, as evidenced by a genome associated with the Great Northern War plague (Estonia). By combining phylogenetic analysis with a systematic historical reconstruction based on textual sources and an innovative phylogenetically informed radiocarbon modelling (PhIRM), we offer a new groundbreaking interdisciplinary approach that solves several fundamental methodological challenges associated with phylogenetic and spatio-temporal reconstruction of historical pandemics.

genomics↗

bioRxiv2023

Medieval social landscape through the genetic history of Cambridgeshire before and after the Black Death

The extent of the devastation of the Black Death pandemic (1346-53) on European populations is known from documentary sources and its bacterial source illuminated by studies of ancient pathogen DNA. What has remained less understood is the effect of the pandemic on human mobility and genetic diversity at local scale in the context of the social stratification of medieval communities. Here we study 275 newly reported ancient genomes from later medieval and post-medieval Cambridgeshire, from individuals buried before, during, and after the Black Death. The majority of individuals examined had local genetic ancestries. Consistent with the function of the institutions, we found a lack of close relatives among the friars and the inmates of the hospital in contrast to their abundance in general urban and rural parish communities. Accounting for the genetic component for height accentuates the disparities between social groups in stature estimated from long bones, as a proxy for health and the quality of life. While we detect long-term shifts in local genetic ancestry in Cambridgeshire that either pre- or postdate the Black Death, we find no evidence of major changes in genetic ancestry nor, in contrast to recent claims, higher differentiation of immune loci between cohorts living before and after the Black Death.

genetics↗

bioRxiv2022

Ancient herpes simplex 1 genomes reveal recent viral structure in Eurasia

Human herpes simplex virus 1 (HSV-1), a life-long infection spread by oral contact, today infects a majority of adults globally1, yet no ancient HSV-1 genomes have yet been published. Phylogeographic clustering of sampled diversity into European, pan-Eurasian, and African groups2, 3 has suggested that the virus co-diverged with anatomically modern humans migrating out of Africa4, although a much younger origin has also been proposed5. The lack of ancient HSV-1 genomes, high rates of recombination, and high mobility of humans in the modern era have impeded the understanding of HSV-1s evolutionary history. Here we present three full ancient European HSV-1 genomes and one partial genome, dating to between the 3rd and 17th century CE, sequenced to up to 9.5x with paired human genomes up to 10.16x. These HSV-1 strains fall within modern Eurasian diversity. We estimate a mean mutation rate of 7.6 x 10-7 - 1.13 x 10-6 for non-African diversity leading to an estimated age of sampled modern Eurasian diversity to 4.68 (3.87 - 5.65) kya. Extrapolation of these rates indicate the age of sampled HSV-1 to 5.29 (4.60-6.12 kya, suggesting lineage replacement coinciding with late Neolithisation and implicating Bronze Age migrations6 in the distribution of HSV-1 through Eurasia.

genomics↗

bioRxiv2018

Ancient Yersinia pestis genomes from across Western Europe reveal early diversification during the First Pandemic (541-750)

The first historically documented pandemic caused by Yersinia pestis started as the Justinianic Plague in 541 within the Roman Empire and continued as the so-called First Pandemic until 750. Although palaeogenomic studies have previously identified the causative agent as Y. pestis, little is known about the bacteriums spread, diversity and genetic history over the course of the pandemic.\n\nTo elucidate the microevolution of the bacterium during this time period, we screened human remains from 20 sites in Austria, Britain, Germany, France and Spain for Y. pestis DNA and reconstructed six new genomes. We present a novel methodological approach assessing SNPs in ancient bacterial genomes, facilitating qualitative analyses of low coverage genomes from a metagenomic background. Phylogenetic analysis reveals the existence of previously undocumented Y. pestis diversity during the 6th-7th centuries, and provides evidence for the presence of multiple distinct Y. pestis strains in Europe. We offer genetic evidence for the presence of the Justinianic Plague in the British Isles, previously only hypothesized from ambiguous documentary accounts, as well as southern France and Spain, and that southern Germany seems to have been affected by at least two distinct Y. pestis strains. Four of the reported strains form a polytomy similar to others seen across the Y. pestis phylogeny, associated with the Second and Third Pandemics. We identified a deletion of a 45 kb genomic region in the most recent First Pandemic strain affecting two virulence factors, intriguingly overlapping with a deletion found in 17th-18th-century genomes of the Second Pandemic.\n\nSignificance StatementThe first historically reported pandemic attributed to Yersinia pestis started with the Justinianic Plague (541-544) and continued for around 200 years as the so-called First Pandemic. To date, only one Y. pestis strain from this pandemic has been reconstructed using ancient DNA. In this study, we present six new genomes from Britain, France, Germany and Spain, demonstrating the geographic range of plague during the First pandemic and showing microdiversity in the Early Medieval Period. Moreover, we detect similar genome decay during the First and Second Pandemic (17th to 18th century) that includes the same two virulence factors, thus providing an example of potential convergent evolution of Y. pestis during large scale epidemics.

evolutionary biology↗