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BackgroundFor genomic selection in populations with a small reference population, combining populations of the same breed or populations of related breeds is an effective way to increase the size of the reference population. However, genomic predictions based on single nucleotide polymorphism (SNP)-chip genotype data using combined populations with different genetic backgrounds or from different breeds have not shown a clear advantage over using within-population or within-breed predictions. The increasing availability of whole-genome sequencing (WGS) data provides new opportunities for combined population genomic prediction. Our objective was to investigate the accuracy of genomic prediction using imputation-based WGS data from combined populations in pigs. Using 80K SNP panel genotypes, WGS genotypes, or genotypes on WGS variants that were pruned based on linkage disequilibrium (LD), three methods [genomic best linear unbiased prediction (GBLUP), single-step (ss)GBLUP, and genomic feature (GF)BLUP] were implemented with different prior information to identify the best method to improve the accuracy of genomic prediction for combined populations in pigs.ResultsIn total, 2089 and 2043 individuals with production and reproduction phenotypes, respectively, from three Yorkshire populations with different genetic backgrounds were genotyped with the PorcineSNP80 panel. Imputation accuracy from 80K to WGS variants reached 92%. The results showed that use of the WGS data compared to the 80K SNP panel did not increase the accuracy of genomic prediction in a single population, but using WGS data with LD pruning and GFBLUP with prior information did yield higher accuracy than the 80K SNP panel. For the 80K SNP panel genotypes, using the combined population resulted in a slight improvement, no change, or even a slight decrease in accuracy in comparison with the single population for GBLUP and ssGBLUP, while accuracy increased by 1 to 2.4% when using WGS data. Notably, the GFBLUP method did not perform well for both the combined population and the single populations.ConclusionsThe use of WGS data was beneficial for combined population genomic prediction. Simply increasing the number of SNPs to the WGS level did not increase accuracy for a single population, while using pruned WGS data based on LD and GFBLUP with prior information could yield higher accuracy than the 80K SNP panel.

Nuage is an electron-dense cytoplasmic structure in germ cells that contains ribonucleoproteins and participates in piRNA biosynthesis. Despite the observation that clustered mitochondria are associated with a specific type of nuage called intermitochondrial cement (pi-body), the importance of mitochondrial functions in nuage formation and spermatogenesis is yet to be determined. We show that a germ cell-specific protein GASZ contains a functional mitochondrial targeting signal and is largely localized at mitochondria both endogenously in germ cells and in somatic cells when ectopically expressed. In addition, GASZ interacts with itself at the outer membrane of mitochondria and promotes mitofusion in a mitofusin/MFN-dependent manner. In mice, deletion of the mitochondrial targeting signal reveals that mitochondrial localization of GASZ is essential for nuage formation, mitochondrial clustering, transposon repression, and spermatogenesis. MFN1 deficiency also leads to defects in mitochondrial activity and male infertility. Our data thus reveal a requirement for GASZ and MFNmediated mitofusion during spermatogenesis.

Kinases use ATP to phosphorylate substrates; recent findings underscore the additional regulatory roles of ATP. Here, we propose a mechanism for allosteric regulation of Akt1 kinase phosphorylation by ATP. Our 4.7-μs molecular dynamics simulations of Akt1 and its mutants in the ATP/ADP bound/unbound states revealed that ATP occupancy of the ATP-binding site stabilizes the closed conformation, allosterically protecting pT308 by restraining phosphatase access and key interconnected residues on the ATP→pT308 allosteric pathway. Following ATP→ADP hydrolysis, pT308 is exposed and readily dephosphorylated. Site-directed mutagenesis validated these predictions and indicated that the mutations do not impair PDK1 and PP2A phosphatase recruitment. We further probed the function of residues around pT308 at the atomic level, and predicted and experimentally confirmed that Akt1(H194R/R273H) double mutant rescues pathology-related Akt1(R273H). Analysis of classical Akt homologs suggests that this mechanism can provide a general model of allosteric kinase regulation by ATP; as such, it offers a potential avenue for allosteric drug discovery.

Spermatogenesis is a highly coordinated process that requires tightly regulated gene expression programmed by transcription factors and epigenetic modifiers. In this study, we found that nuclear respiratory factor (NRF)-1, a key transcription factor for mitochondrial biogenesis, cooperated with DNA methylation to directly regulate the expression of multiple germ cell-specific genes, including In addition, conditional ablation of NRF1 in gonocytes dramatically down-regulated these germline genes, blocked germ cell proliferation, and subsequently led to male infertility in mice. Our data highlight a precise crosstalk between transcriptional regulation by NRF1 and epigenetic modulation during germ cell development and unequivocally demonstrate a novel role of NRF1 in spermatogenesis.-Wang, J., Tang, C., Wang, Q., Su, J., Ni, T., Yang, W., Wang, Y., Chen, W., Liu, X., Wang, S., Zhang, J., Song, H., Zhu, J., Wang, Y. NRF1 coordinates with DNA methylation to regulate spermatogenesis.