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Next-generation high-throughput DNA sequencing technologies have advanced progressively in sequence-based genomic research and novel biological applications with the promise of sequencing DNA at unprecedented speed. These new non-Sanger-based technologies feature several advantages when compared with traditional sequencing methods in terms of higher sequencing speed, lower per run cost and higher accuracy. However, reads from next-generation sequencing (NGS) platforms, such as 454/Roche, ABI/SOLiD and Illumina/Solexa, are usually short, thereby restricting the applications of NGS platforms in genome assembly and annotation. We presented an overview of the challenges that these novel technologies meet and particularly illustrated various bioinformatics attempts on mapping and assembly for problem solving. We then compared the performance of several programs in these two fields, and further provided advices on selecting suitable tools for specific biological applications.

Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N 6 -methyladenosine (m 6 A) messenger RNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deletion of the m 6 A methyltransferase Mettl3 from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and a marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. RNA sequencing revealed 2,073 genes with significant m 6 A modifications in HSCs. Myc was identified as a direct target of m 6 A in HSCs. Mettl3 -deficient HSCs failed to upregulate MYC expression following stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3 -deficient HSCs. Our results reveal a key role of m 6 A in governing HSC differentiation. Lee et al. show that deleting Mettl3 from adult HSCs in mice leads to the accumulation of HSCs in the bone marrow and reduced reconstitution rates due to an inhibition of HSC differentiation.

The publisher is retracting this Review. The same Review was made available online on 28 April 2011 and published in the June issue of Journal of Human Genetics (doi:10.1038/jhg.2011.43). The Journal of Human Genetics and the publisher would like to apologize to the readers of the journal for the inconvenience caused by this inadvertent error.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2–2%) that downregulates ACE2 expression by 37% ( P  = 2.7 × 10 − 8 ) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P  = 4.5 × 10 − 13 ), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1 , MHC, DPP9 and IFNAR2 ). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone. Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2 . A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development ( HAND2 , TBX20 ) and Mendelian forms of thoracic aortic disease ( ELN , FBN1 ). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta. Trans-ancestry genome-wide analyses identify multiple loci associated with ascending aortic diameter. A polygenic score constructed from these loci predicted prevalent risk of thoracic aortic aneurysm in independent populations.

Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N.sup.6-methyladenosine (m.sup.6A) messenger RNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deletion of the m.sup.6A methyltransferase Mettl3 from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and a marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. RNA sequencing revealed 2,073 genes with significant m.sup.6A modifications in HSCs. Myc was identified as a direct target of m.sup.6A in HSCs. Mettl3-deficient HSCs failed to upregulate MYC expression following stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results reveal a key role of m.sup.6A in governing HSC differentiation.

Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N.sup.6-methyladenosine (m.sup.6A) messenger RNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deletion of the m.sup.6A methyltransferase Mettl3 from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and a marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. RNA sequencing revealed 2,073 genes with significant m.sup.6A modifications in HSCs. Myc was identified as a direct target of m.sup.6A in HSCs. Mettl3-deficient HSCs failed to upregulate MYC expression following stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results reveal a key role of m.sup.6A in governing HSC differentiation.

Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27 . We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p  = 1.03e-196) and ERAP1 (OR = 0.86, p  = 1.1e-08), and find IPMK (OR = 9.4, p  = 4.42e-09) and IDO2 (OR = 3.61, p  = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p  = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p  = 2.7e-08), risk genes IPMK and IDO2 , and several additional candidate risk genes, including ADGFR5 , STXBP2 , and ACHE . Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease. Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N -methyladenosine (m A) messenger RNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deletion of the m A methyltransferase Mettl3 from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and a marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. RNA sequencing revealed 2,073 genes with significant m A modifications in HSCs. Myc was identified as a direct target of m A in HSCs. Mettl3-deficient HSCs failed to upregulate MYC expression following stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results reveal a key role of m A in governing HSC differentiation.

Host genetic factors play an important role in diverse host outcomes after influenza A (H7N9) infection. Studying differential responses of inbred mouse lines with distinct genetic backgrounds to influenza virus infection could substantially increase our understanding of the contributory roles of host genetic factors to disease severity. Here, we utilized an integrated approach of mRNA-seq and miRNA-seq to investigate the transcriptome expression and regulation of host genes in C57BL/6J and DBA/2J mouse strains during influenza virus infection. The differential pathogenicity of influenza virus in C57BL/6J and DBA/2J has been fully demonstrated through immunohistochemical staining, histopathological analyses, and viral replication assessment. A transcriptional molecular signature correlates to differential host response to infection has been uncovered. With the introduction of temporal expression pattern analysis, we demonstrated that host factors responsible for influenza virus replication and host–virus interaction were significantly enriched in genes exhibiting distinct temporal dynamics between different inbred mouse lines. A combination of time-series expression analysis and temporal expression pattern analysis has provided a list of promising candidate genes for future studies. An integrated miRNA regulatory network from both mRNA-seq and miRNA-seq revealed several regulatory modules responsible for regulating host susceptibilities and disease severity. Overall, a comprehensive framework for analyzing host susceptibilities to influenza infection was established by integrating mRNA-seq and miRNA-seq data of inbred mouse lines. This work suggests novel putative molecular targets for therapeutic interventions in seasonal and pandemic influenza.