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De novo assembly and phasing of a Korean human genome
Seo, Jeong-Sun,Rhie, Arang,Kim, Junsoo,Lee, Sangjin,Sohn, Min-Hwan,Kim, Chang-Uk,Hastie, Alex,Cao, Han,Yun, Ji-Young,Kim, Jihye,Kuk, Junho,Park, Gun Hwa,Kim, Juhyeok,Ryu, Hanna,Kim, Jongbum,Roh, Mira Nature Publishing Group, a division of Macmillan P 2016 Nature Vol.538 No.7624
<P>Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing(2), next-generation mapping(3), microfluidics-based linked reads(4), and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of unreported and Asian-specific structural variants, and high-quality haplotyping of clinically relevant alleles for precision medicine.</P>
AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development
Park, Jun Won,Kim, Il Yong,Choi, Ji Won,Lim, Hee Jung,Shin, Jae Hoon,Kim, Yo Na,Lee, Seo Hyun,Son, Yeri,Sohn, Mira,Woo, Jong Kyu,Jeong, Joseph H.,Lee, Cheolju,Bae, Yun Soo,Seong, Je Kyung American Association for Cancer Research 2018 Molecular Cancer Research Vol.16 No.8
<P>AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak<I><SUP>−/−</SUP></I> mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak<I><SUP>−/−</SUP></I> mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak<I><SUP>−/−</SUP></I> mice developed lung tumors, and Ahnak<I><SUP>−/−</SUP></I> mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak<I><SUP>−/−</SUP></I> lungs, and the depletion of AMs in Ahnak<I><SUP>−/−</SUP></I> lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer.</P><P><B>Implications:</B> The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. <I>Mol Cancer Res; 16(8); 1287–98. ©2018 AACR</I>.</P>
Ahnak gene deficiency promotes type II pneumocyte hyperplasia and lung tumor development in mice
Jun Won Park,Il Yong Kim,Dong Su Kyeong,Ji Won Choi,Hee Jung Lim,Jae Hoon Shin,Yo Na Kim,Seo Hyun Lee,Yeri Son,Mira Sohn,Jong Kyu Woo,Joseph H. Jeong,Cheolju Lee,Yun Soo Bae,Je Kyung Seong 한국실험동물학회 2018 한국실험동물학회 학술발표대회 논문집 Vol.2018 No.7