Charikleia (Clio) Karageorgiou

Structurally complex genomic regions can foster evolutionary convergence by repeatedly generating gene duplications that yield similar expression patterns and traits across lineages. Focusing on the primate amylase locus, we leveraged high-quality genome assemblies from 53 primate species and multi-tissue transcriptomes from Old World monkeys to reconstruct the evolutionary history of recurrent duplications. We show that lineage-specific long terminal repeat retrotransposon insertions may be associated with initial structural instability, while subsequent duplications are primarily driven by non-allelic homologous recombination. Independent duplications in rhesus macaques, olive baboons, and great apes produced distinct amylase copies with convergent expression in pancreas and salivary glands, and it signals episodic diversifying selection, consistent with emerging functional divergence. Our analyses indicate that an ancestral gene with dual pancreas and salivary expression in Catarrhini duplicated in great apes, facilitating subfunctionalization and regulatory rewiring. These findings illuminate how modular structural and regulatory variation drives evolutionary innovation and molecular convergence.

Previous studies suggested that the copy number of the human salivary amylase gene, AMY1, correlates with starch-rich diets. However, evolutionary analyses are hampered by the absence of accurate, sequence-resolved haplotype variation maps. We identified 30 structurally distinct haplotypes at nucleotide resolution among 98 present-day humans, revealing that the coding sequences of AMY1 copies are evolving under negative selection. Genomic analyses of these haplotypes in archaic hominins and ancient human genomes suggest that a common three-copy haplotype, dating as far back as 800,000 years ago, has seeded rapidly evolving rearrangements through recurrent nonallelic homologous recombination. Additionally, haplotypes with more than three AMY1 copies have significantly increased in frequency among European farmers over the past 4000 years, potentially as an adaptive response to increased starch digestion.

Advances in sequencing technologies have enabled the comparison of high-quality genomes of diverse primate species, revealing vast amounts of divergence due to structural variation. Given their large size, structural variants (SVs) can simultaneously alter the function and regulation of multiple genes. Studies estimate that collectively more than 3.5% of the genome is divergent in humans versus other great apes, impacting thousands of genes. Functional genomics and gene-editing tools in various model systems recently emerged as an exciting frontier - investigating the wide-ranging impacts of SVs on molecular, cellular, and systems-level phenotypes. This review examines existing research and identifies future directions to broaden our understanding of the functional roles of SVs on phenotypic innovations and diversity impacting uniquely human features, ranging from cognition to metabolic adaptations.