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Alzheimer’s disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.

Some genetic causes of male infertility have been identified, but most remain unknown. In this study, 7 of 289 men with azoospermia (2.4%) harbored a mutation in TEX11, a gene expressed in the testes that is critical to chromosomal recombination. Nearly half of all cases of male infertility are thought to be associated with genetic defects. 1 – 3 Up to 20% of infertile men receive a diagnosis of azoospermia. 3 Nonobstructive azoospermia is spermatogenic failure that is defined by the absence of spermatozoa in the seminal fluid. 1 , 4 Azoospermia is a heterogeneous condition with several histologic phenotypes. 5 The most severe form of azoospermia is the Sertoli-cell–only syndrome, which is defined as a complete absence of germ cells. 6 , 7 Azoospermia with meiotic arrest is a milder form of infertility with a cessation at the spermatocyte stage of germ-cell formation. 7 Both the Sertoli-cell–only syndrome . . .

Leukemias bearing heterozygous mutations in the SRSF2 splicing-factor-encoding gene can be therapeutically targeted by pharmacologic inhibition of residual spliceosome function. Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) 1 , 2 , 3 . These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition 4 , 5 , 6 . Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 ( Srsf2 P95H )—which commonly occurs in individuals with MDS and AML—in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2 -mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7 , 8 ) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2 -mutated than in Srsf2 -wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.

UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous X(Utx-) Y(+) mutant male embryos should phenocopy homozygous X(Utx-) X(Utx-) females. However, X(Utx-) Y(+) mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X(+) Y(Uty-) mutant males are viable. In contrast, compound hemizygous X(Utx-) Y(Uty-) males phenocopy homozygous X(Utx-) X(Utx-) females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability.

• Distyly is an intriguing floral adaptation that increases pollen transfer precision and restricts inbreeding. It has been a model system in evolutionary biology since Darwin. Although the S-locus determines the long- and short-styled morphs, the genes were unknown in Turnera. We have now identified these genes. • We used deletion mapping to identify, and then sequence, BAC clones and genome scaffolds to construct S/s haplotypes. We investigated candidate gene expression, hemizygosity, and used mutants, to explore gene function. • The s-haplotype possessed 21 genes collinear with a region of chromosome 7 of grape. The S-haplotype possessed three additional genes and two inversions. TsSPH1 was expressed in filaments and anthers, TsYUC6 in anthers and TsBAHD in pistils. Long-homostyle mutants did not possess TsBAHD and a short-homostyle mutant did not express TsSPH1. • Three hemizygous genes appear to determine S-morph characteristics in T. subulata. Hemizygosity is common to all distylous species investigated, yet the genes differ. The pistil candidate gene, TsBAHD, differs from that of Primula, but both may inactivate brassinosteroids causing short styles. TsYUC6 is involved in auxin synthesis and likely determines pollen characteristics. TsSPH1 is likely involved in filament elongation. We propose an incompatibility mechanism involving TsYUC6 and TsBAHD.

In plants, numerous non-Mendelian inherited dominant effects, including over-, incomplete-, and co-dominance, are frequently observed, yet they remain insufficiently understood. A novel phenotype has been identified in specific soybean transformants overexpressing a single 35S::GmFT2a copy: super-early flowering dominance is exclusively observed in hemizygotes, not in homozygotes. Homozygous individual exhibits siRNA-mediated DNA methylation, causing epigenetic transcriptional silencing, whereas no such effect occurs in hemizygotes. Intriguingly, two distinct rounds of DNA methylation establishment occur, each mediated by a different mechanism. The homozygotes that derived from the hemizygous mother plants carrying 35S::GmFT2a locus was associated with the initiation of CHH-context DNA methylation at 35S promoters mediated by 21 and 22 nucleotide (nt) siRNAs. Subsequently, 24 nt siRNAs contribute to additional CHG- and CG-context DNA methylation at 35S promoters during the homozygosity of genes in plants already homozygous in maternal lineage. Reducing DNA methylation levels can be achieved by generating a hemizygous genotype through a crossing experiment with a recessive genotype. This research has unveiled a phenomenon: hemizygote-dependent dominance resulting from transcriptional silencing in homozygote offsprings. It provides new insights into the molecular mechanism underlying dominant effects.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of α-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.

We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression-not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for producing chimeric mice for use in future long-term studies, including hepatitis virus infection analysis or drug toxicity studies.

Pathogenic variants on the X-chromosome can have more severe consequences for hemizygous males, while heterozygote females can avoid severe consequences due to diploidy and the capacity for nonrandom expression. Thus, when an allele is more common in females this could indicate that it increases the probability of early death in the male hemizygous state, which can be considered a measure of pathogenicity. Importantly, large-scale genomic data now makes it possible to compare allele proportions between the sexes. To discover pathogenic variants on the X-chromosome, we analyzed exome data from 125,748 ancestrally diverse participants in the Genome Aggregation Database (gnomAD). After filtering out duplicates and extremely rare variants, 44,606 of the original 348,221 remained for analysis. We divided the proportion of variant alleles in females by the proportion in males for all variant sites, and then placed each variant into one of three a priori categories: (1) Reference (Primarily synonymous and intronic), (2) Unlikely-to-be-tolerated (Primarily missense), and (3) Least-likely-to-be-tolerated (Primarily frameshift). To assess the impact of ploidy, we compared the distribution of these ratios between pseudoautosomal and non-pseudoautosomal regions. In the non-pseudoautosomal regions, mean female-to-male ratios were lowest among Reference (2.40), greater for Unlikely-to-be-tolerated (2.77) and highest for Least-likely-to-be-tolerated (3.28) variants. Corresponding ratios were lower in the pseudoautosomal regions (1.52, 1.57, and 1.68, respectively), with the most extreme ratio being just below 11. Because pathogenic effects in the pseudoautosomal regions should not drive ratio increases, this maximum ratio provides an upper bound for baseline noise. In the non-pseudoautosomal regions, 319 variants had a ratio over 11. In sum, we identified a measure with a dataset specific threshold for identifying pathogenicity in non-pseudoautosomal X-chromosome variants: the female-to-male allele proportion ratio.

Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions. We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively. STOP genes include many known tumor suppressors, whereas GO genes are enriched for essential genes. Analysis of their chromosomal distribution revealed that recurring deletions preferentially overrepresent STOP genes and underrepresent GO genes. We propose a hypothesis called the cancer gene island model, whereby gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted to maximize proliferative fitness through cumulative haploinsufficiencies. Because hundreds to thousands of genes are hemizygously deleted per tumor, this mechanism may help to drive tumorigenesis across many cancer types.