Principal Investigator David Page
For the past two decades, our laboratory has specialized in sequencing the most structurally complex and most technically challenging target in the genome - the Y chromosome. In 2003, our lab completed the sequence of the human Y chromosome, which was the first sex-specific chromosome to be sequenced from any organism. The ultra-high quality of the human Y chromosome reference sequence has enabled unparalleled insight into the mechanism and kinetics of Y rearrangements, which contribute to spermatogenic failure, gonadoblastoma, and Turner syndrome. In collaboration with the Genome Institute at Washington University and the Human Genome Sequencing Center at Baylor, our laboratory subsequently sequenced the chimpanzee, rhesus macaque, and mouse Y chromosomes, the chicken Z chromosome, and the ampliconic regions of the human X chromosome to the same level of refinement. The technology we invented and developed, Single Haplotype Iterative Mapping and Sequencing (SHIMS), is the only proven technology to accurately assemble large, nearly identical repeats that are frequently found on Y chromosomes. We are currently working to evolve SHIMS, making it cheaper, faster, and more widely adopted, which will revolutionize the way that ultra-high-quality reference-grade sequence is generated in the Page Lab and beyond. We are currently applying the new SHIMS technology to complete the Y chromosome sequences of additional mammals - bull, marmoset, rat, and opossum - as well as the chicken W chromosome.
While previous studies have cemented the Y chromosome's role in male-specific functions (ie. testis differentiation and sperm production), our recent comparative genomic studies revealed that the Y chromosome's influences reach far beyond the reproductive tract. Through a systematic and exhaustive comparison of the Y-chromosome gene contents of eight mammals, we found that Y-chromosome genes with counterparts on the X chromosome form a functionally coherent group. They are enriched for dosage-sensitive, broadly expressed regulators of transcription, translation, and protein stability. The X and Y (male-specific) versions of these genes encode distinct protein isoforms throughout the body. Therefore, fundamental sexual dimorphism exists at the biochemical and molecular level, which has important implications for understanding the differences between males and females in health and disease.