Biology subjects

Sandercock, A. M.

Publications and source records attributed to Sandercock, A. M..

3 recordsLinked to original sources

bioRxiv2023

The road to restoration: Identifying and conserving the adaptive legacy of American chestnut

The American chestnut (Castanea dentata) is a functionally extinct tree species that was decimated by an invasive fungal pathogen in the early 20th century. Disease resistant chestnuts have been developed through hybridization and genetic modification, but these populations may lack the adaptive genomic diversity necessary to restore the species across its climatically diverse historical range. An understanding of the genomic architecture of local adaptation in wild American chestnut and identification of seed zones for germplasm conservation are necessary in order to deploy locally adapted, disease-resistant American chestnut populations. Here, we characterize the genomic basis of climate adaptation in remnant wild American chestnut, define seed zones based on climate envelopes and adaptive diversity, and make sampling recommendations for germplasm conservation. Whole genome re-sequencing of 384 trees coupled with genotype-environment association methods suggest the species range can be most parsimoniously subdivided into three seed zones characterized by relatively homogeneous allele frequencies relative to rangewide adaptive diversity. Using these data, we developed a method to estimate the number of samples required from each seed zone to recapitulate standing adaptive diversity in each seed zone, and found that on average, 21-29 trees will need to be conserved to capture 95% of the wild adaptive diversity. Taken together, these results will inform the development of an ex situ germplasm conservation and breeding plan to develop locally adapted blight-resistant American chestnut populations, and provide a blueprint for developing restoration plans for other imperiled tree species.

genomics↗

bioRxiv2022

Whole-genome resequencing reveals the population structure, genomic diversity, and demographic history of American chestnut (Castanea dentata)

American chestnut (Castanea dentata) was once the most economically and ecologically important hardwood species in the United States. In the first half of the 20th century, an exotic fungal pathogen - Cryphonectria parasitica - decimated the species, killing approximately four billion trees. Two approaches to developing blight resistant American chestnut populations show promise, but both will require introduction of adaptive genomic diversity from wild germplasm to produce diverse, locally adapted reforestation populations. Here we characterize population structure, demographic history, and genomic diversity in a range-wide sample of 384 wild American chestnuts to inform conservation and breeding with blight resistant varieties. Population structure analyses with DAPC and ADMIXTURE suggest that the chestnut range can be roughly divided into northeast, central, and southwest populations. Within-population genomic diversity estimates revealed a clinal pattern with the highest diversity in the southwest, which likely reflects bottleneck events associated with Quaternary glaciation. Finally, we identified genomic regions under positive selection within each population, which suggests that defense against fungal pathogens is a common target of selection across all populations. Taken together, these results show that American chestnut underwent a postglacial expansion from the southern portion of its range leading to three extant populations. These populations will serve as management units for breeding adaptive genetic variation into the blight-resistant tree populations for targeted reintroduction efforts.

genomics↗

bioRxiv2019

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis.

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics. Author SummaryHere we show that antibody-drug conjugates (ADCs) can be re-purposed from cancer immunotherapeutics to anti-protozoals by changing the specificity of the immunoglobulin to target a trypanosome cell surface receptor. Trypanosomes were used as a model system due to the availability of receptor null cell lines that allowed the unambiguous demonstration that ADCs targeted to a parasite surface receptor could be specifically internalised via receptor-mediated endocytosis. A single low dose of the resulting ADC was able to cure a stage 1 mouse model of trypanosome infection. We have used toxins and conjugation chemistry that are identical to anti cancer ADCs demonstrating the ability to piggy-back onto the huge research efforts and resources that are being invested in the development of such ADCs. The potential for development of ADCs against a wide range of human pathogens is vast, where only epitope binding sites need vary in order to provide selectivity. This provides a far-reaching opportunity for the rapid development of novel anti-protozoals for the targeted killing of a wide range of pathogens that cause disease worldwide, especially in developing countries.

microbiology↗