Biology subjects

Gordon, I. J.

Publications and source records attributed to Gordon, I. J..

8 recordsLinked to original sources

bioRxiv2025

Rational Design of Multiclade Coronavirus Spike Immunodominant Domain Nanoparticles Elicit Broad Antibody Responses

Four seasonal endemic human coronaviruses (EhCoVs), HKU1-CoV, OC43-CoV, 229E-CoV, and NL63-CoV, are culprits of mild upper respiratory and periodic severe diseases in vulnerable populations. Despite their prevalence, understanding EhCoVs antigenic and immune signatures remains elusive. SARS-CoV-2 has evolved as the fifth EhCoV, requiring seasonal vaccination in most parts of the world, and currently, no other EhCoV vaccines are available. SARS-CoV-2 co-infection with EhCoVs increases disease severity; thus, combined vaccination may provide increased protection against seasonal EhCoVs overall. Here, we explored Spike (S) receptor binding domain (RBD) vs. N-terminal domain (NTD) B-cell immunodominance in EhCoV-positive convalescent donors and immunogenicity in mice. We found that while antibody and B-cell isotypes were relatively dominant to S NTD, mice immunized with S RBD elicited significantly higher binding and neutralizing antibody (nAb) responses. With that knowledge, we used computational methods to infer that EhCoV S sequences evolve into two main clades and designed chimeric immunodominant domains (IDDs) from both clades for each EhCoV. IDDs were scaffolded onto two-component nanoparticles (NPs) displaying each IDD separately (monovalent IDD NP); three {beta}-EhCoV IDDs (Mosaic-3 IDD NP); or five EhCoVs IDDs (Mosaic-5 IDD NP). Mice immunized with mosaic IDD NPs, but not soluble IDD antigens nor monovalent IDD NPs, elicited potent, broadly cross-reactive binding and neutralizing antibody (Ab) responses against SARS-CoV-2 variants, other EhCoVs, and Sarbecoviruses. System serology revealed that all four IDD immunogens elicited distinct Ab subclasses and Fc-effector functions, with mosaic-5 IDD NPs eliciting the most de novo Ab subclasses, distributions, and broader Fc-mediated immune mechanisms. Dissection of vaccine-immune sera revealed polyclonal Ab responses against multiple non-overlapping cross-reactive S epitopes. Due to elicitation of broad Ab responses with combinatory functionality, IDD NPs open new horizons for developing first-in-class supraseasonal EhCoV vaccine candidates, with potential to decrease frequent SARS-CoV-2 sequence updates and protect against other EhCoVs. Moreover, elicitation of Ab breadth that spans pandemic-threat Sarbecoviruses gives mosaic IDD NPs promise towards pandemic preparedness.

bioengineering↗

bioRxiv2024

Extensive haplotype diversity in a butterfly colour pattern supergene is fuelled by incomplete recombination suppression

Supergenes can evolve when recombination-suppressing mechanisms like inversions promote co-inheritance of alleles at two or more polymorphic loci that affect a complex trait. Theory shows that such genetic architectures can be favoured under balancing selection or local adaptation in the face of gene flow, but they can also bring costs associated with reduced opportunities for recombination. These costs may in turn be offset by rare gene flux between inverted and ancestral haplotypes, with a range of possible outcomes. We aimed to shed light on these processes by investigating the BC supergene, a large genomic region comprising multiple rearrangements associated with three distinct wing color morphs in Danaus chrysippus, a butterfly known as the African monarch, African queen and plain tiger. Using whole-genome resequencing data from 174 individuals, we first confirm the effects of BC on wing color pattern: background melanism is associated with SNPs in the promoter region of yellow, within an inverted subregion of the supergene, while forewing tip pattern is most likely associated with copy number variation in a separate subregion of the supergene. We then show that haplotype diversity within the supergene is surprisingly extensive: there are at least six divergent haplotype groups that experience suppressed recombination with respect to each other. Despite high divergence between these haplotype groups, we identify an unexpectedly large number of natural recombinant haplotypes. Several of the inferred crossovers occurred between adjacent inversion modules, while others occurred within inversions. Furthermore, we show that new haplotype groups have arisen through recombination between two pre-existing ones. Specifically, an allele for dark coloration in the promoter of yellow has recombined into distinct haplotype backgrounds on at least two separate occasions. Overall, our findings paint a picture of dynamic evolution of supergene haplotypes, fuelled by incomplete recombination suppression.

evolutionary biology↗

bioRxiv2024

Synthetase and Hydrolase Specificity Collectively Excludes Deoxyguanosine from Bacterial Alarmone

In response to starvation, virtually all bacteria pyrophosphorylate the 3-hydroxy group of GTP or GDP to produce two messenger nucleotides collectively denoted as (p)ppGpp. Also known as alarmones, (p)ppGpp reprograms bacterial physiology to arrest growth and promote survival. Intriguingly, although cellular concentration of dGTP is two orders of magnitude lower than that of GTP, alarmone synthetases are highly selective against using 2-deoxyguanosine (2dG) nucleotides as substrates. We thus hypothesize that production of 2dG alarmone, (p)pp(dG)pp, is highly deleterious, which drives a strong negative selection to exclude 2dG nucleotides from alarmone signaling. In this work, we show that the B. subtilis SasB synthetase prefers GDP over dGDP with 65,000-fold higher kcat/Km, a specificity stricter than RNA polymerase selecting against 2-deoxynucleotides. Using comparative chemical proteomics, we found that although most known alarmone-binding proteins in Escherichia coli cannot distinguish ppGpp from pp(dG)pp, hydrolysis of pp(dG)pp by the essential hydrolase, SpoT, is 1,000-fold slower. This inability to degrade 2-deoxy-3-pyrophosphorylated substrate is a common feature of the alarmone hydrolase family. We further show that SpoT is a binuclear metallopyrophoshohydrolase and that hydrolysis of ppGpp and pp(dG)pp shares the same metal dependence. Our results support a model in which 2-OH directly coordinates the Mn2+ at SpoT active center to stabilize the hydrolysis-productive conformation of ppGpp. Taken together, our study reveals a vital role of 2-OH in alarmone degradation, provides new insight on the catalytic mechanism of alarmone hydrolases, and leads to the conclusion that 2dG nucleotides must be strictly excluded from alarmone synthesis because bacteria lack the key machinery to down-regulate such products.

microbiology↗

bioRxiv2023

Transposable element insertions are associated with Batesian mimicry in the pantropical butterfly Hypolimnas misippus

Hypolimnas misippus is a Batesian mimic of the toxic African Queen butterfly (Danaus chrysippus). Female H. misippus butterflies use two major wing patterning loci (M and A) to imitate the four colour morphs of D. chrysippus found in different regions of Africa. In this study, we examine the evolution of the M locus and identify it as an example of adaptive atavism. This phenomenon involves a morphological reversion to an ancestral character that results in an adaptive phenotype. We show that H. misippus has re-evolved a wing pattern present in other Hypolimnas species for Batesian mimicry of a D. chrysippus morph. Using haplotagging, a linked-read sequencing technology, we discover two large transposable element (TE) insertions located at the M locus and establish that these insertions are present in the dominant allele responsible for producing the ancestral and mimetic phenotype. By conducting a comparative analysis involving additional Hypolimnas species, we demonstrate that the dominant allele is derived. This suggests that the TEs disrupt a cis-regulatory element, leading to the reversion to an ancestral phenotype that is then utilized for Batesian mimicry of a distinct model, a different morph of D. chrysippus. Our findings present a compelling instance of convergent evolution and adaptive atavism, in which the same pattern element has independently evolved multiple times in Hypolimnas butterflies, repeatedly playing a role in Batesian mimicry of diverse model species.

evolutionary biology↗

bioRxiv2023

The Hypolimnas misippus genome supports a common origin of the W chromosome in Lepidoptera

Moths and butterflies (Lepidoptera) have a heterogametic sex chromosome system with females carrying ZW chromosomes and males ZZ. The lack of W chromosomes in early diverging lepidopteran lineages has led to the suggestion of an ancestral Z0 system in this clade and a B chromosome origin of the W. This contrasts with the canonical model of W chromosome evolution in which the W would have originated from the same homologous autosomal pair as the Z chromosome. Despite the distinct models proposed, the rapid evolution of the W chromosome has hindered the elucidation of its origin. Here, we present high-quality, chromosome-level genome assemblies of two Hypolimnas species (Hypolimnas missipus and Hypolimnas bolina) and use the H. misippus assembly to explore the evolution of W chromosomes in butterflies and moths. We show that in H. misippus the W chromosome has higher similarity to the Z chromosome than any other chromosome, which could suggest a possible origin from the same homologous autosome pair as the Z chromosome. However, using genome assemblies of closely related species (ditrysian lineages) containing assembled W chromosomes, we present contrasting evidence suggesting that the W chromosome might have evolved from a B chromosome instead. Crucially, by using a synteny analysis to infer homology, we show that W chromosomes are likely to share a common evolutionary origin in Lepidoptera. This study highlights the difficulty of studying the evolution of W chromosomes and contributes to better understanding its evolutionary origins. SignificanceButterflies and moths have a sex determination system in which females carry two different sex chromosomes, Z and W, while males carry two copies of the Z. The evolutionary origin of the W chromosome has been elusive, with many possible scenarios being suggested, such as the independent evolution of W chromosomes in many butterfly and moth species. Here, we present genome assemblies of two Hypolimnas butterfly species and use one of them to shed light on the evolution of the W chromosome. We show that W chromosomes across butterflies and moths are very similar which suggests a shared common origin.

genomics↗

bioRxiv2021

Stepwise evolution of a butterfly supergene via duplication and inversion

Supergenes maintain adaptive clusters of alleles in the face of genetic mixing. Although usually attributed to inversions, supergenes can be complex, and reconstructing the precise processes that led to recombination suppression and their timing is challenging. We investigated the origin of the BC supergene, which controls variation in warning colouration in the African Monarch butterfly, Danaus chrysippus. By generating chromosome-scale assemblies for all three alleles, we identified multiple structural differences. Most strikingly, we find that a region of >1 million bp underwent several segmental duplications at least 7.5 million years ago. The resulting duplicated fragments appear to have triggered four inversions in surrounding parts of the chromosome, resulting in stepwise growth of the region of suppressed recombination. Phylogenies for the inversions are incongruent with the species tree, and suggest that structural polymorphisms have persisted for at least 4.1 million years. In addition to the role of duplications in triggering inversions, our results suggest a previously undescribed mechanism of recombination suppression through independent losses of divergent duplicated tracts. Overall, our findings add support for a stepwise model of supergene evolution involving a variety of structural changes.

evolutionary biology↗

bioRxiv2021

Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 g/mL; IC80 < 0.0006 to 0.0251 g/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs. One Sentence SummaryUltrapotent antibodies from convalescent donors neutralize and mitigate resistance of SARS-CoV-2 variants of concern.

immunology↗

bioRxiv2019

Whole-chromosome hitchhiking driven by a male-killing endosymbiont

Neo-sex chromosomes are found in many taxa, but the forces driving their emergence and spread are poorly understood. The female-specific neo-W chromosome of the African monarch (or queen) butterfly Danaus chrysippus presents an intriguing case study because it is restricted to a single contact zone population, involves a putative colour patterning supergene, and co-occurs with infection by the the male-killing endosymbiont Spiroplasma. We investigated the origin and evolution of this system using whole genome sequencing. We first identify the BC supergene, a broad region of suppressed recombination across nearly half a chromosome, which links two colour patterning loci. Association analysis suggests that the genes yellow and arrow in this region control the forewing colour pattern differences between D. chrysippus subspecies. We then show that the same chromosome has recently formed a neo-W that has spread through the contact zone within [~]2200 years. We also assembled the genome of the male-killing Spiroplasma, and find that it shows perfect genealogical congruence with the neo-W, suggesting that the neo-W has hitchhiked to high frequency as the male killer has spread through the population. The complete absence of female crossing-over in the Lepidoptera causes whole-chromosome hitchhiking of a single neo-W haplotype, carrying a single allele of the BC supergene, and dragging multiple non-synonymous mutations to high frequency. This has created a population of infected females that all carry the same recessive colour patterning allele, making the phenotypes of each successive generation highly dependent on uninfected male immigrants. Our findings show how hitchhiking can occur between the unlinked genomes of host and endosymbiont, with dramatic consequences.

evolutionary biology↗