Freshwater unionid bivalves currently face severe anthropogenic challenges. Over 70% of species in the United States are threatened, endangered or extinct due to pollution, damming of waterways and overfishing. These species are notable for their unusual life history strategy, parasite-host co-evolution and biparental mitochondrial inheritance. Among this clade, the washboard mussel Megalonaias nervosa is one species that remains prevalent across the Southeastern United States, with robust population sizes. We have created a reference genome for M. nervosa to determine how genome content has evolved in the face of these widespread environmental challenges. We observe dynamic changes in genome content, with a burst of recent transposable element proliferation causing a 382Mb expansion in genome content. Birth-death models suggest rapid expansions among gene families, with a mutation rate of 1.16×10-8 duplications per gene per generation. Cytochrome P450 gene families have experienced exceptional recent amplification beyond expectations based on genome-wide birth-death processes. These genes are associated with increased rates of amino acid changes, a signature of selection driving evolution of detox genes. Fitting evolutionary models of adaptation from standing genetic variation, we can compare adaptive potential across species and mutation types. The large population size in M. nervosa suggests a 4.7-fold advantage in the ability to adapt from standing genetic variation compared with a low diversity endemic E. hopetonensis. Estimates suggest that gene family evolution may offer an exceptional substrate of genetic variation in M. nervosa, with Psgv =0.185 compared with Psgv =0.067 for single nucleotide changes. Hence, we suggest that gene family evolution is a source of 'hopeful monsters' within the genome that may facilitate adaptation when selective pressures shift. These results suggest that gene family expansion is a key driver of adaptive evolution in this key species of freshwater Unionidae that is currently facing widespread environmental challenges. This work has clear implications for conservation genomics on freshwater bivalves as well as evolutionary theory. This genome represents a first step to facilitate reverse ecological genomics in Unionidae and identify the genetic underpinnings of phenotypic diversity.