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Ying Lin

Bio: Ying Lin is an academic researcher from University of Electronic Science and Technology of China. The author has contributed to research in topics: Single-nucleotide polymorphism & Genome-wide association study. The author has an hindex of 19, co-authored 44 publications receiving 1742 citations. Previous affiliations of Ying Lin include Peking Union Medical College & University of California, San Diego.

Papers
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Journal ArticleDOI
30 Jul 2015-Nature
TL;DR: In this paper, the authors identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts.
Abstract: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people1, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

331 citations

Journal ArticleDOI
17 Jul 2014-Nature
TL;DR: Establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which the transcription factors p63 and PAX6 act together to specify LSCs is found, suggesting a central role of the WNT7A–PAX6 axis in corNEal epithelial cell fate determination, and point to a new strategy for treating corneAL surface diseases.
Abstract: The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non-transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.

203 citations

Journal ArticleDOI
TL;DR: A successful application of exome sequencing is shown to identify a gene for an autosomal dominant disorder, and a gene potentially responsible for high myopia in a monogenic form is identified.
Abstract: Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.

177 citations

Journal ArticleDOI
TL;DR: Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues, a finding consistent with it having a role in the development of glaucoma.
Abstract: We performed a genome-wide association study for primary open-angle glaucoma (POAG) in 1,007 cases with high-pressure glaucoma (HPG) and 1,009 controls from southern China. We observed genome-wide significant association at multiple SNPs near ABCA1 at 9q31.1 (rs2487032; P = 1.66 × 10(-8)) and suggestive evidence of association in PMM2 at 16p13.2 (rs3785176; P = 3.18 × 10(-6)). We replicated these findings in a set of 525 HPG cases and 912 controls from Singapore and a further set of 1,374 POAG cases and 4,053 controls from China. We observed genome-wide significant association with more than one SNP at the two loci (P = 2.79 × 10(-19) for rs2487032 representing ABCA1 and P = 5.77 × 10(-10) for rs3785176 representing PMM2). Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues. In addition, ABCA1 is highly expressed in the ganglion cell layer of the retina, a finding consistent with it having a role in the development of glaucoma.

158 citations

Journal ArticleDOI
Ching-Yu Cheng1, Kenji Yamashiro2, Li Jia Chen3, Jeeyun Ahn4, Lulin Huang5, Lvzhen Huang6, Chui Ming Gemmy Cheung7, Masahiro Miyake2, Peter Cackett8, Ian Yeo7, Augustinus Laude9, Ranjana Mathur7, Junxiong Pang10, Kar Seng Sim10, Adrian Koh7, Peng Chen1, Shu Yen Lee7, Doric Wong7, Choi Mun Chan7, Boon Kwang Loh7, Yaoyao Sun6, Sonia Davila1, Isao Nakata2, Hideo Nakanishi2, Yumiko Akagi-Kurashige2, Norimoto Gotoh2, Akitaka Tsujikawa2, Fumihiko Matsuda2, Keisuke Mori11, Shin Yoneya11, Yoichi Sakurada12, Hiroyuki Iijima12, Tomohiro Iida, Shigeru Honda13, Timothy Y Y Lai3, Pancy O. S. Tam3, Haoyu Chen3, Shibo Tang14, Xiaoyan Ding14, Feng Wen14, Fang Lu5, Xiongze Zhang14, Yi Shi5, Peiquan Zhao15, Bowen Zhao16, Jinghong Sang16, Bo Gong5, Rajkumar Dorajoo10, Jian-Min Yuan17, Woon-Puay Koh1, Rob M. van Dam1, Yechiel Friedlander18, Ying Lin5, Martin L. Hibberd10, Jia Nee Foo10, Ningli Wang16, Chang Hua Wong10, Gavin Tan7, Sang Jun Park19, Mayuri Bhargava1, Lingam Gopal1, Thet Naing1, Jiemin Liao1, Peng Guan Ong, Paul Mitchell20, Peng Zhou21, Xuefeng Xie, Jinlong Liang, Junpu Mei, Xin Jin, Seang-Mei Saw1, Mineo Ozaki, Takanori Mizoguchi, Yasuo Kurimoto, Se Joon Woo19, Hum Chung22, Hyeong Gon Yu22, Joo Young Shin22, Dong Ho Park23, In Taek Kim23, Woohyok Chang24, Min Sagong24, Sang Joon Lee25, Hyun Woong Kim26, Ji Eun Lee27, Yi Li10, Jianjun Liu1, Yik Ying Teo1, Chew-Kiat Heng1, Tock Han Lim9, Suk-Kyun Yang28, Kyuyoung Song28, Eranga N. Vithana1, Tin Aung1, Jin Xin Bei14, Yi Xin Zeng29, E. Shyong Tai1, Xiaoxin Li6, Zhenglin Yang5, Kyu Hyung Park19, Chi Pui Pang3, Nagahisa Yoshimura2, Tien Yin Wong1, Chiea Chuen Khor1 
TL;DR: The findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asia may also have a distinct genetic signature.
Abstract: Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

156 citations


Cited by
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01 Aug 2010
TL;DR: In this paper, the identification of lincRNAs (lincRNA-p21) that serve as a repressor in p53-dependent transcriptional responses was reported, and the observed transcriptional repression was mediated through the physical association with hnRNP-K at repressed genes and regulation of p53 mediates apoptosis.
Abstract: Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

1,593 citations

Journal ArticleDOI
TL;DR: The Brush Foundation studies on human growth and development, begun in 1931 and terminated in 1942, have been intensively reviewed and studied by Dr. Greulich and Miss Pyle in the formulation of this Radiographic Atlas of Skeletal Development of the Hand and Wrist.
Abstract: The Brush Foundation studies on human growth and development, begun in 1931 and terminated in 1942, have been intensively reviewed and studied by Dr Greulich and Miss Pyle in the formulation of this Radiographic Atlas of Skeletal Development of the Hand and Wrist Serial radiographs of from 2 to 20 hand-films made at successive examinations of each of 1000 boys and girls made up the radiographic material Standards were selected that were judged to be the most representative of the central tendency or anatomic mode of each chronologic age group from birth through 18 years

1,547 citations

Journal ArticleDOI
22 Sep 2016
TL;DR: Primary open-angle glaucoma (POAG) is the most common type and management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.
Abstract: Glaucoma is an optic neuropathy that is characterized by the progressive degeneration of the optic nerve, leading to visual impairment. Glaucoma is the main cause of irreversible blindness worldwide, but typically remains asymptomatic until very severe. Open-angle glaucoma comprises the majority of cases in the United States and western Europe, of which, primary open-angle glaucoma (POAG) is the most common type. By contrast, in China and other Asian countries, angle-closure glaucoma is highly prevalent. These two types of glaucoma are characterized based on the anatomic configuration of the aqueous humour outflow pathway. The pathophysiology of POAG is not well understood, but it is an optic neuropathy that is thought to be associated with intraocular pressure (IOP)-related damage to the optic nerve head and resultant loss of retinal ganglion cells (RGCs). POAG is generally diagnosed during routine eye examination, which includes fundoscopic evaluation and visual field assessment (using perimetry). An increase in IOP, measured by tonometry, is not essential for diagnosis. Management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.

955 citations

Journal ArticleDOI
TL;DR: Molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with “inflammageing” or parainflammation are highlighted and suggested to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation.
Abstract: Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called "inflamm-aging." Despite research there is no clear understanding about the causes of "inflamm-aging" that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer's disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with "inflammageing" or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.

663 citations

Journal ArticleDOI
TL;DR: The results suggest that the Nimblegen platform, which is the only one to use high-density overlapping baits, covers fewer genomic regions than the other platforms but requires the least amount of sequencing to sensitively detect small variants.
Abstract: Whole exome sequencing by high-throughput sequencing of target-enriched genomic DNA (exome-seq) has become common in basic and translational research as a means of interrogating the interpretable part of the human genome at relatively low cost. We present a comparison of three major commercial exome sequencing platforms from Agilent, Illumina and Nimblegen applied to the same human blood sample. Our results suggest that the Nimblegen platform, which is the only one to use high-density overlapping baits, covers fewer genomic regions than the other platforms but requires the least amount of sequencing to sensitively detect small variants. Agilent and Illumina are able to detect a greater total number of variants with additional sequencing. Illumina captures untranslated regions, which are not targeted by the Nimblegen and Agilent platforms. We also compare exome sequencing and whole genome sequencing (WGS) of the same sample, demonstrating that exome sequencing can detect additional small variants missed by WGS.

504 citations