Single-cell RNA-sequencing reveals Transcriptional Changes and Clonal Architecture associated with Post-Transplant Relapse in Acute Myeloid Leukemia

"Acute myeloid leukemia (AML) is a malignancy characterized by overproduction of myeloid precursors at the expense of more differentiated, functional hematopoietic cells, resulting in anemia, thrombocytopenia, and neutropenia. Despite initial sensitivity to chemotherapy, a majority of patients with AML ultimately relapse. Among the challenges associated with relapse, post-allogeneic stem cell transplant relapse is particularly intractable because of our relative lack of understanding - and thus lack of effective treatment options - of the underlying mechanisms."--IntroductionZiheng Xu (1), Christopher A. Miller (2, 3), Sridhar N. Srivatsan (2), Catrina C. Fronick (3), Robert S. Fulton (3), Timothy J. Ley (2, 3, 4), and Allegra A. Petti (2, 3) ; 1. Washington University School of Medicine. 2. Division of Oncology, Washington University School of Medicine. 3. McDonnell Genome Institute, Washington University School of Medicine. 4. Department of Genetics, Washington University School of Medicine.Includes bibliographical reference

Sequence analysis in Bos taurus reveals pervasiveness of X–Y arms races in mammalian lineages

Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome o

TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits

Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases