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Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

ABSTRACT: Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.

SUBMITTER: Guo MH

PROVIDER: S-EPMC5255587 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

Guo Michael H MH Nandakumar Satish K SK Ulirsch Jacob C JC Zekavat Seyedeh M SM Buenrostro Jason D JD Natarajan Pradeep P Salem Rany M RM Chiarle Roberto R Mitt Mario M Kals Mart M Pärn Kalle K Fischer Krista K Milani Lili L Mägi Reedik R Palta Priit P Gabriel Stacey B SB Metspalu Andres A Lander Eric S ES Kathiresan Sekar S Hirschhorn Joel N JN Esko Tõnu T Sankaran Vijay G VG

Proceedings of the National Academy of Sciences of the United States of America 20161228 3

Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-b ...[more]

PMID: 28031487

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Project description:Macaques are the most widely distributed nonhuman primates and used as animal models in biomedical research. The availability of full-genome sequences from them would be essential to both biomedical and primate evolutionary studies. Previous studies have reported whole-genome sequences from rhesus macaque (Macaca mulatta) and cynomolgus macaque (M. fascicularis, CE), both of which belong to the fascicularis group. Here, we present a 37-fold coverage genome sequence of the Tibetan macaque (M. thibetana; TM). TM is an endemic species to China belonging to the sinica group. On the basis of mapping to the rhesus macaque genome, we identified approximately 11.9 million single-nucleotide variants), of which 3.9 million were TM specific, as assessed by comparison two Chinese rhesus macaques (CR) and two CE genomes. Some genes carried TM-specific homozygous nonsynonymous variants (TSHNVs), which were scored as deleterious in human by both PolyPhen-2 and SIFT (Sorting Tolerant From Intolerant) and were enriched in the eye disease genes. In total, 273 immune response and disease-related genes carried at least one TSHNV. The heterozygosity rates of two CRs (0.002617 and 0.002612) and two CEs (0.003004 and 0.003179) were approximately three times higher than that of TM (0.000898). Polymerase chain reaction resequencing of 18 TM individuals showed that 29 TSHNVs exhibited high allele frequencies, thus confirming their low heterozygosity. Genome-wide genetic divergence analysis demonstrated that TM was more closely related to CR than to CE. We further detected unusual low divergence regions between TM and CR. In addition, after applying statistical criteria to detect putative introgression regions (PIRs) in the TM genome, up to 239,620 kb PIRs (8.84% of the genome) were identified. Given that TM and CR have overlapping geographical distributions, had the same refuge during the Middle Pleistocene, and show similar mating behaviors, it is highly likely that there was an ancient introgression event between them. Moreover, demographic inferences revealed that TM exhibited a similar demographic history as other macaques until 0.5 Ma, but then it maintained a lower effective population size until present time. Our study has provided new insight into the macaque evolutionary history, confirming hybridization events between macaque species groups based on genome-wide data.

Project description:BackgroundSugarcane smut can cause losses in cane yield and sugar content that range from 30% to total crop failure. Losses tend to increase with the passage of years. Sporisorium scitamineum is the fungus that causes sugarcane smut. This fungus has the potential to infect all sugarcane species unless a species is resistant to biotrophic fungal pathogens. However, it remains unclear how the fungus breaks through the cell walls of sugarcane and causes the formation of black or gray whip-like structures on the sugarcane plants.ResultsHere, we report the first high-quality genome sequence of S. scitamineum assembled de novo with a contig N50 of 41 kb, a scaffold N50 of 884 kb and genome size 19.8 Mb, containing an estimated 6,636 genes. This phytopathogen can utilize a wide range of carbon and nitrogen sources. A reduced set of genes encoding plant cell wall hydrolytic enzymes leads to its biotrophic lifestyle, in which damage to the host should be minimized. As a bipolar mating fungus, a and b loci are linked and the mating-type locus segregates as a single locus. The S. scitamineum genome has only 6 G protein-coupled receptors (GPCRs) grouped into five classes, which are responsible for transducing extracellular signals into intracellular responses, however, the genome is without any PTH11-like GPCR. There are 192 virulence associated genes in the genome of S. scitamineum, among which 31 expressed in all the stages, which mainly encode for energy metabolism and redox of short-chain compound related enzymes. Sixty-eight candidates for secreted effector proteins (CSEPs) were found in the genome of S. scitamineum, and 32 of them expressed in the different stages of sugarcane infection, which are probably involved in infection and/or triggering defense responses. There are two non-ribosomal peptide synthetase (NRPS) gene clusters that are involved in the generation of ferrichrome and ferrichrome A, while the terpenes gene cluster is composed of three unknown function genes and seven biosynthesis related genes.ConclusionsAs a destructive pathogen to sugar industry, the S. scitamineum genome will facilitate future research on the genomic basis and the pathogenic mechanisms of sugarcane smut.

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Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

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Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

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