Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome–linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box–containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to analyse copy number variation in 23 individuals with unexplained 46,XY DSD due to gonadal dysgenesis (GD). Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. Surprisingly this patient lacked any signs of campomelic dysplasia, suggesting that the deletion affected expression of SOX9 only in the gonad. Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. Thirdly, we identified a small deletion immediately downstream of GATA4, supporting a role for GATA4 in gonad development in humans. These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases.

Genomic sequencing is increasingly used by medical practitioners in the care of their patients. Its use is primarily in identifying the cause of rare, undiagnosed conditions. Yet sequencing can generate multiple types of clinically relevant results, including carrier results that predict risks to future offspring, which is information that adults have interest in learning.¹ As this technology gains favor in clinical practice, it will be challenging to uphold the standard for test results to be returned in person by a knowledgeable practitioner, typically a genetic counselor or medical geneticist.² Not only is this face-to-face encounter impractical owing to workforce limtations, but increasing use of sequencing will migrate into mainstream medicine and primary care practitioners have significant constraints on their time to add discussions of multiple results. As such, less resource-intensive alternative delivery modes are needed for return of carrier results.³ Such a resource would enable more primary care physicians to effectively use this emerging technology.

Precision public health is a relatively new field that integrates components of precision medicine, such as human genomics research, with public health concepts to help improve population health. Despite interest in advancing precision public health initiatives using human genomics research, current and future opportunities in this emerging field remain largely undescribed. To that end, we provide examples of promising opportunities and current applications of genomics research within precision public health and outline future directions within five major domains of public health: biostatistics, environmental health, epidemiology, health policy and health services, and social and behavioral science. To further extend applications of genomics within precision public health research, three key cross-cutting challenges will need to be addressed: developing policies that implement precision public health initiatives at multiple levels, improving data integration and developing more rigorous methodologies, and incorporating initiatives that address health equity. Realizing the potential to better integrate human genomics within precision public health will require transdisciplinary efforts that leverage the strengths of both precision medicine and public health.