Genetic diversity in the IZUMO1-JUNO protein-receptor pair involved in human reproduction

Abstract

Fertilization in mammals begins with the union of egg and sperm, an event that starts a cascade of cellular processes. The molecular-level understanding of these processes can guide the development of new strategies for controlling and/or promoting fertilization, and inform researchers and medical professional on the best choice of interventions. The proteins encoded by the IZUMO1 and JUNO genes form a ligand-receptor protein pair involved in the recognition of sperm and egg. Due to their role in the fertilization process, these proteins are potential targets for the development of novel anti-contraceptive, as well as infertility treatments. Here we present a comprehensive analysis of these gene sequences, with the objective of identifying evolutionary patterns that may support their relevance as targets for preventing or improving fertility among humans. JUNO and IZUMO1 gene sequences were identified within the genomes of over 2,000 humans sequenced in the 1000 Genomes Project. The human sequences were subjected to analyses of nucleotide diversity, deviation from neutrality of genetic variation, population-based differentiation (FST), haplotype inference, and whole chromosome scanning for signals of positive or of balancing selection. Derived alleles were determined by comparison to archaic hominin and other primate genomes. The potential effect of common non-synonymous variants on protein-protein interaction was also assessed. IZUMO1 displays higher variability among human individuals than JUNO. Genetic differentiation between continental population pairs was within whole-genome estimates for all but the JUNO gene in the African population group with respect to the other 4 population groups (American, East Asian, South Asian, and European). Tajima’s D values demonstrated deviation from neutrality for both genes in comparison to a group of genes identified in the literature as under balancing or positive selection. Tajima’s D for IZUMO1 aligns with values calculated for genes presumed to be under balancing selection, whereas JUNO’s value aligned with genes presumed to be under positive selection. These inferences on selection are both supported by SNP density, nucleotide diversity and haplotype analysis. A JUNO haplotype carrying 3 derived alleles out of 5, one of which is a missense mutation implicated in polyspermy, was found to be significant in a population of African ancestry. Polyspermy has a disadvantageous impact on fertility and its presence in approximately 30% of the population of African ancestry may be associated to a potentially beneficial role of this haplotype. This role has not been established and may be related to a non-reproductive role of JUNO. The high degree of conservation of the JUNO sequence combined with a dominant haplotype across multiple population groups supports JUNO as a potential target for the development of contraceptive treatments. In addition to providing a detailed account of human genetic diversity across these 2 important and related genes, this study also provides a framework for large population-based studies investigating protein-protein interactions at the genome level.

Sperm induction of somatic cell-cell fusion as a novel functional test

“…In addition to the potential uses of SPICER for the diagnosis of infertility, this assay could be used to evaluate potential sperm donors and animal studs. Moreover, our SPICER tool has the potential to aid screening for compounds that enhance fertilization (new fertility treatments) or that block gamete interactions ( Stepanenko et al, 2022 ), or to easily determine the effect of genetic variations of JUNO ( Allingham and Floriano, 2021 ; Takaiso et al, 2016 ). SPICER could also facilitate studies aimed at resolving standing enigmas of sperm-egg fusion ( Deneke and Pauli, 2021 ; Yanagimachi, 2022 ).…”

Sperm induction of somatic cell-cell fusion as a novel functional test

“…In addition to the potential uses of SPICER for diagnosis of infertility, this assay could be used to evaluate potential sperm donors and animal studs. Moreover, our SPICER tool has the potential to aid screening for compounds that enhance fertilization (new fertility treatments) or that block gamete interactions (Stepanenko et al 2022), or to easily determine the effect of genetic variations of JUNO (Allingham and Floriano 2021; Takaiso et al 2016). SPICER could also facilitate studies aimed at resolving standing enigmas of sperm-egg fusion (Deneke and Pauli 2021; Yanagimachi 2022).…”

Evidence for Correlated Evolution of Sexual Selection and Pseudogenization in Primate Fertilization

“…Though many important molecules have been described for their role in mammalian fertilization (e.g., sperm–egg plasma membrane fusion; Inoue et al, 2013; Allingham & Floriano, 2021; Brukman et al, 2022), a complete catalogue of the genes and proteins that mediate fertilization is not known for any single species, and the identification of all genes involved in any single step in fertilization can be incomplete even in the most well-studied species (Carlisle & Swanson, 2021). The catalog of fertilization genes is known to evolve in part by whole-gene duplication, the addition of new paralogs into related fertilization functions, and the loss of functional members of such gene families (recently reviewed by Carlisle et al, 2022; Rivera & Swanson, 2022).…”