Novel adaptations must originate and function within an already established genome [1]. As a result, the ability of a species to adapt to new environmental challenges is predicted to be highly contingent on the evolutionary history of its lineage [2-6]. Despite a growing appreciation of the importance of historical contingency in the adaptive evolution of single proteins [7-11], we know surprisingly little about its role in shaping complex adaptations that require evolutionary change in multiple genes. One such adaptation, extreme resistance to tetrodotoxin (TTX), has arisen in several species of snakes through coevolutionary arms races with toxic amphibian prey, which select for TTX-resistant voltage-gated sodium channels (Nav) [12-16]. Here, we show that the relatively recent origins of extreme toxin resistance, which involve the skeletal muscle channel Nav1.4, were facilitated by ancient evolutionary changes in two other members of the same gene family. A substitution conferring TTX resistance to Nav1.7, a channel found in small peripheral neurons, arose in lizards ∼170 million years ago (mya) and was present in the common ancestor of all snakes. A second channel found in larger myelinated neurons, Nav1.6, subsequently evolved resistance in four different snake lineages beginning ∼38 mya. Extreme TTX resistance has evolved at least five times within the past 12 million years via changes in Nav1.4, but only within lineages that previously evolved resistant Nav1.6 and Nav1.7. Our results show that adaptive protein evolution may be contingent upon enabling substitutions elsewhere in the genome, in this case, in paralogs of the same gene family.

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Background: Adjuvant endocrine therapy (AET) significantly reduces recurrence and mortality in women with estrogen receptor-positive breast cancer. Adherence to AET is about 50-60% for five-years and while numerous studies have identified barriers to AET adherence, few have identified the role of social support as a facilitator. Therefore, the objective of this study is to explore the role of social support during the on-going management of AET. Methods:We conducted semi-structured in-depth interviews with breast cancer survivors (n=22) who filled a prescription for AET in the previous 12 months. Women were recruited from Los Angeles, California and Houston, Texas between 2014-2015. Interview questions prompted discussion about AET and how social support affects AET adherence. We analyzed interview transcripts with a grounded theory approach and grouped social support into four categories (emotional, informational, instrumental, and appraisal), then used a thematic content analysis to identify the sources and delivery of support.Results: Women described that informational support was provided by medical providers who explained the purpose, benefits, and management of AET. Emotional support in the form of reassurance, communication, and empathy was provided by family, survivorship groups, medical providers, and spirituality/religiosity. Women identified several organizations and exercises that provided them with instrumental and appraisal support in the form of physical and emotional benefits, which was also provided by family, friends, and medical providers. Conclusion:We identified that social support delivered to breast cancer survivors provided women with educational, physical, and emotional benefits that may play an important role in their continuation of AET.