Biological sex is often perceived as straightforward, leading to generalized definitions of males and females. However, molecular genetics reveals complexity of gene regulation involved in sex determination, hormone regulation, and development of secondary sexual characteristics. Genetic variants can influence these pathways in diverse ways. The genetic basis of sex and sexual identity knowledge is further complicated by limitations of commonly applied autosomal-based statistical methods, and the lack of studies addressing heterogeneity of secondary sexual characteristics in humans. Absence of genetic data due to noted issues may contribute to the propagation of oversimplified public narratives. Ambiguity in regulatory frameworks may lead to further legal and ethical complications. Similar dynamics have emerged in the genetics of race, where scientific complexity is being applied in clinical care to avoid overgeneralizing any demographic group to an individual. The fields of genetics and clinical genetics view ancestry and personal genetic insights as a stronger framework for clinical utility than admixed classifiers (race or sex), thereby increasing the focus on genetic variant inheritance and their biological impacts. The use of admixed classifiers must be separated from clinical decision-making when ancestry and personal genetic insights are available. The physiological genomics community should remain vigilant against oversimplifications to safeguard continued advancements in precision and personalized medicine. Given that sex differences influence nearly all diseases and physiological processes, unresolved uncertainties in this area may significantly impede progress in physiological genomics and patient care.
Jeremy W. Prokop (Thu,) studied this question.
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