Mammal placental phenotypes are predictable from microRNA repertoires.

Despite >100 million years of mammal diversification, similar placental morphologies have independently evolved multiple times, presenting a long-standing evolutionary puzzle: what genetic mechanisms lead to convergent forms? MicroRNAs (miRNAs), despite their diversity in mammals and known roles as developmental regulators, remain under-examined as drivers of morphological evolution. We identified presence-absence patterns for 429 miRNA gene families across 300 eutherian genomes and discovered that placental phenotype is highly predictable from genomic miRNA repertoires (classification accuracy >94-97%). We identified 30 miRNA gene families associated with placentation type, whose gene targets are enriched for developmental processes. Notably, convergent placental morphologies consistently involve identical miRNA families, revealing that evolution is constrained to predictable genetic pathways. We demonstrate evidence of mechanism through MIR-11968, associated with cotyledonary placentation and displaying tissue-restricted expression in cows. MiRNA-mediated regulation therefore constrains placental morphological diversification into reproducible programs, offering insights into how genetic architecture shapes the predictability of convergent evolution. Significance StatementThe genetic architecture that repeatedly guides distinct mammal lineages towards similar complex placental phenotypes has, until now, remained elusive. We leverage an extensive comparative genomic dataset of 429 microRNA gene families across 300 eutherian genomes and identify 30 specific microRNA gene families whose presence or absence patterns are strongly associated with different placentation types. We discover that placental phenotype is highly predictable from genomic microRNA repertoires, and that convergent placental morphologies consistently involve identical microRNA families. We provide evidence of the role MiR11968 in the cotyledonary placental phenotype, exhibiting tissue-restricted expression in cows. This striking pattern reveals a fundamental principle of evolution: that the genetic pathways available for complex morphological innovation are far more constrained and predictable than previously appreciated.