A highly efficient in vivo plasmid editing tool based on CRISPR-Cas12a and phage λ Red recombineering Publication date: Available online 10 September 2019 Source: Journal of Genetics and Genomics Author(s): Yiman Geng, Hai-Qin Yan, Pei Li, Gai-Xian Ren, Xiao-Peng Guo, Peiqi Yin, Leiliang Zhang, Zhaohui Qian, Zhendong Zhao, Yi-Cheng Sun

OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia Publication date: Available online 13 August 2019 Source: Journal of Genetics and Genomics Author(s): Jun Yao, Huasha Zeng, Min Zhang, Qinjun Wei, Ying Wang, Haiyuan Yang, Yajie Lu, Rongfeng Li, Qiang Xiong, Lining Zhang, Zhibin Chen, Guangqian Xing, Xin Cao, Yifan Dai Abstract Oxysterol binding protein like 2 (OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotype-phenotype associations, the OSBPL2-disrupted Bama miniature (BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer (SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss (HL) with degeneration/apoptosis of cochlea hair cells (HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet (HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss (NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.

The expression tractability of biological traits shaped by natural selection Publication date: Available online 13 August 2019 Source: Journal of Genetics and Genomics Author(s): Li Liu, Jianguo Wang, Jian-Rong Yang, Feng Wang, Xionglei He Abstract Understanding how gene expression is translated to phenotype is central to modern molecular biology, and the success is contingent on the intrinsic tractability of the specific traits under examination. However, an a priori estimate of trait tractability from the perspective of gene expression is unavailable. Motivated by the concept of entropy in a thermodynamic system, we here propose such an estimate (ST) by gauging the number (N) of expression states that underlie the same trait abnormality, with large ST corresponding to large N. By analyzing over 200 yeast morphological traits, we show that ST predicts the tractability of an expression-trait relationship. We further show that ST is ultimately determined by natural selection, which builds co-regulated gene modules to minimize possible expression states.

Establishment of wheat-Thinopyrum ponticum translocation lines with resistance to Puccinia graminis f. sp. tritici Ug99 Publication date: Available online 13 August 2019 Source: Journal of Genetics and Genomics Author(s): Hongwei Li, Willem H.P. Boshoff, Zacharias A. Pretorius, Qi Zheng, Bin Li, Zhensheng Li

Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells Publication date: Available online 13 August 2019 Source: Journal of Genetics and Genomics Author(s): Zhitao Gao, Chuan Tong, Yao Wang, Deyun Chen, Zhiqiang Wu, Weidong Han Abstract Chimeric antigen receptor T-cell (CAR T) therapy is a kind of effective cancer immunotherapy. However, designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches (e.g., daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing (fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies (clone MM12T or clone MM27) or proteins (H02H or H08H) were used to block CD38 or the CAR single-chain variable fragment (scFv) domain, respectively, on the T cell surface. The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-α, IFN-γ and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.

Progressive heterosis in genetically defined tetraploid maize Publication date: Available online 9 August 2019 Source: Journal of Genetics and Genomics Author(s): Jacob D. Washburn, Mitchell J. McElfresh, James A. Birchler Abstract Progressive heterosis, i.e., the additional hybrid vigor in double-cross tetraploid hybrids not found in their single-cross tetraploid parents, has been documented in a number of species including alfalfa, potato, and maize. In this study, four artificially induced maize tetraploids, directly derived from standard inbred lines, were crossed in pairs to create two single-cross hybrids. These hybrids were then crossed to create double-cross hybrids containing genetic material from all four original lines. Replicated field-based phenotyping of the materials over four years indicated a strong progressive heterosis phenotype in tetraploids but not in their diploid counterparts. In particular, the above ground dry weight phenotype of double-cross tetraploid hybrids was on average 34% and 56% heavier than that of the single-cross tetraploid hybrids and the double-cross diploid counterparts, respectively. Additionally, whole-genome resequencing of the original inbred lines and further analysis of these data did not show the expected spectrum of alleles to explain tetraploid progressive heterosis under the complementation of complete recessive model. These results underscore the reality of the progressive heterosis phenotype, its potential utility for increasing crop biomass production, and the need for exploring alternative hypothesis to explain it at a molecular level.

Gut microbiota from end-stage renal disease patients disrupt gut barrier function by excessive production of phenol Publication date: Available online 2 August 2019 Source: Journal of Genetics and Genomics Author(s): Xifan Wang, Yanling Hao, Xiaoxue Liu, Shoujuan Yu, Weibo Zhang, Songtao Yang, Zhengquan Yu, Fazheng Ren

Rare variants in novel and known genes associated with primary angle closure glaucoma based on whole exome sequencing of 549 probands Publication date: 20 July 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 7 Author(s): Wenmin Sun, Xueshan Xiao, Shiqiang Li, Jiamin Ouyang, Xueqing Li, Xiaoyun Jia, Xing Liu, Qingjiong Zhang

Mapping quantitative trait loci using binned genotypes Publication date: 20 July 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 7 Author(s): Wen Yao, Guangwei Li, Yanru Cui, Yiming Yu, Qifa Zhang, Shizhong Xu Abstract Precise mapping of quantitative trait loci (QTLs) is critical for assessing genetic effects and identifying candidate genes for quantitative traits. Interval and composite interval mappings have been the methods of choice for several decades, which have provided tools for identifying genomic regions harboring causal genes for quantitative traits. Historically, the concept was developed on the basis of sparse marker maps where genotypes of loci within intervals could not be observed. Currently, genomes of many organisms have been saturated with markers due to the new sequencing technologies. Genotyping by sequencing usually generates hundreds of thousands of single nucleotide polymorphisms (SNPs), which often include the causal polymorphisms. The concept of interval no longer exists, prompting the necessity of a norm change in QTL mapping technology to make use of the high-volume genomic data. Here we developed a statistical method and a software package to map QTLs by binning markers into haplotype blocks, called bins. The new method detects associations of bins with quantitative traits. It borrows the mixed model methodology with a polygenic control from genome-wide association studies (GWAS) and can handle all kinds of experimental populations under the linear mixed model (LMM) framework. We tested the method using both simulated data and data from populations of rice. The results showed that this method has higher power than the current methods. An R package named binQTL is available from GitHub.

OsGCD1, a novel player in rice intine construction Publication date: 20 July 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 7 Author(s): Xiaorong Huang, Mengmeng Run, Meng-Xiang Sun