My entry into high throughput systems-scale genomics began with the creation of the first computer video-acquisition sequencing system as I was completing my postdoctoral fellowship. I was the first to describe and characterize sequence error rates within genomic data available with GeneBank as we were developing base calling data interpretation algorithms. As a faculty member, mapping DNase I-sensitive chromatin domains in human spermatozoa followed in parallel with an in-depth developmental analysis using humanized animal models. We showed topoisomerase II nicking is one of the first events that readies a chromatin domain for transcription (1). My laboratory was one of the first to embrace a genome-wide systems approach to directly address whether we identified the exception or the rule of the rule. This included the development of chromosome-specific aCGH to map genome-wide DNA/protein interactions supplemented with the 454 sequencing in collaboration with the Joint Genome Initiative as we transitioned to the Illumina Hi-Seq 2500. We have extended our capabilities to the 4D metamorphosis of the male gamete’s genome (2). Data acquisition and analysis continually required the creation of custom computer code that was not available when the projects were initiated. My program’s goals have expanded to include understanding how the delivery of paternal RNAs at fertilization contributes to the lifecourse of a healthy child.
Contrary to dogma, we showed that at the time of fertilization, the spermatozoon delivers a cadre of unique mRNAs along with small RNAs, including antisense and microRNAs, to the oocyte (3). This concept has expanded to RNA elements and directly tested as components of early human development from the human type a dark spermatogonia to blastocyst (4). As a system, the transcriptionally and translationally inactive sperm’s unique attributes have pushed us to develop a series of whole-genome analysis tools to objectively assess fertility status as a bellwether of disease (5). As we translate this technology to the clinic, we have helped shape public policy to appreciate the impact of the environment on the father’s contribution to the child (6).