Wenjuan Zhu

All Publications

• AP2B1, a protein involved in endocytic trafficking, is associated with congenital heart defects when mutated GENES & DISEASES Guzman, C., Zhu, W., Jha, A., Tong, Y., Arrigo, A., Bahar, I., Lo, C., Lin, J. 2026; 13 (6): 102035

  View details for DOI 10.1016/j.gendis.2026.102035

  View details for Web of Science ID 001826889400001

  View details for PubMedID 42437049

  View details for PubMedCentralID PMC13355575

• Tirzepatide Regulates Pacemaker Function by Modulating cAMP and Calcium Dynamics in Human Sinoatrial Node Cells. Circulation Ren, L., Belbachir, N., Zhang, H., Thai, P. N., Huang, R., Zhu, W., Wu, X., Xie, M., Gao, J., Kim, H. Y., Liu, T., Sun, J., Ghazizadeh, Z., Navedo, M. F., Wu, J. C. 2026; 153 (25): 2110-2113

  View details for DOI 10.1161/CIRCULATIONAHA.125.076669

  View details for PubMedID 42330097

  View details for PubMedCentralID PMC13288756

• KCTD1/KCTD15 Complexes Repress AP-2α and AP-2β to Regulate Neural Crest-Dependent Craniofacial Morphogenesis and Scalp Skin Development. The Journal of investigative dermatology Raymundo, J. R., Senapati, B., Zhu, W., Lin, A. E., Vitagliano, L., Marneros, A. G. 2026

  Abstract

  KCTD1 and KCTD15 form pentameric complexes that regulate neural crest cell (NCC) and keratinocyte functions, and dominant-negative mutations in their genes cause aplasia cutis congenita (ACC) and craniofacial abnormalities. Although KCTD1/KCTD15 complexes have been proposed to modulate multiple developmental pathways in vitro, the key downstream mechanisms responsible for these phenotypes in vivo remain unclear. Here, we investigated the function of KCTD1/KCTD15 complexes specifically in NCCs. Using conditional mouse models, cell lineage tracing, and genetic epistasis approaches, we show that KCTD1/KCTD15 complexes regulate NCC-dependent craniofacial development and midline scalp skin formation primarily by repressing the transcriptional activity of AP-2α and AP-2β. Loss of KCTD1/KCTD15 in NCCs resulted in ACC, cranial suture abnormalities, nasal bone hypoplasia, incisor agenesis, eyelid defects, pigmentation abnormalities, and cleft palate. Genetic reduction of AP-2α and AP-2β dosage in NCCs lacking KCTD1/KCTD15 markedly rescued these defects, establishing derepressed AP-2 activity as the principal pathogenic mechanism. Conversely, NCC-specific loss of AP-2α/AP-2β produced partially overlapping craniofacial defects, demonstrating that craniofacial morphogenesis is highly sensitive to AP-2 dosage. These findings identify a KCTD1/KCTD15-AP-2 regulatory axis as a central mechanism controlling neural crest-derived craniofacial development and scalp skin formation and establish ACC as a neurocristopathy arising from dysregulated AP-2 activity.

  View details for DOI 10.1016/j.jid.2026.05.027

  View details for PubMedID 42285336

• Inhibition of CXCL10 and IFN-γ ameliorates myocarditis in preclinical models of SARS-CoV-2 mRNA vaccination. Science translational medicine Cao, X., Manhas, A., Chen, Y. I., Caudal, A., Mondejar-Parreño, G., Zhu, W., Liu, W., Kong, X., Zeng, W., Liu, L., Zhao, S. R., Jahng, J. W., Utz, P. J., Nadeau, K. C., Nishiga, M., Wu, J. C. 2025; 17 (828): eadq0143

  Abstract

  Messenger RNA (mRNA) vaccines against SARS-CoV-2 are highly effective and were instrumental in curbing the COVID-19 pandemic. However, rare cases of noninfective myocarditis, particularly in young males and typically after the second dose, have been observed. Here, we explore the mediators of this myocarditis to better understand and to enhance the safety of future mRNA vaccines. Through analysis of human plasma data and in vitro experiments with human macrophages and T cells, we identified increased C-X-C motif chemokine ligand 10 (CXCL10) and interferon-γ (IFN-γ) after exposure to BNT162b2 (Pfizer) or mRNA-1273 (Moderna). Neutralization of CXCL10 and IFN-γ during the second dose (21 days after the first dose) reduced vaccine-induced cardiac injury in mice. Neutralization also reduced cardiac stress markers such as the release of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and expression of inflammatory genes in human induced pluripotent stem cell (iPSC)-derived cardiac spheroids. When exposed to these cytokines in vitro, human iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired contractility, arrhythmogenicity, and proinflammatory gene expression patterns. Genistein, a phytoestrogen implicated in reducing cardiovascular inflammation, mitigated these effects in iPSC-CMs. In mice exposed to these cytokines or receiving BNT162b2 vaccination, genistein treatment reduced cardiac injury markers and attenuated infiltration of neutrophils and macrophages into the heart. These findings implicate CXCL10-IFN-γ signaling as a contributor to myocardial injury in experimental models of mRNA vaccination and indicate that pharmacologic modulation, such as with genistein, may mitigate cytokine-driven injury.

  View details for DOI 10.1126/scitranslmed.adq0143

  View details for PubMedID 41370400

• Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target. Cell Zhang, H., Thai, P. N., Shivnaraine, R. V., Ren, L., Wu, X., Siepe, D. H., Liu, Y., Tu, C., Shin, H. S., Caudal, A., Mukherjee, S., Leitz, J., Wen, W. T., Liu, W., Zhu, W., Chiamvimonvat, N., Wu, J. C. 2024

  Abstract

  Cardiac fibrosis impairs cardiac function, but no effective clinical therapies exist. To address this unmet need, we employed a high-throughput screening for antifibrotic compounds using human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs). Counter-screening of the initial candidates using iPSC-derived cardiomyocytes and iPSC-derived endothelial cells excluded hits with cardiotoxicity. This screening process identified artesunate as the lead compound. Following profibrotic stimuli, artesunate inhibited proliferation, migration, and contraction in human primary CFs, reduced collagen deposition, and improved contractile function in 3D-engineered heart tissues. Artesunate also attenuated cardiac fibrosis and improved cardiac function in heart failure mouse models. Mechanistically, artesunate targeted myeloid differentiation factor 2 (MD2) and inhibited MD2/Toll-like receptor 4 (TLR4) signaling pathway, alleviating fibrotic gene expression in CFs. Our study leverages multiscale drug screening that integrates a human iPSC platform, tissue engineering, animal models, in silico simulations, and multiomics to identify MD2 as a therapeutic target for cardiac fibrosis.

  View details for DOI 10.1016/j.cell.2024.09.034

  View details for PubMedID 39413786

• Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target Cell Zhang, H. 2024

  Abstract

  Cardiac fibrosis impairs cardiac function, but no effective clinical therapies exist. To address this unmet need, we employed a high-throughput screening for antifibrotic compounds using human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs). Counter-screening of the initial candidates using iPSC-derived cardiomyocytes and iPSC-derived endothelial cells excluded hits with cardiotoxicity. This screening process identified artesunate as the lead compound. Following profibrotic stimuli, artesunate inhibited proliferation, migration, and contraction in human primary CFs, reduced collagen deposition, and improved contractile function in 3D-engineered heart tissues. Artesunate also attenuated cardiac fibrosis and improved cardiac function in heart failure mouse models. Mechanistically, artesunate targeted myeloid differentiation factor 2 (MD2) and inhibited MD2/Toll-like receptor 4 (TLR4) signaling pathway, alleviating fibrotic gene expression in CFs. Our study leverages multiscale drug screening that integrates a human iPSC platform, tissue engineering, animal models, in silico simulations, and multiomics to identify MD2 as a therapeutic target for cardiac fibrosis.

  View details for DOI 10.1016/j.cell.2024.09.034

• Generation of two induced pluripotent stem cell lines from patients with Williams syndrome. Stem cell research Dai, Y., Zhu, W., Flores Banuelos, A. G., Li, J., Mukherjee, S., Algaze, C., Wu, J. C. 2024; 78: 103460

  Abstract

  Williams syndrome (WS) is a relatively rare genetic disorder. It arises from a microdeletion in chromosome 7q11.23, resulting in the loss of one copy of more than 20 genes. Disorders in multiple systems, including cardiovascular and nervous systems, occur in patients with WS. Here, we generated two human induced pluripotent stem cell (iPSC) lines from WS patients. Both lines expressed pluripotency markers at gene and protein levels. They possessed normal karyotypes and the potential to differentiate into three germ layers. They serve as a useful tool to study disease mechanism, test drugs, and identify promising therapeutics for patients with WS.

  View details for DOI 10.1016/j.scr.2024.103460

  View details for PubMedID 38861775

• AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis. The Journal of investigative dermatology Zhang, H., Raymundo, J. R., Daly, K. E., Zhu, W., Senapati, B., Zhong, H., Ahilan, A. R., Marneros, A. G. 2024

  Abstract

  AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2β. Through inactivation of AP-2α, AP-2β, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2β in keratinocytes is compensated for by AP-2α, (2) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2α/AP-2β results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2β in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2β in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2α-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2α/AP-2β are critical regulators of epidermal homeostasis in the adult skin.

  View details for DOI 10.1016/j.jid.2023.12.017

  View details for PubMedID 38237728

• KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions and their impairment causes aplasia cutis. The Journal of clinical investigation Raymundo, J. R., Zhang, H., Smaldone, G., Zhu, W., Daly, K. E., Glennon, B. J., Pecoraro, G., Salvatore, M., Devine, W. A., Lo, C. W., Vitagliano, L., Marneros, A. G. 2023

  Abstract

  Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a longstanding enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we find that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other's loss, and that disease mutations are dominant-negative, resulting in lack of KCTD1/KCTD15 function. We demonstrate that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes results in abnormal skin appendages, but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells results in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.

  View details for DOI 10.1172/JCI174138

  View details for PubMedID 38113115

• AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis. bioRxiv : the preprint server for biology Zhang, H., Raymundo, J., Daly, K. E., Zhu, W., Senapati, B., Marneros, A. G. 2023

  Abstract

  AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2β. Through inactivation of AP-2α, AP-2β, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2β in keratinocytes is compensated for by AP-2α, (2) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2α/AP-2β results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2β in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2β in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2α-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2α/AP-2β are critical regulators of epidermal homeostasis in the adult skin.

  View details for DOI 10.1101/2023.12.03.569763

  View details for PubMedID 38105942

  View details for PubMedCentralID PMC10723278

• Generation of two induced pluripotent stem cell lines from patients with Down syndrome. Stem cell research Zhu, W., Liu, W., Yu, R., Manning, M., Waran Romfh, A., Wu, J. C. 2023; 72: 103204

  Abstract

  Down syndrome (DS) is caused by trisomy of Homo sapiens chromosome 21 (HSA21) and is by far the most common chromosomal disorder accompanied by neurodevelopmental disorders and congenital heart disease. Here, we generated two induced pluripotent stem cell (iPSC) lines from two patients with DS. These two lines exhibited normal morphology, trisomy 21 karyotype, pluripotency and differentiation capability into derivatives of three germ layers. The patient-specific iPSC lines arean invaluable resource in research to model DS-related cellular and molecular pathologies and test possible therapeutic strategies for DS.

  View details for DOI 10.1016/j.scr.2023.103204

  View details for PubMedID 37734318

• Contribution of LRP1 in Human Congenital Heart Disease Correlates with Its Roles in the Outflow Tract and Atrioventricular Cushion Development GENES Arrigo, A. B., Zhu, W., Williams, K. A., Guzman-Moreno, C., Lo, C., Lin, J. I. 2023; 14 (4)

  Abstract

  Due to the prevalence of congenital heart disease in the human population, determining the role of variants in congenital heart disease (CHD) can give a better understanding of the cause of the disorder. A homozygous missense mutation in the LDL receptor-related protein 1 (Lrp1) in mice was shown to cause congenital heart defects, including atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV). Integrative analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets and spatial transcriptomics of human and mouse hearts indicated that LRP1 is predominantly expressed in mesenchymal cells and mainly located in the developing outflow tract and atrioventricular cushion. Gene burden analysis of 1922 CHD individuals versus 2602 controls with whole-exome sequencing showed a significant excess of rare damaging LRP1 mutations in CHD (odds ratio (OR) = 2.22, p = 1.92 × 10-4), especially in conotruncal defect with OR of 2.37 (p = 1.77 × 10-3) and atrioventricular septal defect with OR of 3.14 (p = 0.0194). Interestingly, there is a significant relationship between those variants that have an allele frequency below 0.01% and atrioventricular septal defect, which is the phenotype observed previously in a homozygous N-ethyl-N-nitrosourea (ENU)-induced Lrp1 mutant mouse line.

  View details for DOI 10.3390/genes14040947

  View details for Web of Science ID 000977574000001

  View details for PubMedID 37107705

  View details for PubMedCentralID PMC10137934

• Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease CELL STEM CELL Xu, X., Jin, K., Bais, A. S., Zhu, W., Yagi, H., Feinstein, T. N., Nguyen, P. K., Criscione, J. D., Liu, X., Beutner, G., Karunakaran, K. B., Rao, K. S., He, H., Adams, P., Kuo, C. K., Kostka, D., Pryhober, G. S., Shiva, S., Ganapathiraju, M. K., Porter, G. A., Ivy-Lin, J., Aronow, B., Lo, C. W. 2022; 29 (5): 840-+

  Abstract

  Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.

  View details for DOI 10.1016/j.stem.2022.03.003

  View details for Web of Science ID 000804044900005

  View details for PubMedID 35395180

  View details for PubMedCentralID PMC9302582

• Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta GENES Zhu, W., Williams, K., Young, C., Lin, J., Teekakirikul, P., Lo, C. W. 2022; 13 (4)

  Abstract

  Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of CoA. Previous studies have shown a rare MYH6 variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster (PCDHA delCNVs) are significantly associated with CoA and BAV. Here, analysis of a non-Icelandic white CHD cohort (n = 166) recovered rare MYH6 variants in 10.9% of CoA and 32.7% of BAV/CoA patients, yielding odds ratios of 18.6 (p = 2.5 × 10-7) and 20.5 (p = 7.4 × 10-5) for the respective association of MYH6 variants with CoA and BAV/CoA. In combination with the PCHDA delCNVs, they accounted for a third of CoA cases. Gene expression datasets for the human and mouse embryonic heart showed that both genes are predominantly expressed in the atria, not the ventricle. Moreover, cis-eQTLs analysis showed the PCHDA delCNV is associated with reduced atrial expression of PCHDA10, a gene in the delCNV interval. Together, these findings showed that PCDHA/MYH6 variants account for a substantial fraction of CoA cases. An atrial rather than ventricular hemodynamic model for CoA is indicated, consistent with the known early atrial functional dominance of the human embryonic heart.

  View details for DOI 10.3390/genes13040636

  View details for Web of Science ID 000786816400001

  View details for PubMedID 35456442

  View details for PubMedCentralID PMC9032275

• Genetic resiliency associated with dominant lethal<i> TPM1</i> mutation causing atrial septal defect with high heritability CELL REPORTS MEDICINE Teekakirikul, P., Zhu, W., Xu, X., Young, C. B., Tan, T., Smith, A. M., Wang, C., Peterson, K. A., Gabriel, G. C., Ho, S., Sheng, Y., de Bellaing, A., Sonnenberg, D. A., Lin, J., Fotiou, E., Tenin, G., Wang, M. X., Wu, Y. L., Feinstein, T., Devine, W., Gou, H., Bais, A. S., Glennon, B. J., Zahid, M., Wong, T. C., Ahmad, F., Rynkiewicz, M. J., Lehman, W. J., Keavney, B., Alastalo, T., Freckmann, M., Orwig, K., Murray, S., Ware, S. M., Zhao, H., Feingold, B., Lo, C. W. 2022; 3 (2): 100501

  Abstract

  Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

  View details for DOI 10.1016/j.xcrm.2021.100501

  View details for Web of Science ID 000759511900005

  View details for PubMedID 35243414

  View details for PubMedCentralID PMC8861813

• Single-cell transcriptome analysis yields new insights into the pathogenic mechanisms and possible genetic etiology of cardiomyopathies Zhu, W., Teekakirikul, P., Guo, D., Yan, B., Lo, C. OXFORD UNIV PRESS. 2021: 3331

  View details for Web of Science ID 000720456903632

• The transcriptional landscape of the clustered protocadherins in the cardiovascular system Zhu, W., Chhibbar, P., Lo, C. OXFORD UNIV PRESS. 2021: 3202

  View details for Web of Science ID 000720456903503

• Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease HUMAN GENETICS AND GENOMICS ADVANCES Teekakirikul, P., Zhu, W., Gabriel, G. C., Young, C. B., Williams, K., Martin, L. J., Hill, J. C., Richards, T., Billaud, M., Phillippi, J. A., Wang, J., Wu, Y., Tan, T., Devine, W., Lin, J., Bais, A. S., Klonowski, J., de Bellaing, A., Saini, A., Wang, M. X., Emerel, L., Salamacha, N., Wyman, S. K., Lee, C., Li, H., Miron, A., Zhang, J., Xing, J., McNamara, D. M., Fung, E., Kirshbom, P., Mahle, W., Kochilas, L. K., He, Y., Garg, V., White, P., McBride, K. L., Benson, D., Gleason, T. G., Mital, S., Lo, C. W. 2021; 2 (3)

  Abstract

  Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

  View details for DOI 10.1016/j.xhgg.2021.100037

  View details for Web of Science ID 000787665000006

  View details for PubMedID 34888534

  View details for PubMedCentralID PMC8653519

• Genetic Architecture and Selection of Chinese Cattle Revealed by Whole Genome Resequencing MOLECULAR BIOLOGY AND EVOLUTION Mei, C., Wang, H., Liao, Q., Wang, L., Cheng, G., Wang, H., Zhao, C., Zhao, S., Song, J., Guang, X., Liu, G. E., Li, A., Wu, X., Wang, C., Fang, X., Zhao, X., Smith, S. B., Yang, W., Tian, W., Gui, L., Zhang, Y., Hill, R. A., Jiang, Z., Xin, Y., Jia, C., Sun, X., Wang, S., Yang, H., Wang, J., Zhu, W., Zan, L. 2018; 35 (3): 688-699

  Abstract

  The bovine genetic resources in China are diverse, but their value and potential are yet to be discovered. To determine the genetic diversity and population structure of Chinese cattle, we analysed the whole genomes of 46 cattle from six phenotypically and geographically representative Chinese cattle breeds, together with 18 Red Angus cattle (RAN) genomes, 11 Japanese black cattle (JBC) genomes and taurine and indicine genomes available from previous studies. Our results showed that Chinese cattle originated from hybridization between Bos taurus and Bos indicus. Moreover, we found that the level of genetic variation in Chinese cattle depends upon the degree of indicine content. We also discovered many potential selective sweep regions associated with domestication related to breed-specific characteristics, with selective sweep regions including genes associated with coat colour (ERCC2, MC1R, ZBTB17 and MAP2K1), dairy traits (NCAPG, MAPK7, FST, ITFG1, SETMAR, PAG1, CSN3 and RPL37A), and meat production/quality traits (such as BBS2, R3HDM1, IGFBP2, IGFBP5, MYH9, MYH4 and MC5R). These findings substantially expand the catalogue of genetic variants in cattle and reveal new insights into the evolutionary history and domestication traits of Chinese cattle.

  View details for DOI 10.1093/molbev/msx322

  View details for Web of Science ID 000427260700015

  View details for PubMedID 29294071

• Whole-genome sequencing of the endangered bovine species Gayal (<i>Bos frontalis</i>) provides new insights into its genetic features SCIENTIFIC REPORTS Mei, C., Wang, H., Zhu, W., Wang, H., Cheng, G., Qu, K., Guang, X., Li, A., Zhao, C., Yang, W., Wang, C., Xin, Y., Zan, L. 2016; 6: 19787

  Abstract

  Gayal (Bos frontalis) is a semi-wild and endangered bovine species that differs from domestic cattle (Bos taurus and Bos indicus), and its genetic background remains unclear. Here, we performed whole-genome sequencing of one Gayal for the first time, with one Red Angus cattle and one Japanese Black cattle as controls. In total, 97.8 Gb of sequencing reads were generated with an average 11.78-fold depth and >98.44% coverage of the reference sequence (UMD3.1). Numerous different variations were identified, 62.24% of the total single nucleotide polymorphisms (SNPs) detected in Gayal were novel, and 16,901 breed-specific nonsynonymous SNPs (BS-nsSNPs) that might be associated with traits of interest in Gayal were further investigated. Moreover, the demographic history of bovine species was first analyzed, and two population expansions and two population bottlenecks were identified. The obvious differences among their population sizes supported that Gayal was not B. taurus. The phylogenic analysis suggested that Gayal was a hybrid descendant from crossing of male wild gaur and female domestic cattle. These discoveries will provide valuable genomic information regarding potential genomic markers that could predict traits of interest for breeding programs of these cattle breeds and may assist relevant departments with future conservation and utilization of Gayal.

  View details for DOI 10.1038/srep19787

  View details for Web of Science ID 000368788200001

  View details for PubMedID 26806430

  View details for PubMedCentralID PMC4726396