Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility

Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.

Potato Virus X-induced LeHB-1 Silencing Delays Tomato Fruit Ripening

Tomato (Solanum lycopersicum) fruit ripening is a complex genetic trait correlating with notable fruit phenotypic, physiologic, and biochemical changes. Transcription factors (TFs) play crucial roles during this process. LeHB-1, an HD-zip homeobox protein, is a ripening-related TF and acts as an important regulator of fruit ripening. However, the detailed biochemical and molecular basis of LeHB-1 on tomato fruit ripening is unclear. In the current study, the biologic functions of LeHB-1 were determined by a potato virus X (PVX)-mediated gene-silencing approach. The results indicate that PVX-induced LeHB-1 silencing in tomato could decrease pigment accumulation and delay fruit ripening. Compared with controls, nonripening flesh retains a greater pH value and a lesser anthocyanin content. By evaluating expression levels of genes related to tomato fruit ripening, we inferred that LeHB-1 located at the downstream of LeMADS-RIN-mediated regulatory network. In addition, LeHB-1 silencing mainly disturbed phytoene desaturation and isomerization, and led to a decrease in trans-lycopene accumulation, but did not influence flavonoid biosynthesis directly in tomato fruit. The findings provide a theoretical foundation for illustrating the biologic functions of LeHB-1 in tomato fruit ripening and quality.

Toward a Genetic Understanding of Glaucoma—Breakthroughs and Challenges from Studies of Exfoliation Glaucoma

Glaucoma is a complex group of diseases causing progressive degeneration of the optic nerve. Despite strong evidence of hereditary contributions to glaucoma, relatively few genetic mutations associated with glaucoma risk have thus far been identified. Glaucoma likely represents a complex genetic trait influenced by multiple loci and many confounding factors, increasing the challenge in identifying glaucoma’s hereditary basis. In this article, a brief history of the search for glaucoma-causing mutations is presented, highlighting recent breakthroughs that have identified lysyl oxidase-like 1 (LOXL1) as a major genetic risk factor contributing to exfoliative glaucoma. In considering challenges that remain ahead, our central tenet is that the search for glaucoma’s genetic elements will continue to require experimental ingenuity and synergistic approaches involving animal models that render the complexity of glaucoma more tractable.

Gene expression profiling of suicide completers

Despite strong evidence for a role of biological factors in the etiology and pathology of suicide, the study of traditional neurotransmitter systems has been able to explain only a small proportion of the neurobiology of what is now recognized as a complex genetic trait. The use of microarrays to simultaneously examine the expression levels of thousands of gene transcripts has vastly expanded our capacity to detect the involvement of additional genes and pathways in suicidality, and has opened many new avenues for the discovery of the biological underpinnings of suicide completion. This review examines microarray studies which have been used to identify genes displaying altered expression in suicide completers, and highlights some of the important methodological considerations and metabolic pathways which have emerged from these analyses.