Alleles in metabolic and oxygen-sensing genes are associated with antagonistic pleiotropic effects on life history traits and population fitness in an ecological model insect.

Genes with opposing effects on fitness at different life stages are the mechanistic basis for evolutionary theories of aging and life history. Examples come from studies of mutations in model organisms, but there is little knowledge of genetic bases of life history tradeoffs in natural populations. Here, we test the hypothesis that alleles affecting oxygen sensing in Glanville fritillary butterflies have opposing effects on larval versus adult fitness-related traits. Intermediate-frequency alleles in Succinate dehydrogenase d, and to a lesser extent Hypoxia inducible factor 1α, are associated in larvae with variation in metabolic rate and activation of the hypoxia inducible factor (HIF) pathway, which affects tracheal development and delivery of oxygen to adult flight muscles. A dominant Sdhd allele is likely to cause antagonistic pleiotropy for fitness through its opposing effects on larval metabolic and growth rate versus adult flight and dispersal, and may have additional effects arising from sensitivity to low-iron host plants. Prior results in Glanville fritillaries indicate that fitness of alleles in Sdhd and another antagonistically pleiotropic metabolic gene, Phosphoglucose isomerase, depend strongly on the size and distribution of host plant patches. Hence, these intermediate-frequency alleles are involved in ecoevolutionary dynamics involving life history tradeoffs.

Discovery of antitumor lectins from rainforest tree root transcriptomes.

Glycans are multi-branched sugars that are displayed from lipids and proteins. Through their diverse polysaccharide structures they can potentiate a myriad of cellular signaling pathways involved in development, growth, immuno-communication and survival. Not surprisingly, disruption of glycan synthesis is fundamental to various human diseases; including cancer, where aberrant glycosylation drives malignancy. Here, we report the discovery of a novel mannose-binding lectin, ML6, which selectively recognizes and binds to these irregular tumor-specific glycans to elicit potent and rapid cancer cell death. This lectin was engineered from gene models identified in a tropical rainforest tree root transcriptome and is unusual in its six canonical mannose binding domains (QxDxNxVxY), each with a unique amino acid sequence. Remarkably, ML6 displays antitumor activity that is >105 times more potent than standard chemotherapeutics, while being almost completely inactive towards non-transformed, healthy cells. This activity, in combination with results from glycan binding studies, suggests ML6 differentiates healthy and malignant cells by exploiting divergent glycosylation pathways that yield naïve and incomplete cell surface glycans in tumors. Thus, ML6 and other high-valence lectins may serve as novel biochemical tools to elucidate the glycomic signature of different human tumors and aid in the rational design of carbohydrate-directed therapies. Further, understanding how nature evolves proteins, like ML6, to combat the changing defenses of competing microorganisms may allow for fundamental advances in the way we approach combinatorial therapies to fight therapeutic resistance in cancer.