Bivalves are characterized by highly variable genome sizes and extremely high levels of heterozygosity, which present an obstacle for complete and accurate genome assemblies. In this work, we present the first long-read-based de novo genome assembly of a wild male Manila clam (Ruditapes philippinarum) from North America. Relying on both short and long read data, the estimated heterozygosity (3.7% to 4%) in R. philippinarum is, to our knowledge, the highest observed so far in the entire Mollusca phylum. Additionally, taking advantage of large RNA-seq dataset from different tissues of both sexes, we investigated gene expression, alternative splicing, tissue specificity, sequence evolution, tissue-specific co-expression network and sexual constrasting genetic markers. We found that gene expression and alternative splicing follow similar patterns across tissues, mainly due to the large overlap between differentially expressed and spliced genes in pairwise comparisons between tissues and between sexes. The tissue-specific co-expression network indicates high complexity in gonads gene regulation. Both differentially expressed and spliced genes present higher tissue specificity and sequence evolution, consistent with relaxed functional constraints. As a general trend, genes in gonad-associated modules present high tissue specificity, low intermodular connectivity, and rapid evolution. Nevertheless, a male gonad-associated module shows a different trend, with extremely low tissue specificity but high intermodular connectivity, indicating the possible role of functional pleiotropy in this subset of genes. Intriguingly, we found that sexual contrasting SNPs are located in the genes overrepresented in mitochondrial related functions, supporting the potential association between mitochondria and sexual differentiation in bivalves.