218 results on '"Mullikin JC"'
Search Results
2. Functional Characterization of the Morpheus Gene Family
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Bekpen, C, Baker, C, Hebert, MD, Sahin, HB, Johnson, ME, Celik, A, Mullikin, JC, and Eichler, EE
- Abstract
The burst of segmental duplications during human and great ape evolution focuses on a set of “core” duplicons encoding great-ape-specific gene families. Characterization of these gene families is complicated by their high copy number, incomplete sequence, and polymorphic nature. We investigate the structure, transcriptional diversity, and protein localization of the nuclear pore complex-interacting protein (NPIP) or Morpheus gene family. The corresponding core, LCRA, encodes one of the most rapidly evolving genes in the human genome; LCRA has expanded to ~20 copies from a single ancestral locus in Old World monkey and is associated with most of the recurrent chromosome 16 microdeletions implicated in autism and mental retardation. Phylogenetic analysis and cDNA sequencing suggest two distinct subfamilies or subtypes, NPIPA and NPIPB. The latter expanded recently within the great apes due to a series of structural changes within the canonical gene structure. Among Old World monkey, we observe a testis-specific pattern of expression that contrasts with the ubiquitous pattern observed among human tissues. This change in the expression profile coincides with the structural events that reshaped the structure and organization of the gene family. Most of the expressed human copies are capable of producing an open reading frame. Immunofluorescence analyses of the morpheus genes showed a primary localization to both the nucleus and its periphery. We show that morpheus genes may be upregulated upon pI:C treatment and find evidence of human autoantibodies produced against the NPIPB protein, raising the possibility that morpheus genes may be related to immune- or autoimmune-related function.
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- 2022
3. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
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Lalaoui, N, Boyden, SE, Oda, H, Wood, GM, Stone, DL, Chau, D, Liu, L, Stoffels, M, Kratina, T, Lawlor, KE, Zaal, KJM, Hoffmann, PM, Etemadi, N, Shield-Artin, K, Biben, C, Tsai, WL, Blake, MD, Kuehn, HS, Yang, D, Anderton, H, Silke, N, Wachsmuth, L, Zheng, L, Moura, NS, Beck, DB, Gutierrez-Cruz, G, Ombrello, AK, Pinto-Patarroyo, GP, Kueh, AJ, Herold, MJ, Hall, C, Wang, H, Chae, JJ, Dmitrieva, NI, McKenzie, M, Light, A, Barham, BK, Jones, A, Romeo, TM, Zhou, Q, Aksentijevich, I, Mullikin, JC, Gross, AJ, Shum, AK, Hawkins, ED, Masters, SL, Lenardo, MJ, Boehm, M, Rosenzweig, SD, Pasparakis, M, Voss, AK, Gadina, M, Kastner, DL, Silke, J, Lalaoui, N, Boyden, SE, Oda, H, Wood, GM, Stone, DL, Chau, D, Liu, L, Stoffels, M, Kratina, T, Lawlor, KE, Zaal, KJM, Hoffmann, PM, Etemadi, N, Shield-Artin, K, Biben, C, Tsai, WL, Blake, MD, Kuehn, HS, Yang, D, Anderton, H, Silke, N, Wachsmuth, L, Zheng, L, Moura, NS, Beck, DB, Gutierrez-Cruz, G, Ombrello, AK, Pinto-Patarroyo, GP, Kueh, AJ, Herold, MJ, Hall, C, Wang, H, Chae, JJ, Dmitrieva, NI, McKenzie, M, Light, A, Barham, BK, Jones, A, Romeo, TM, Zhou, Q, Aksentijevich, I, Mullikin, JC, Gross, AJ, Shum, AK, Hawkins, ED, Masters, SL, Lenardo, MJ, Boehm, M, Rosenzweig, SD, Pasparakis, M, Voss, AK, Gadina, M, Kastner, DL, and Silke, J
- Abstract
RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.
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- 2020
4. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
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Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Shi, Jianxin, Mai, Xu, Goldstein, Alisa M., Trower, Adam J., Bishop, D. Timothy, Iles, Mark M., Duffy, David L., Macgregor, Stuart, Amundadottir, Laufey T., Law, Matthew H., Loftus, Stacie K., Pavan, William J., Brown, Kevin M., Lee, Je, Brossard, M, Martin, Ng, Moses, Ek, Song, F, Barrett, Jh, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Taylor, Jc, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Bianchi Scarrà, G, Dȩbniak, T, Duffy, Dl, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Montgomery, Gw, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Wu, W, Qureshi, Aa, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Hayward, Nk, Han, J, Schulze, Hj, Dunning, Am, Bishop, Jan, Demenais, F, Amos, Ci, Macgregor, S, Iles, Mm, Barnabas, Bb, Bouffard, Gg, Brooks, Sy, Coleman, H, Dekhtyar, L, Guan, X, Ho, Sl, Legaspi, R, Maduro, Ql, Masiello, Ca, Mcdowell, Jc, Montemayor, C, Mullikin, Jc, Park, M, Riebow, Nl, Schandler, K, Schmidt, B, Sison, C, Smith, R, Stantripop, S, Thomas, Jw, Thomas, Pj, Vemulapalli, M, and Young, Ac.
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0301 basic medicine ,Hemeproteins ,Linkage disequilibrium ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Quantitative trait locus ,Melanocyte ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,03 medical and health sciences ,Heme-Binding Proteins ,0302 clinical medicine ,Genetics ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Genetic Predisposition to Disease ,Melanoma ,Genetics (clinical) ,Cells, Cultured ,Genetic association ,Research ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Expression quantitative trait loci ,Interferon Regulatory Factors ,Melanocytes ,Carrier Proteins - Abstract
Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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- 2018
5. Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot
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Sapp, JC, Johnston, JJ, Driscoll, K, Heidlebaugh, AR, Miren Sagardia, A, Dogbe, DN, Umstead, KL, Turbitt, E, Alevizos, I, Baron, J, Bönnemann, C, Brooks, B, Donkervoort, S, Jee, YH, Linehan, WM, McMahon, FJ, Moss, J, Mullikin, JC, Nielsen, D, Pelayo, E, Remaley, AT, Siegel, R, Su, H, Zarate, C, Barnabas, BB, Bouffard, GG, Brooks, SY, Coleman, H, Dekhtyar, L, Guan, X, Han, J, Ho, SL, Legaspi, R, Maduro, QL, Masiello, CA, McDowell, JC, Montemayor, C, Park, M, Riebow, NL, Schandler, K, Scharer, C, Schmidt, B, Sison, C, Stantripop, S, Thomas, JW, Thomas, PJ, Vemulapalli, M, Young, AC, Manolio, TA, Biesecker, BB, Biesecker, LG, Sapp, JC, Johnston, JJ, Driscoll, K, Heidlebaugh, AR, Miren Sagardia, A, Dogbe, DN, Umstead, KL, Turbitt, E, Alevizos, I, Baron, J, Bönnemann, C, Brooks, B, Donkervoort, S, Jee, YH, Linehan, WM, McMahon, FJ, Moss, J, Mullikin, JC, Nielsen, D, Pelayo, E, Remaley, AT, Siegel, R, Su, H, Zarate, C, Barnabas, BB, Bouffard, GG, Brooks, SY, Coleman, H, Dekhtyar, L, Guan, X, Han, J, Ho, SL, Legaspi, R, Maduro, QL, Masiello, CA, McDowell, JC, Montemayor, C, Park, M, Riebow, NL, Schandler, K, Scharer, C, Schmidt, B, Sison, C, Stantripop, S, Thomas, JW, Thomas, PJ, Vemulapalli, M, Young, AC, Manolio, TA, Biesecker, BB, and Biesecker, LG
- Abstract
© 2018 While consensus regarding the return of secondary genomic findings in the clinical setting has been reached, debate about such findings in the research setting remains. We developed a hybrid, research-clinical translational genomics process for research exome data coupled with a CLIA-validated secondary findings analysis. Eleven intramural investigators from ten institutes at the National Institutes of Health piloted this process. Nearly 1,200 individuals were sequenced and 14 secondary findings were identified in 18 participants. Positive secondary findings were returned by a genetic counselor following a standardized protocol, including referrals for specialty follow-up care for the secondary finding local to the participants. Interviews were undertaken with 13 participants 4 months after receipt of a positive report. These participants reported minimal psychologic distress within a process to assimilate their results. Of the 13, 9 reported accessing the recommended health care services. A sample of 107 participants who received a negative findings report were surveyed 4 months after receiving it. They demonstrated good understanding of the negative secondary findings result and most expressed reassurance (64%) from that report. However, a notable minority (up to 17%) expressed confusion regarding the distinction of primary from secondary findings. This pilot shows it is feasible to couple CLIA-compliant secondary findings to research sequencing with minimal harms. Participants managed the surprise of a secondary finding with most following recommended follow up, yet some with negative findings conflated secondary and primary findings. Additional work is needed to understand barriers to follow-up care and help participants distinguish secondary from primary findings.
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- 2018
6. Initial sequencing and analysis of the human genome
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Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC, Baldwin, J, Devon, K, Dewar, K, Doyle, M, FitzHugh, W, Funke, R, Gage, D, Harris, K, Heaford, A, Howland, J, Kann, L, Lehoczky, J, LeVine, R, McEwan, P, McKernan, K, Meldrim, J, Mesirov, JP, Miranda, C, Morris, W, Naylor, J, Raymond, C, Rosetti, M, Santos, R, Sheridan, A, Sougnez, C, Stange-Thomann, N, Stojanovic, N, Subramanian, A, Wyman, D, Rogers, J, Sulston, J, Ainscough, R, Beck, S, Bentley, D, Burton, J, Clee, C, Carter, N, Coulson, A, Deadman, R, Deloukas, P, Dunham, A, Dunham, I, Durbin, R, French, L, Grafham, D, Gregory, S, Hubbard, T, Humphray, S, Hunt, A, Jones, M, Lloyd, C, McMurray, A, Matthews, L, Mercer, S, Milne, S, Mullikin, JC, Mungall, A, Plumb, R, Ross, M, Shownkeen, R, Sims, S, Waterston, RH, Wilson, RK, Hillier, LW, McPherson, JD, Marra, MA, Mardis, ER, Fulton, LA, Chinwalla, AT, Pepin, KH, Gish, WR, Chissoe, SL, Wendl, MC, Delehaunty, KD, Miner, TL, Delehaunty, A, Kramer, JB, Cook, LL, Fulton, RS, Johnson, DL, Minx, PJ, Clifton, SW, Hawkins, T, Branscomb, E, Predki, P, Richardson, P, Wenning, S, Slezak, T, Doggett, N, Cheng, JF, Olsen, A, Lucas, S, Elkin, C, Uberbacher, E, Frazier, M, Gibbs, RA, Muzny, DM, Scherer, SE, Bouck, JB, Sodergren, EJ, Worley, KC, Rives, CM, Gorrell, JH, Metzker, ML, Naylor, SL, Kucherlapati, RS, Nelson, DL, Weinstock, GM, Sakaki, Y, Fujiyama, A, Hattori, M, Yada, T, Toyoda, A, Itoh, T, Kawagoe, C, Watanabe, H, Totoki, Y, Taylor, T, Weissenbach, J, Heilig, R, Saurin, W, Artiguenave, F, Brottier, P, Bruls, T, Pelletier, E, Robert, C, Wincker, P, Smith, DR, Doucette-Stamm, L, Rubenfield, M, Weinstock, K, Lee, HM, Dubois, J, Rosenthal, A, Platzer, M, Nyakatura, G, Taudien, S, Rump, A, Yang, H, Yu, J, Wang, J, Huang, G, Gu, J, Hood, L, Rowen, L, Madan, A, Qin, S, Davis, RW, Federspiel, NA, Abola, AP, Proctor, MJ, Myers, RM, Schmutz, J, Dickson, M, Grimwood, J, Cox, DR, Olson, MV, Kaul, R, Shimizu, N, Kawasaki, K, Minoshima, S, Evans, GA, Athanasiou, M, Schultz, R, Roe, BA, Chen, F, Pan, H, Ramser, J, Lehrach, H, Reinhardt, R, McCombie, WR, de la Bastide, M, Dedhia, N, Blöcker, H, Hornischer, K, Nordsiek, G, Agarwala, R, Aravind, L, Bailey, JA, Bateman, A, Batzoglou, S, Birney, E, Bork, P, Brown, DG, Burge, CB, Cerutti, L, Chen, HC, Church, D, Clamp, M, Copley, RR, Doerks, T, Eddy, SR, Eichler, EE, Furey, TS, Galagan, J, Gilbert, JG, Harmon, C, Hayashizaki, Y, Haussler, D, Hermjakob, H, Hokamp, K, Jang, W, Johnson, LS, Jones, TA, Kasif, S, Kaspryzk, A, Kennedy, S, Kent, WJ, Kitts, P, Koonin, EV, Korf, I, Kulp, D, Lancet, D, Lowe, TM, McLysaght, A, Mikkelsen, T, Moran, JV, Mulder, N, Pollara, VJ, Ponting, CP, Schuler, G, Schultz, J, Slater, G, Smit, AF, Stupka, E, Szustakowski, J, Thierry-Mieg, D, Thierry-Mieg, J, Wagner, L, Wallis, J, Wheeler, R, Williams, A, Wolf, YI, Wolfe, KH, Yang, SP, Yeh, RF, Collins, F, Guyer, MS, Peterson, J, Felsenfeld, A, Wetterstrand, KA, Patrinos, A, Morgan, MJ, de Jong, P, Catanese, JJ, Osoegawa, K, Shizuya, H, Choi, S, Chen, YJ, and Szustakowki, J
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Genetics ,Cancer genome sequencing ,Chimpanzee genome project ,Multidisciplinary ,Cancer Genome Project ,Gene density ,DNA sequencing theory ,Hybrid genome assembly ,Computational biology ,Biology ,Genome ,Personal genomics - Abstract
The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
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- 2016
7. A second generation human haplotype map of over 3.1 million SNPs
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Frazer, KA, Ballinger, DG, Cox, DR, Hinds, DA, Stuve, LL, Gibbs, RA, Belmont, JW, Boudreau, A, Hardenbol, P, Leal, SM, Pasternak, S, Wheeler, DA, Willis, TD, Yu, F, Yang, H, Zeng, C, Gao, Y, Hu, H, Hu, W, Li, C, Lin, W, Liu, S, Pan, H, Tang, X, Wang, J, Wang, W, Yu, J, Zhang, B, Zhang, Q, Zhao, H, Zhou, J, Gabriel, SB, Barry, R, Blumenstiel, B, Camargo, A, Defelice, M, Faggart, M, Goyette, M, Gupta, S, Moore, J, Nguyen, H, Onofrio, RC, Parkin, M, Roy, J, Stahl, E, Winchester, E, Ziaugra, L, Altshuler, D, Shen, Y, Yao, Z, Huang, W, Chu, X, He, Y, Jin, L, Liu, Y, Sun, W, Wang, H, Wang, Y, Xiong, X, Xu, L, Waye, MM, Tsui, SK, Xue, H, Wong, JT, Galver, LM, Fan, JB, Gunderson, K, Murray, SS, Oliphant, AR, Chee, MS, Montpetit, A, Chagnon, F, Ferretti, V, Leboeuf, M, Olivier, JF, Phillips, MS, Roumy, S, Sallée, C, Verner, A, Hudson, TJ, Kwok, PY, Cai, D, Koboldt, DC, Miller, RD, Pawlikowska, L, Taillon-Miller, P, Xiao, M, Tsui, LC, Mak, W, Song, YQ, Tam, PK, Nakamura, Y, Kawaguchi, T, Kitamoto, T, Morizono, T, Nagashima, A, Ohnishi, Y, Sekine, A, Tanaka, T, Tsunoda, T, Deloukas, P, Bird, CP, Delgado, M, Dermitzakis, ET, Gwilliam, R, Hunt, S, Morrison, J, Powell, D, Stranger, BE, Whittaker, P, Bentley, DR, Daly, MJ, de Bakker, PI, Barrett, J, Chretien, YR, Maller, J, McCarroll, S, Patterson, N, Pe'er, I, Price, A, Purcell, S, Richter, DJ, Sabeti, P, Saxena, R, Schaffner, SF, Sham, PC, Varilly, P, Stein, LD, Krishnan, L, Smith, AV, Tello-Ruiz, MK, Thorisson, GA, Chakravarti, A, Chen, PE, Cutler, DJ, Kashuk, CS, Lin, S, Abecasis, GR, Guan, W, Li, Y, Munro, HM, Qin, ZS, Thomas, DJ, McVean, G, Auton, A, Bottolo, L, Cardin, N, Eyheramendy, S, Freeman, C, Marchini, J, Myers, S, Spencer, C, Stephens, M, Donnelly, P, Cardon, LR, Clarke, G, Evans, DM, Morris, AP, Weir, BS, Mullikin, JC, Sherry, ST, Feolo, M, Skol, A, Zhang, H, Matsuda, I, Fukushima, Y, Macer, DR, Suda, E, Rotimi, CN, Adebamowo, CA, Ajayi, I, Aniagwu, T, Marshall, PA, Nkwodimmah, C, Royal, CD, Leppert, MF, Dixon, M, Peiffer, A, Qiu, R, Kent, A, Kato, K, Niikawa, N, Adewole, IF, Knoppers, BM, Foster, MW, Clayton, EW, Watkin, J, Muzny, D, Nazareth, L, Sodergren, E, Weinstock, GM, Yakub, I, Birren, BW, Wilson, RK, Fulton, LL, Rogers, J, Burton, J, Carter, NP, Clee, CM, Griffiths, M, Jones, MC, McLay, K, Plumb, RW, Ross, MT, Sims, SK, Willey, DL, Chen, Z, Han, H, Kang, L, Godbout, M, Wallenburg, JC, L'Archevêque, P, Bellemare, G, Saeki, K, An, D, Fu, H, Li, Q, Wang, Z, Wang, R, Holden, AL, Brooks, LD, McEwen, JE, Guyer, MS, Wang, VO, Peterson, JL, Shi, M, Spiegel, J, Sung, LM, Zacharia, LF, Collins, FS, Kennedy, K, Jamieson, R, and Stewart, J
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Male ,Recombination, Genetic ,Genetics ,Linkage disequilibrium ,education.field_of_study ,Multidisciplinary ,Homozygote ,Racial Groups ,Haplotype ,Population ,Single-nucleotide polymorphism ,Tag SNP ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Article ,Haplotypes ,Humans ,Female ,Selection, Genetic ,International HapMap Project ,education ,Imputation (genetics) ,Genetic association - Abstract
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r 2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r 2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. ©2007 Nature Publishing Group., link_to_OA_fulltext
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- 2016
8. The cnidarian Hydractinia echinata employs canonical and highly adapted histones to pack its DNA
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Torok, A, Schiffer, PH, Schnitzler, CE, Ford, K, Mullikin, JC, Baxevanis, AD, Bacic, A, Frank, U, Gornik, SG, Torok, A, Schiffer, PH, Schnitzler, CE, Ford, K, Mullikin, JC, Baxevanis, AD, Bacic, A, Frank, U, and Gornik, SG
- Abstract
BACKGROUND: Cnidarians are a group of early branching animals including corals, jellyfish and hydroids that are renowned for their high regenerative ability, growth plasticity and longevity. Because cnidarian genomes are conventional in terms of protein-coding genes, their remarkable features are likely a consequence of epigenetic regulation. To facilitate epigenetics research in cnidarians, we analysed the histone complement of the cnidarian model organism Hydractinia echinata using phylogenomics, proteomics, transcriptomics and mRNA in situ hybridisations. RESULTS: We find that the Hydractinia genome encodes 19 histones and analyse their spatial expression patterns, genomic loci and replication-dependency. Alongside core and other replication-independent histone variants, we find several histone replication-dependent variants, including a rare replication-dependent H3.3, a female germ cell-specific H2A.X and an unusual set of five H2B variants, four of which are male germ cell-specific. We further confirm the absence of protamines in Hydractinia. CONCLUSIONS: Since no protamines are found in hydroids, we suggest that the novel H2B variants are pivotal for sperm DNA packaging in this class of Cnidaria. This study adds to the limited number of full histone gene complements available in animals and sets a comprehensive framework for future studies on the role of histones and their post-translational modifications in cnidarian epigenetics. Finally, it provides insight into the evolution of spermatogenesis.
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- 2016
9. Genome-wide detection and characterization of positive selection in human populations
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Sabeti, PC, Varilly, P, Fry, B, Lohmueller, J, Hostetter, E, Cotsapas, C, Xie, X, Byrne, EH, McCarroll, SA, Gaudet, R, Schaffner, SF, Lander, ES, Frazer, KA, Ballinger, DG, Cox, DR, Hinds, DA, Stuve, LL, Gibbs, RA, Belmont, JW, Boudreau, A, Hardenbol, P, Leal, SM, Pasternak, S, Wheeler, DA, Willis, TD, Yu, F, Yang, H, Zeng, C, Gao, Y, Hu, H, Hu, W, Li, C, Lin, W, Liu, S, Pan, H, Tang, X, Wang, J, Wang, W, Yu, J, Zhang, B, Zhang, Q, Zhao, H, Zhou, J, Gabriel, SB, Barry, R, Blumenstiel, B, Camargo, A, Defelice, M, Faggart, M, Goyette, M, Gupta, S, Moore, J, Nguyen, H, Onofrio, RC, Parkin, M, Roy, J, Stahl, E, Winchester, E, Ziaugra, L, Altshuler, D, Shen, Y, Yao, Z, Huang, W, Chu, X, He, Y, Jin, L, Liu, Y, Sun, W, Wang, H, Wang, Y, Xiong, X, Xu, L, Waye, MM, Tsui, SK, Xue, H, Wong, JT, Galver, LM, Fan, JB, Gunderson, K, Murray, SS, Oliphant, AR, Chee, MS, Montpetit, A, Chagnon, F, Ferretti, V, Leboeuf, M, Olivier, JF, Phillips, MS, Roumy, S, Sallée, C, Verner, A, Hudson, TJ, Kwok, PY, Cai, D, Koboldt, DC, Miller, RD, Pawlikowska, L, Taillon-Miller, P, Xiao, M, Tsui, LC, Mak, W, Song, YQ, Tam, PK, Nakamura, Y, Kawaguchi, T, Kitamoto, T, Morizono, T, Nagashima, A, Ohnishi, Y, Sekine, A, Tanaka, T, Tsunoda, T, Deloukas, P, Bird, CP, Delgado, M, Dermitzakis, ET, Gwilliam, R, Hunt, S, Morrison, J, Powell, D, Stranger, BE, Whittaker, P, Bentley, DR, Daly, MJ, de Bakker, PI, Barrett, J, Chretien, YR, Maller, J, McCarroll, S, Patterson, N, Pe'er, I, Price, A, Purcell, S, Richter, DJ, Sabeti, P, Saxena, R, Sham, PC, Stein, LD, Krishnan, L, Smith, AV, Tello-Ruiz, MK, Thorisson, GA, Chakravarti, A, Chen, PE, Cutler, DJ, Kashuk, CS, Lin, S, Abecasis, GR, Guan, W, Li, Y, Munro, HM, Qin, ZS, Thomas, DJ, McVean, G, Auton, A, Bottolo, L, Cardin, N, Eyheramendy, S, Freeman, C, Marchini, J, Myers, S, Spencer, C, Stephens, M, Donnelly, P, Cardon, LR, Clarke, G, Evans, DM, Morris, AP, Weir, BS, Johnson, TA, Mullikin, JC, Sherry, ST, Feolo, M, Skol, A, Zhang, H, Matsuda, I, Fukushima, Y, Macer, DR, Suda, E, Rotimi, CN, Adebamowo, CA, Ajayi, I, Aniagwu, T, Marshall, PA, Nkwodimmah, C, Royal, CD, Leppert, MF, Dixon, M, Peiffer, A, Qiu, R, Kent, A, Kato, K, Niikawa, N, Adewole, IF, Knoppers, BM, Foster, MW, Clayton, EW, Watkin, J, Muzny, D, Nazareth, L, Sodergren, E, Weinstock, GM, Yakub, I, Birren, BW, Wilson, RK, Fulton, LL, Rogers, J, Burton, J, Carter, NP, Clee, CM, Griffiths, M, Jones, MC, McLay, K, Plumb, RW, Ross, MT, Sims, SK, Willey, DL, Chen, Z, Han, H, Kang, L, Godbout, M, Wallenburg, JC, L'Archevêque, P, Bellemare, G, Saeki, K, An, D, Fu, H, Li, Q, Wang, Z, Wang, R, Holden, AL, Brooks, LD, McEwen, JE, Guyer, MS, Wang, VO, Peterson, JL, Shi, M, Spiegel, J, Sung, LM, Zacharia, LF, Collins, FS, Kennedy, K, Jamieson, R, and Stewart, J
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Models, Molecular ,Population ,Single-nucleotide polymorphism ,Human genetic variation ,Biology ,Polymorphism, Single Nucleotide ,Article ,Antiporters ,Gene Frequency ,Humans ,International HapMap Project ,Selection, Genetic ,education ,Selection (genetic algorithm) ,Genetics ,education.field_of_study ,Multidisciplinary ,Natural selection ,Geography ,Edar Receptor ,Genome, Human ,Haplotype ,Regional Index: Eurasia ,Protein Structure, Tertiary ,Europe ,Genetics, Population ,Haplotypes ,Human genome - Abstract
With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia. ©2007 Nature Publishing Group., link_to_OA_fulltext
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- 2007
10. Functional constraint and small insertions and deletions in the ENCODE regions of the human genome
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Clark, TG, Andrew, T, Cooper, GM, Margulies, EH, Mullikin, JC, Balding, DJ, Clark, TG, Andrew, T, Cooper, GM, Margulies, EH, Mullikin, JC, and Balding, DJ
- Abstract
BACKGROUND: We describe the distribution of indels in the 44 Encyclopedia of DNA Elements (ENCODE) regions (about 1% of the human genome) and evaluate the potential contributions of small insertion and deletion polymorphisms (indels) to human genetic variation. We relate indels to known genomic annotation features and measures of evolutionary constraint. RESULTS: Indel rates are observed to be reduced approximately 20-fold to 60-fold in exonic regions, 5-fold to 10-fold in sequence that exhibits high evolutionary constraint in mammals, and up to 2-fold in some classes of regulatory elements (for instance, formaldehyde assisted isolation of regulatory elements [FAIRE] and hypersensitive sites). In addition, some noncoding transcription and other chromatin mediated regulatory sites also have reduced indel rates. Overall indel rates for these data are estimated to be smaller than single nucleotide polymorphism (SNP) rates by a factor of approximately 2, with both rates measured as base pairs per 100 kilobases to facilitate comparison. CONCLUSION: Indel rates exhibit a broadly similar distribution across genomic features compared with SNP density rates, with a reduction in rates in coding transcription and evolutionarily constrained sequence. However, unlike indels, SNP rates do not appear to be reduced in some noncoding functional sequences, such as pseudo-exons, and FAIRE and hypersensitive sites. We conclude that indel rates are greatly reduced in transcribed and evolutionarily constrained DNA, and discuss why indel (but not SNP) rates appear to be constrained at some regulatory sites.
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- 2007
11. Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis.
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Pierson TM, Adams DA, Markello T, Golas G, Yang S, Sincan M, Simeonov DR, Fuentes Fajardo K, Hansen NF, Cherukuri PF, Cruz P, Teer JK, Mullikin JC, Boerkoel CF, Gahl WA, Tifft CJ, NISC Comparative Sequencing Program, Pierson, Tyler Mark, Adams, David A, and Markello, Thomas
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- 2012
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12. Familial kyphoscoliosis: association with the IRX homeobox gene family.
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Miller NH, Justice CM, Cruz PD, Maskeri B, Mullikin JC, Swindle K, Wilson AF, Aubin C, Stokes IAF, Labelle H, and Moreau A
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- 2010
13. The genome of the colonial hydroid Hydractinia reveals that their stem cells use a toolkit of evolutionarily shared genes with all animals.
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Schnitzler CE, Chang ES, Waletich J, Quiroga-Artigas G, Wong WY, Nguyen AD, Barreira SN, Doonan LB, Gonzalez P, Koren S, Gahan JM, Sanders SM, Bradshaw B, DuBuc TQ, Febrimarsa, de Jong D, Nawrocki EP, Larson A, Klasfeld S, Gornik SG, Moreland RT, Wolfsberg TG, Phillippy AM, Mullikin JC, Simakov O, Cartwright P, Nicotra M, Frank U, and Baxevanis AD
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- Animals, Evolution, Molecular, Transcriptome, Stem Cells metabolism, Male, Phylogeny, Single-Cell Analysis methods, Hydrozoa genetics, Genome
- Abstract
Hydractinia is a colonial marine hydroid that shows remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, Hydractinia symbiolongicarpus and Hydractinia echinata , placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell-type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia 's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia 's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from nonself., (© 2024 Schnitzler et al.; Published by Cold Spring Harbor Laboratory Press.)
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- 2024
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14. Random forest classifiers trained on simulated data enable accurate short read-based genotyping of structural variants in the alpha globin region at Chr16p13.3.
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Hansen NF, Wang X, Tegegn MB, Liu Z, Gouveia MH, Hill G, Lin JC, Okulosubo T, Shriner D, Thein SL, and Mullikin JC
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In regions where reads don't align well to a reference, it is generally difficult to characterize structural variation using short read sequencing. Here, we utilize machine learning classifiers and short sequence reads to genotype structural variants in the alpha globin locus on chromosome 16, a medically-relevant region that is challenging to genotype in individuals. Using models trained only with simulated data, we accurately genotype two hard-to-distinguish deletions in two separate human cohorts. Furthermore, population allele frequencies produced by our methods across a wide set of ancestries agree more closely with previously-determined frequencies than those obtained using currently available genotyping software., Competing Interests: Competing interests The authors declare that they have no competing interests.
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- 2023
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15. The genome of the colonial hydroid Hydractinia reveals their stem cells utilize a toolkit of evolutionarily shared genes with all animals.
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Schnitzler CE, Chang ES, Waletich J, Quiroga-Artigas G, Wong WY, Nguyen AD, Barreira SN, Doonan L, Gonzalez P, Koren S, Gahan JM, Sanders SM, Bradshaw B, DuBuc TQ, Febrimarsa, de Jong D, Nawrocki EP, Larson A, Klasfeld S, Gornik SG, Moreland RT, Wolfsberg TG, Phillippy AM, Mullikin JC, Simakov O, Cartwright P, Nicotra M, Frank U, and Baxevanis AD
- Abstract
Hydractinia is a colonial marine hydroid that exhibits remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, H. symbiolongicarpus and H. echinata , placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia 's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia 's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from non-self., Competing Interests: Competing interests: The authors declare no competing financial interests.
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- 2023
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16. Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.
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Sok P, Sabo A, Almli LM, Jenkins MM, Nembhard WN, Agopian AJ, Bamshad MJ, Blue EE, Brody LC, Brown AL, Browne ML, Canfield MA, Carmichael SL, Chong JX, Dugan-Perez S, Feldkamp ML, Finnell RH, Gibbs RA, Kay DM, Lei Y, Meng Q, Moore CA, Mullikin JC, Muzny D, Olshan AF, Pangilinan F, Reefhuis J, Romitti PA, Schraw JM, Shaw GM, Werler MM, Harpavat S, and Lupo PJ
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- Humans, Exome genetics, Homozygote, Parents, Case-Control Studies, Membrane Proteins genetics, Biliary Atresia epidemiology, Biliary Atresia genetics, Biliary Atresia diagnosis
- Abstract
The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex., (© 2023 Wiley Periodicals LLC.)
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- 2023
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17. A family of unusual immunoglobulin superfamily genes in an invertebrate histocompatibility complex.
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Huene AL, Sanders SM, Ma Z, Nguyen AD, Koren S, Michaca MH, Mullikin JC, Phillippy AM, Schnitzler CE, Baxevanis AD, and Nicotra ML
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- Animals, Membrane Proteins chemistry, Membrane Proteins genetics, Protein Domains, Tyrosine chemistry, Tyrosine genetics, Hydrozoa genetics, Hydrozoa immunology, Immunoglobulins chemistry, Immunoglobulins genetics, Major Histocompatibility Complex genetics
- Abstract
Most colonial marine invertebrates are capable of allorecognition, the ability to distinguish between themselves and conspecifics. One long-standing question is whether invertebrate allorecognition genes are homologous to vertebrate histocompatibility genes. In the cnidarian Hydractinia symbiolongicarpus, allorecognition is controlled by at least two genes, Allorecognition 1 ( Alr1 ) and Allorecognition 2 ( Alr2 ), which encode highly polymorphic cell-surface proteins that serve as markers of self. Here, we show that Alr1 and Alr2 are part of a family of 41 Alr genes, all of which reside in a single genomic interval called the Allorecognition Complex (ARC). Using sensitive homology searches and highly accurate structural predictions, we demonstrate that the Alr proteins are members of the immunoglobulin superfamily (IgSF) with V-set and I-set Ig domains unlike any previously identified in animals. Specifically, their primary amino acid sequences lack many of the motifs considered diagnostic for V-set and I-set domains, yet they adopt secondary and tertiary structures nearly identical to canonical Ig domains. Thus, the V-set domain, which played a central role in the evolution of vertebrate adaptive immunity, was present in the last common ancestor of cnidarians and bilaterians. Unexpectedly, several Alr proteins also have immunoreceptor tyrosine-based activation motifs and immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails, suggesting they could participate in pathways homologous to those that regulate immunity in humans and flies. This work expands our definition of the IgSF with the addition of a family of unusual members, several of which play a role in invertebrate histocompatibility.
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- 2022
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18. Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.
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Li J, Yang W, Wang YJ, Ma C, Curry CJ, McGoldrick D, Nickerson DA, Chong JX, Blue EE, Mullikin JC, Reefhuis J, Nembhard WN, Romitti PA, Werler MM, Browne ML, Olshan AF, Finnell RH, Feldkamp ML, Pangilinan F, Almli LM, Bamshad MJ, Brody LC, Jenkins MM, and Shaw GM
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- Exome genetics, Humans, Infant, Mutation, Missense genetics, Exome Sequencing, Anophthalmos epidemiology, Microphthalmos epidemiology, Microphthalmos genetics
- Abstract
Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease., (© 2022 Wiley Periodicals LLC.)
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- 2022
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19. The complete sequence of a human genome.
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Nurk S, Koren S, Rhie A, Rautiainen M, Bzikadze AV, Mikheenko A, Vollger MR, Altemose N, Uralsky L, Gershman A, Aganezov S, Hoyt SJ, Diekhans M, Logsdon GA, Alonge M, Antonarakis SE, Borchers M, Bouffard GG, Brooks SY, Caldas GV, Chen NC, Cheng H, Chin CS, Chow W, de Lima LG, Dishuck PC, Durbin R, Dvorkina T, Fiddes IT, Formenti G, Fulton RS, Fungtammasan A, Garrison E, Grady PGS, Graves-Lindsay TA, Hall IM, Hansen NF, Hartley GA, Haukness M, Howe K, Hunkapiller MW, Jain C, Jain M, Jarvis ED, Kerpedjiev P, Kirsche M, Kolmogorov M, Korlach J, Kremitzki M, Li H, Maduro VV, Marschall T, McCartney AM, McDaniel J, Miller DE, Mullikin JC, Myers EW, Olson ND, Paten B, Peluso P, Pevzner PA, Porubsky D, Potapova T, Rogaev EI, Rosenfeld JA, Salzberg SL, Schneider VA, Sedlazeck FJ, Shafin K, Shew CJ, Shumate A, Sims Y, Smit AFA, Soto DC, Sović I, Storer JM, Streets A, Sullivan BA, Thibaud-Nissen F, Torrance J, Wagner J, Walenz BP, Wenger A, Wood JMD, Xiao C, Yan SM, Young AC, Zarate S, Surti U, McCoy RC, Dennis MY, Alexandrov IA, Gerton JL, O'Neill RJ, Timp W, Zook JM, Schatz MC, Eichler EE, Miga KH, and Phillippy AM
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- Cell Line, Chromosomes, Artificial, Bacterial genetics, Chromosomes, Human genetics, Humans, Reference Values, Genome, Human, Human Genome Project, Sequence Analysis, DNA standards
- Abstract
Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.
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- 2022
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20. Exome sequencing identifies variants in infants with sacral agenesis.
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Pitsava G, Feldkamp ML, Pankratz N, Lane J, Kay DM, Conway KM, Hobbs C, Shaw GM, Reefhuis J, Jenkins MM, Almli LM, Moore C, Werler M, Browne ML, Cunniff C, Olshan AF, Pangilinan F, Brody LC, Sicko RJ, Finnell RH, Bamshad MJ, McGoldrick D, Nickerson DA, Mullikin JC, Romitti PA, and Mills JL
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- Exome genetics, Humans, Infant, Sacrococcygeal Region abnormalities, Abnormalities, Multiple genetics, Meningocele
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Background: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA., Methods: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced., Results: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children., Conclusions: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies., (© 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
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- 2022
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21. KLF3 and PAX6 are candidate driver genes in late-stage, MSI-hypermutated endometrioid endometrial carcinomas.
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Rudd ML, Hansen NF, Zhang X, Urick ME, Zhang S, Merino MJ, Mullikin JC, Brody LC, and Bell DW
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- Cohort Studies, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Exome, Female, Humans, Microsatellite Instability, Middle Aged, Mutation, Uterine Neoplasms genetics, Uterine Neoplasms pathology, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid pathology, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, PAX6 Transcription Factor genetics, PAX6 Transcription Factor metabolism
- Abstract
Endometrioid endometrial carcinomas (EECs) are the most common histological subtype of uterine cancer. Late-stage disease is an adverse prognosticator for EEC. The purpose of this study was to analyze EEC exome mutation data to identify late-stage-specific statistically significantly mutated genes (SMGs), which represent candidate driver genes potentially associated with disease progression. We exome sequenced 15 late-stage (stage III or IV) non-ultramutated EECs and paired non-tumor DNAs; somatic variants were called using Strelka, Shimmer, SomaticSniper and MuTect. Additionally, somatic mutation calls were extracted from The Cancer Genome Atlas (TCGA) data for 66 late-stage and 270 early-stage (stage I or II) non-ultramutated EECs. MutSigCV (v1.4) was used to annotate SMGs in the two late-stage cohorts and to derive p-values for all mutated genes in the early-stage cohort. To test whether late-stage SMGs are statistically significantly mutated in early-stage tumors, q-values for late-stage SMGs were re-calculated from the MutSigCV (v1.4) early-stage p-values, adjusting for the number of late-stage SMGs tested. We identified 14 SMGs in the combined late-stage EEC cohorts. When the 14 late-stage SMGs were examined in the TCGA early-stage data, only Krüppel-like factor 3 (KLF3) and Paired box 6 (PAX6) failed to reach significance as early-stage SMGs, despite the inclusion of enough early-stage cases to ensure adequate statistical power. Within TCGA, nonsynonymous mutations in KLF3 and PAX6 were, respectively, exclusive or nearly exclusive to the microsatellite instability (MSI)-hypermutated molecular subgroup and were dominated by insertions-deletions at homopolymer tracts. In conclusion, our findings are hypothesis-generating and suggest that KLF3 and PAX6, which encode transcription factors, are MSI target genes and late-stage-specific SMGs in EEC., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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22. Clinical and genomic analysis of a large Chinese family with familial cortical myoclonic tremor with epilepsy and SAMD12 intronic repeat expansion.
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Zhou Y, Sood R, Wang Q, Carrington B, Park M, Young AC, Birnbaum D, Liu Z, Ashizawa T, Mullikin JC, Koubeissi MZ, and Liu P
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- Adult, Anticonvulsants therapeutic use, Carbamazepine therapeutic use, China, Electroencephalography, Epilepsies, Myoclonic drug therapy, Epileptic Syndromes, Female, Humans, Introns, Magnetic Resonance Imaging, Male, Middle Aged, Phenotype, Exome Sequencing, DNA Repeat Expansion, Epilepsies, Myoclonic genetics, Genomics, Nerve Tissue Proteins genetics, Pedigree, Tremor genetics
- Abstract
Objective: Our goal was to perform detailed clinical and genomic analysis of a large multigenerational Chinese family with 21 individuals showing symptoms of Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE) that we have followed for over 20 years., Methods: Patients were subjected to clinical evaluation, routine EEG, and structural magnetic resonance imaging. Whole exome sequencing, repeat-primed PCR, long-range PCR, and PacBio sequencing were performed to characterize the disease-causing mutation in this family., Results: All evaluated patients manifested adult-onset seizures and presented with progressive myoclonic postural tremors starting after the third or fourth decade of life. Seizures typically diminished markedly in frequency with implementation of antiseizure medications but did not completely cease. The electroencephalogram of affected individuals showed generalized or multifocal spikes and slow wave complexes. An expansion of TTTTA motifs with addition of TTTCA motifs in intron 4 of SAMD12 was identified to segregate with the disease phenotype in this family. Furthermore, we found that the mutant allele is unstable and can undergo both contraction and expansion by changes in the number of repeat motifs each time it is passed to the next generation. The size of mutant allele varied from 5 to 5.5 kb with 549-603 copies of TTTTA and 287-343 copies of TTTCA repeat motifs in this family., Significance: Our study provides a detailed description of clinical progression of FCMTE symptoms and its management with antiseizure medications. Our method of repeat analysis by PacBio sequencing of long-range PCR products does not require high-quality DNA and hence can be easily applied to other families to elucidate any correlation between the repeat size and phenotypic variables, such as, age of onset, and severity of symptoms., Competing Interests: None of the authors have any conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2021
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23. A robust benchmark for detection of germline large deletions and insertions.
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Zook JM, Hansen NF, Olson ND, Chapman L, Mullikin JC, Xiao C, Sherry S, Koren S, Phillippy AM, Boutros PC, Sahraeian SME, Huang V, Rouette A, Alexander N, Mason CE, Hajirasouliha I, Ricketts C, Lee J, Tearle R, Fiddes IT, Barrio AM, Wala J, Carroll A, Ghaffari N, Rodriguez OL, Bashir A, Jackman S, Farrell JJ, Wenger AM, Alkan C, Soylev A, Schatz MC, Garg S, Church G, Marschall T, Chen K, Fan X, English AC, Rosenfeld JA, Zhou W, Mills RE, Sage JM, Davis JR, Kaiser MD, Oliver JS, Catalano AP, Chaisson MJP, Spies N, Sedlazeck FJ, and Salit M
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- Diploidy, Genomic Structural Variation, Humans, Molecular Sequence Annotation, Sequence Analysis, DNA, Germ-Line Mutation genetics, INDEL Mutation genetics
- Abstract
New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping.
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- 2020
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24. Author Correction: A robust benchmark for detection of germline large deletions and insertions.
- Author
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Zook JM, Hansen NF, Olson ND, Chapman L, Mullikin JC, Xiao C, Sherry S, Koren S, Phillippy AM, Boutros PC, Sahraeian SME, Huang V, Rouette A, Alexander N, Mason CE, Hajirasouliha I, Ricketts C, Lee J, Tearle R, Fiddes IT, Barrio AM, Wala J, Carroll A, Ghaffari N, Rodriguez OL, Bashir A, Jackman S, Farrell JJ, Wenger AM, Alkan C, Soylev A, Schatz MC, Garg S, Church G, Marschall T, Chen K, Fan X, English AC, Rosenfeld JA, Zhou W, Mills RE, Sage JM, Davis JR, Kaiser MD, Oliver JS, Catalano AP, Chaisson MJP, Spies N, Sedlazeck FJ, and Salit M
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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25. Telomere-to-telomere assembly of a complete human X chromosome.
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Miga KH, Koren S, Rhie A, Vollger MR, Gershman A, Bzikadze A, Brooks S, Howe E, Porubsky D, Logsdon GA, Schneider VA, Potapova T, Wood J, Chow W, Armstrong J, Fredrickson J, Pak E, Tigyi K, Kremitzki M, Markovic C, Maduro V, Dutra A, Bouffard GG, Chang AM, Hansen NF, Wilfert AB, Thibaud-Nissen F, Schmitt AD, Belton JM, Selvaraj S, Dennis MY, Soto DC, Sahasrabudhe R, Kaya G, Quick J, Loman NJ, Holmes N, Loose M, Surti U, Risques RA, Graves Lindsay TA, Fulton R, Hall I, Paten B, Howe K, Timp W, Young A, Mullikin JC, Pevzner PA, Gerton JL, Sullivan BA, Eichler EE, and Phillippy AM
- Subjects
- Centromere genetics, CpG Islands genetics, DNA Methylation, DNA, Satellite genetics, Female, Humans, Hydatidiform Mole genetics, Male, Pregnancy, Reproducibility of Results, Testis metabolism, Chromosomes, Human, X genetics, Genome, Human genetics, Telomere genetics
- Abstract
After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist
1,2 . Here we present a human genome assembly that surpasses the continuity of GRCh382 , along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3 , we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.- Published
- 2020
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26. Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas.
- Author
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Pemov A, Dewan R, Hansen NF, Chandrasekharappa SC, Ray-Chaudhury A, Jones K, Luo W, Heiss JD, Mullikin JC, Chittiboina P, Stewart DR, and Asthagiri AR
- Subjects
- Adult, Gene Dosage, Genomics, Genotype, Humans, Longitudinal Studies, Male, Meningioma pathology, Mutation, Neurofibromatosis 2 pathology, Prospective Studies, Skull pathology, Spine pathology, Tumor Burden, Exome Sequencing, Young Adult, Meningioma genetics, Neurofibromatosis 2 genetics
- Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant Mendelian tumor predisposition disorder caused by germline pathogenic variants in the tumor suppressor NF2. Meningiomas are the second most common neoplasm in NF2, often occurring in multiple intracranial and spinal locations within the same patient. In this prospective longitudinal study, we assessed volumes and growth rates of ten spinal and ten cranial benign meningiomas in seven NF2 patients that concluded with surgical resection and performed whole-exome sequencing and copy-number variant (CNV) analysis of the tumors. Our comparison of the volume and the growth rate of NF2-associated spinal and cranial meningiomas point to the differences in timing of tumor initiation and/or to the differences in tumor progression (e.g., non-linear, saltatory growth) at these two anatomical locations. Genomic investigation of these tumors revealed that somatic inactivation of NF2 is the principal and perhaps the only driver of tumor initiation; and that tumor progression likely occurs via accumulation of CNVs, rather than point mutations. Results of this study contribute to a better understanding of NF2-associated meningiomas clinical behavior and their genetic underpinnings.
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- 2020
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27. Admixture mapping identifies genetic regions associated with blood pressure phenotypes in African Americans.
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Liu Z, Shriner D, Hansen NF, Rotimi CN, and Mullikin JC
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- Aged, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Phenotype, Black or African American genetics, Blood Pressure genetics, Chromosome Mapping methods, Genetic Loci, Polymorphism, Single Nucleotide, White People genetics
- Abstract
Hypertension occurs at a higher rate in African Americans than in European Americans. Based on the assumption that causal variants are more frequently found on DNA segments inherited from the ancestral population with higher disease risk, we employed admixture mapping to identify genetic loci with excess local African ancestry associated with blood pressure. Chromosomal regions 1q21.2-21.3, 4p15.1, 19q12 and 20p13 were significantly associated with diastolic blood pressure (β = 5.28, -7.94, -6.82 and 5.89, P-value = 6.39E-04, 2.07E-04, 6.56E-05 and 5.04E-04, respectively); 1q21.2-21.3 and 19q12 were also significantly associated with mean arterial pressure (β = 5.86 and -6.40, P-value = 5.32E-04 and 6.37E-04, respectively). We further selected SNPs that had large allele frequency differences within these regions and tested their association with blood pressure. SNP rs4815428 was significantly associated with diastolic blood pressure after Bonferroni correction (β = -2.42, P-value = 9.57E-04), and it partially explained the admixture mapping signal at 20p13. SNPs rs771205 (β = -1.99, P-value = 3.37E-03), rs3126067, rs2184953 and rs58001094 (the latter three exhibit strong linkage disequilibrium, β = -2.3, P-value = 1.4E-03) were identified to be significantly associated with mean arterial pressure, and together they fully explained the admixture signal at 1q21.2-21.3. Although no SNP at 4p15.1 showed large ancestral allele frequency differences in our dataset, we detected association at low-frequency African-specific variants that mapped predominantly to the gene PCDH7, which is most highly expressed in aorta. Our results suggest that these regions may harbor genetic variants that contribute to the different prevalence of hypertension., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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28. HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.
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Gourh P, Safran SA, Alexander T, Boyden SE, Morgan ND, Shah AA, Mayes MD, Doumatey A, Bentley AR, Shriner D, Domsic RT, Medsger TA Jr, Ramos PS, Silver RM, Steen VD, Varga J, Hsu V, Saketkoo LA, Schiopu E, Khanna D, Gordon JK, Kron B, Criswell LA, Gladue H, Derk CT, Bernstein EJ, Bridges SL Jr, Shanmugam VK, Kolstad KD, Chung L, Kafaja S, Jan R, Trojanowski M, Goldberg A, Korman BD, Steinbach PJ, Chandrasekharappa SC, Mullikin JC, Adeyemo A, Rotimi C, Wigley FM, Kastner DL, Boin F, and Remmers EF
- Subjects
- Black or African American genetics, Alleles, Amino Acid Sequence genetics, Antigens, Viral genetics, Antigens, Viral immunology, Autoantigens immunology, Computational Biology, Datasets as Topic, Female, Genetic Predisposition to Disease, HLA Antigens immunology, Humans, Male, Mimiviridae immunology, Phycodnaviridae immunology, Protein Structure, Secondary genetics, Risk Assessment, Scleroderma, Systemic epidemiology, Scleroderma, Systemic immunology, Sequence Homology, Amino Acid, White People genetics, Autoantibodies immunology, Autoantigens genetics, HLA Antigens genetics, Molecular Mimicry immunology, Scleroderma, Systemic genetics
- Abstract
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1 * 08:04 and HLA-DRB1 * 11:02 alleles were associated with overall SSc risk, and the HLA-DRB1 * 08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1 * 13:01 and HLA-DRB1 * 07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1 * 13:01 allele with the ATA
+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1 * 13:01 allele frequency in multiple populations was observed ( r = 0.98, P = 3 × 10-6 ). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc., Competing Interests: Competing interest statement: M.D.M. received consulting fees from Mitsubishi Tanabe, Astellas, Boehringer Ingelheim, Gerson Lehrman Group, Smart Analyst, and Guidepoint Global. R.T.D. received consulting fees from Eicos Sciences. D.K. received consulting fees from Actelion, Bristol-Myers Squibb, CSL Behring, Inventiva, EMD Merck-Serono, Sanofi-Aventis, GlaxoSmithKline, Corbus, Cytori, UCB, Bayer, Boehringer Ingelheim, and Genentech-Roche, and research support from Bayer, Bristol-Myers Squibb, and Pfizer, and owns stock or stock options in Eicos Sciences, Inc. (CiViBioPharma, Inc.). L.A.S. received consulting fees from Axon Pharma. H.G. received consulting fees from Pfizer, AbbVie, Actelion, and Horizon Pharmaceuticals. C.T.D. received research support from Gilead, Actelion, and Cytori. V.K.S. received research support from AbbVie. E.J.B. received consulting fees from Genentech. L.C. received consulting fees or served on the board of Reata, Bristol-Myers Squibb, Boehringer-Ingelheim, Eicos, and Mitsubishi Tanabe. S.L.B. and M.J.D. are coauthors on a 2015 research article., (Copyright © 2020 the Author(s). Published by PNAS.)- Published
- 2020
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29. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.
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Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, Zaal KJM, Hoffmann PM, Etemadi N, Shield-Artin K, Biben C, Tsai WL, Blake MD, Kuehn HS, Yang D, Anderton H, Silke N, Wachsmuth L, Zheng L, Moura NS, Beck DB, Gutierrez-Cruz G, Ombrello AK, Pinto-Patarroyo GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dmitrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters SL, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL, and Silke J
- Subjects
- Animals, Caspase 3 metabolism, Female, Hereditary Autoinflammatory Diseases genetics, Hereditary Autoinflammatory Diseases pathology, Humans, MAP Kinase Kinase Kinases genetics, MAP Kinase Kinase Kinases metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases deficiency, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Caspase 8 metabolism, Hereditary Autoinflammatory Diseases metabolism, Mutation, Receptor-Interacting Protein Serine-Threonine Kinases metabolism
- Abstract
RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage
1-7 . The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8 . Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.- Published
- 2020
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30. Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.
- Author
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Jenkins MM, Almli LM, Pangilinan F, Chong JX, Blue EE, Shapira SK, White J, McGoldrick D, Smith JD, Mullikin JC, Bean CJ, Nembhard WN, Lou XY, Shaw GM, Romitti PA, Keppler-Noreuil K, Yazdy MM, Kay DM, Carter TC, Olshan AF, Moore KJ, Nascone-Yoder N, Finnell RH, Lupo PJ, Feldkamp ML, Nickerson DA, Bamshad MJ, Brody LC, and Reefhuis J
- Subjects
- Family, Humans, Congenital Abnormalities genetics, Congenital Abnormalities prevention & control, Gene-Environment Interaction, Exome Sequencing
- Abstract
Background: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens., Methods: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA., Results: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol., Conclusions: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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31. Single Cell Sequencing of the Pineal Gland: The Next Chapter.
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Coon SL, Fu C, Hartley SW, Holtzclaw L, Mays JC, Kelly MC, Kelley MW, Mullikin JC, Rath MF, Savastano LE, and Klein DC
- Abstract
The analysis of pineal cell biology has undergone remarkable development as techniques have become available which allow for sequencing of entire transcriptomes and, most recently, the sequencing of the transcriptome of individual cells. Identification of at least nine distinct cell types in the rat pineal gland has been made possible, allowing identification of the precise cells of origin and expression of transcripts for the first time. Here the history and current state of knowledge generated by these transcriptomic efforts is reviewed, with emphasis on the insights suggested by the findings., (Copyright © 2019 Coon, Fu, Hartley, Holtzclaw, Mays, Kelly, Kelley, Mullikin, Rath, Savastano and Klein.)
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- 2019
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32. Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1-associated atypical neurofibromas.
- Author
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Pemov A, Hansen NF, Sindiri S, Patidar R, Higham CS, Dombi E, Miettinen MM, Fetsch P, Brems H, Chandrasekharappa SC, Jones K, Zhu B, Wei JS, Mullikin JC, Wallace MR, Khan J, Legius E, Widemann BC, and Stewart DR
- Subjects
- Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Humans, Mutation genetics, Transcription Factors, Nerve Sheath Neoplasms, Neurofibroma, Neurofibroma, Plexiform, Neurofibromatosis 1 genetics, Neurofibrosarcoma
- Abstract
Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation., Methods: In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs., Results: We identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only., Conclusions: The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.)
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- 2019
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33. Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.
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Kong R, Duan H, Sheng Z, Xu K, Acharya P, Chen X, Cheng C, Dingens AS, Gorman J, Sastry M, Shen CH, Zhang B, Zhou T, Chuang GY, Chao CW, Gu Y, Jafari AJ, Louder MK, O'Dell S, Rowshan AP, Viox EG, Wang Y, Choi CW, Corcoran MM, Corrigan AR, Dandey VP, Eng ET, Geng H, Foulds KE, Guo Y, Kwon YD, Lin B, Liu K, Mason RD, Nason MC, Ohr TY, Ou L, Rawi R, Sarfo EK, Schön A, Todd JP, Wang S, Wei H, Wu W, Mullikin JC, Bailer RT, Doria-Rose NA, Karlsson Hedestam GB, Scorpio DG, Overbaugh J, Bloom JD, Carragher B, Potter CS, Shapiro L, Kwong PD, and Mascola JR
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing classification, B-Lymphocytes cytology, B-Lymphocytes metabolism, Crystallography, X-Ray, Female, HEK293 Cells, HIV Antibodies chemistry, HIV Antibodies classification, HIV-1 metabolism, Humans, Macaca mulatta, Male, Peptides chemistry, Protein Structure, Tertiary, env Gene Products, Human Immunodeficiency Virus chemistry, env Gene Products, Human Immunodeficiency Virus immunology, env Gene Products, Human Immunodeficiency Virus metabolism, AIDS Vaccines immunology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, Peptides immunology
- Abstract
The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization., (Published by Elsevier Inc.)
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- 2019
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34. De novo assembly of the goldfish ( Carassius auratus ) genome and the evolution of genes after whole-genome duplication.
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Chen Z, Omori Y, Koren S, Shirokiya T, Kuroda T, Miyamoto A, Wada H, Fujiyama A, Toyoda A, Zhang S, Wolfsberg TG, Kawakami K, Phillippy AM, Mullikin JC, and Burgess SM
- Subjects
- Animals, Asia, Carps genetics, Evolution, Molecular, Exons genetics, Genomics methods, Genotype, Phenotype, Zebrafish genetics, Gene Duplication genetics, Genome genetics, Goldfish genetics
- Abstract
For over a thousand years, the common goldfish ( Carassius auratus ) was raised throughout Asia for food and as an ornamental pet. As a very close relative of the common carp ( Cyprinus carpio ), goldfish share the recent genome duplication that occurred approximately 14 million years ago in their common ancestor. The combination of centuries of breeding and a wide array of interesting body morphologies provides an exciting opportunity to link genotype to phenotype and to understand the dynamics of genome evolution and speciation. We generated a high-quality draft sequence and gene annotations of a "Wakin" goldfish using 71X PacBio long reads. The two subgenomes in goldfish retained extensive synteny and collinearity between goldfish and zebrafish. However, genes were lost quickly after the carp whole-genome duplication, and the expression of 30% of the retained duplicated gene diverged substantially across seven tissues sampled. Loss of sequence identity and/or exons determined the divergence of the expression levels across all tissues, while loss of conserved noncoding elements determined expression variance between different tissues. This assembly provides an important resource for comparative genomics and understanding the causes of goldfish variants.
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- 2019
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35. Author Correction: Applications and efficiencies of the first cat 63 K DNA array.
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Gandolfi B, Alhaddad H, Abdi M, Bach LH, Creighton EK, Davis BW, Decker JE, Dodman NH, Ginns EI, Grahn JC, Grahn RA, Haase B, Haggstrom J, Hamilton MJ, Helps CR, Kurushima JD, Lohi H, Longeri M, Malik R, Meurs KM, Montague MJ, Mullikin JC, Murphy WJ, Nilson SM, Pedersen NC, Peterson CB, Rusbridge C, Saif R, Shelton GD, Warren WC, Wasim M, and Lyons LA
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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- 2019
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36. DNA methylation in mice is influenced by genetics as well as sex and life experience.
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Grimm SA, Shimbo T, Takaku M, Thomas JW, Auerbach S, Bennett BD, Bucher JR, Burkholder AB, Day F, Du Y, Duncan CG, French JE, Foley JF, Li J, Merrick BA, Tice RR, Wang T, Xu X, Bushel PR, Fargo DC, Mullikin JC, and Wade PA
- Subjects
- Animals, CpG Islands, DNA Methylation physiology, Female, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Pregnancy, Pregnancy, Animal physiology, Sex Factors, Species Specificity, Whole Genome Sequencing, DNA Methylation genetics, Epigenesis, Genetic, Pregnancy, Animal genetics
- Abstract
DNA methylation is an essential epigenetic process in mammals, intimately involved in gene regulation. Here we address the extent to which genetics, sex, and pregnancy influence genomic DNA methylation by intercrossing 2 inbred mouse strains, C57BL/6N and C3H/HeN, and analyzing DNA methylation in parents and offspring using whole-genome bisulfite sequencing. Differential methylation across genotype is detected at thousands of loci and is preserved on parental alleles in offspring. In comparison of autosomal DNA methylation patterns across sex, hundreds of differentially methylated regions are detected. Comparison of animals with different histories of pregnancy within our study reveals a CpG methylation pattern that is restricted to female animals that had borne offspring. Collectively, our results demonstrate the stability of CpG methylation across generations, clarify the interplay of epigenetics with genetics and sex, and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology.
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- 2019
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37. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center.
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Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, and Gunay-Aygun M
- Subjects
- Abnormalities, Multiple genetics, Adolescent, Adult, Blepharoptosis diagnosis, Blepharoptosis genetics, Child, Child, Preschool, Electroretinography, Eye Abnormalities genetics, Eye Diseases genetics, Female, Hepatorenal Syndrome genetics, High-Throughput Nucleotide Sequencing, Humans, Infant, Kidney Diseases, Cystic genetics, Male, Nystagmus, Pathologic diagnosis, Nystagmus, Pathologic genetics, Ocular Motility Disorders diagnosis, Ocular Motility Disorders genetics, Ophthalmoscopy, Polymerase Chain Reaction, Prospective Studies, Retinal Degeneration diagnosis, Retinal Degeneration genetics, Retinoscopy, Slit Lamp Microscopy, Visual Acuity physiology, Exome Sequencing, Young Adult, Abnormalities, Multiple diagnosis, Cerebellum abnormalities, Eye Abnormalities diagnosis, Eye Diseases diagnosis, Genotype, Hepatorenal Syndrome diagnosis, Kidney Diseases, Cystic diagnosis, Retina abnormalities
- Abstract
Purpose: Joubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in JS patients, with correlation to systemic findings and genotype., Design: Patients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial., Participants: Ninety-nine patients with JS examined at a single center., Methods: All patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible., Main Outcome Measures: The VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG., Results: Among patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified., Conclusions: We recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation., (Published by Elsevier Inc.)
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- 2018
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38. Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.
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Gourh P, Remmers EF, Boyden SE, Alexander T, Morgan ND, Shah AA, Mayes MD, Doumatey A, Bentley AR, Shriner D, Domsic RT, Medsger TA Jr, Steen VD, Ramos PS, Silver RM, Korman B, Varga J, Schiopu E, Khanna D, Hsu V, Gordon JK, Saketkoo LA, Gladue H, Kron B, Criswell LA, Derk CT, Bridges SL Jr, Shanmugam VK, Kolstad KD, Chung L, Jan R, Bernstein EJ, Goldberg A, Trojanowski M, Kafaja S, Maksimowicz-McKinnon KM, Mullikin JC, Adeyemo A, Rotimi C, Boin F, Kastner DL, and Wigley FM
- Subjects
- Adenosine Triphosphatases genetics, Adult, Extracellular Matrix Proteins genetics, Female, Genetic Variation, Humans, Male, Middle Aged, Principal Component Analysis, White People genetics, Exome Sequencing, Black or African American genetics, Gene Regulatory Networks genetics, Genetic Predisposition to Disease ethnology, Scleroderma, Systemic ethnology, Scleroderma, Systemic genetics
- Abstract
Objective: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients., Methods: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls., Results: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10
-4 )., Conclusion: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility., (© 2018, American College of Rheumatology.)- Published
- 2018
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39. Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-β, hedgehog, and FGF signaling.
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Roessler E, Hu P, Marino J, Hong S, Hart R, Berger S, Martinez A, Abe Y, Kruszka P, Thomas JW, Mullikin JC, Wang Y, Wong WSW, Niederhuber JE, Solomon BD, Richieri-Costa A, Ribeiro-Bicudo LA, and Muenke M
- Subjects
- Fibroblast Growth Factors genetics, Gene Frequency, Genetic Association Studies, Genotype, Hedgehog Proteins genetics, Holoprosencephaly diagnosis, Humans, Inheritance Patterns, Mutation, Phenotype, Syndrome, Transforming Growth Factor beta genetics, Fibroblast Growth Factors metabolism, Genetic Predisposition to Disease, Hedgehog Proteins metabolism, Holoprosencephaly genetics, Holoprosencephaly metabolism, Signal Transduction, Transforming Growth Factor beta metabolism
- Abstract
Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers., (© 2018 Wiley Periodicals, Inc.)
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- 2018
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40. Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot.
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Sapp JC, Johnston JJ, Driscoll K, Heidlebaugh AR, Miren Sagardia A, Dogbe DN, Umstead KL, Turbitt E, Alevizos I, Baron J, Bönnemann C, Brooks B, Donkervoort S, Jee YH, Linehan WM, McMahon FJ, Moss J, Mullikin JC, Nielsen D, Pelayo E, Remaley AT, Siegel R, Su H, Zarate C, Manolio TA, Biesecker BB, and Biesecker LG
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- Female, Genetic Counseling methods, Genomics methods, Humans, Incidental Findings, Male, Middle Aged, Pilot Projects, Exome genetics
- Abstract
While consensus regarding the return of secondary genomic findings in the clinical setting has been reached, debate about such findings in the research setting remains. We developed a hybrid, research-clinical translational genomics process for research exome data coupled with a CLIA-validated secondary findings analysis. Eleven intramural investigators from ten institutes at the National Institutes of Health piloted this process. Nearly 1,200 individuals were sequenced and 14 secondary findings were identified in 18 participants. Positive secondary findings were returned by a genetic counselor following a standardized protocol, including referrals for specialty follow-up care for the secondary finding local to the participants. Interviews were undertaken with 13 participants 4 months after receipt of a positive report. These participants reported minimal psychologic distress within a process to assimilate their results. Of the 13, 9 reported accessing the recommended health care services. A sample of 107 participants who received a negative findings report were surveyed 4 months after receiving it. They demonstrated good understanding of the negative secondary findings result and most expressed reassurance (64%) from that report. However, a notable minority (up to 17%) expressed confusion regarding the distinction of primary from secondary findings. This pilot shows it is feasible to couple CLIA-compliant secondary findings to research sequencing with minimal harms. Participants managed the surprise of a secondary finding with most following recommended follow up, yet some with negative findings conflated secondary and primary findings. Additional work is needed to understand barriers to follow-up care and help participants distinguish secondary from primary findings., (Published by Elsevier Inc.)
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- 2018
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41. Author Correction: Applications and efficiencies of the first cat 63K DNA array.
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Gandolfi B, Alhaddad H, Abdi M, Bach LH, Creighton EK, Davis BW, Decker JE, Dodman NH, Ginns EI, Grahn JC, Grahn RA, Haase B, Haggstrom J, Hamilton MJ, Helps CR, Kurushima JD, Lohi H, Longeri M, Malik R, Meurs KM, Montague MJ, Mullikin JC, Murphy WJ, Nilson SM, Pedersen NC, Peterson CB, Rusbridge C, Saif R, Shelton GD, Warren WC, Wasim M, and Lyons LA
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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- 2018
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42. Applications and efficiencies of the first cat 63K DNA array.
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Gandolfi B, Alhaddad H, Abdi M, Bach LH, Creighton EK, Davis BW, Decker JE, Dodman NH, Ginns EI, Grahn JC, Grahn RA, Haase B, Haggstrom J, Hamilton MJ, Helps CR, Kurushima JD, Lohi H, Longeri M, Malik R, Meurs KM, Montague MJ, Mullikin JC, Murphy WJ, Nilson SM, Pedersen NC, Peterson CB, Rusbridge C, Saif R, Shelton GD, Warren WC, Wasim M, and Lyons LA
- Abstract
The development of high throughput SNP genotyping technologies has improved the genetic dissection of simple and complex traits in many species including cats. The properties of feline 62,897 SNPs Illumina Infinium iSelect DNA array are described using a dataset of over 2,000 feline samples, the most extensive to date, representing 41 cat breeds, a random bred population, and four wild felid species. Accuracy and efficiency of the array's genotypes and its utility in performing population-based analyses were evaluated. Average marker distance across the array was 37,741 Kb, and across the dataset, only 1% (625) of the markers exhibited poor genotyping and only 0.35% (221) showed Mendelian errors. Marker polymorphism varied across cat breeds and the average minor allele frequency (MAF) of all markers across domestic cats was 0.21. Population structure analysis confirmed a Western to Eastern structural continuum of cat breeds. Genome-wide linkage disequilibrium ranged from 50-1,500 Kb for domestic cats and 750 Kb for European wildcats (Felis silvestris silvestris). Array use in trait association mapping was investigated under different modes of inheritance, selection and population sizes. The efficient array design and cat genotype dataset continues to advance the understanding of cat breeds and will support monogenic health studies across feline breeds and populations.
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- 2018
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43. A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope.
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Zhou T, Zheng A, Baxa U, Chuang GY, Georgiev IS, Kong R, O'Dell S, Shahzad-Ul-Hussan S, Shen CH, Tsybovsky Y, Bailer RT, Gift SK, Louder MK, McKee K, Rawi R, Stevenson CH, Stewart-Jones GBE, Taft JD, Waltari E, Yang Y, Zhang B, Shivatare SS, Shivatare VS, Lee CD, Wu CY, Mullikin JC, Bewley CA, Burton DR, Polonis VR, Shapiro L, Wong CH, Mascola JR, Kwong PD, and Wu X
- Subjects
- Amino Acid Sequence, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing genetics, Antibodies, Neutralizing metabolism, Antigens, Viral chemistry, Antigens, Viral immunology, Binding Sites, Epitope Mapping, Epitopes chemistry, Epitopes immunology, Epitopes metabolism, Glycopeptides chemistry, Glycopeptides immunology, Glycosylation, HIV Antibodies chemistry, HIV Antibodies genetics, HIV Antibodies metabolism, HIV Envelope Protein gp120 chemistry, HIV Envelope Protein gp120 metabolism, Humans, Models, Molecular, Molecular Conformation, Polysaccharides chemistry, Protein Binding immunology, Somatic Hypermutation, Immunoglobulin immunology, Structure-Activity Relationship, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV-1 immunology, Polysaccharides immunology
- Abstract
Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center. Somatic hypermutation occurred preferentially at antibody residues that interacted with these glycans, suggesting somatic development of glycan recognition. Resistance to VRC-PG05 in donor #74 involved shifting of glycan-N448 to N446 or mutation of glycan-proximal residue E293. HIV-1 neutralization can thus be achieved at the silent face center by glycan-recognizing antibody; along with other known epitopes, the VRC-PG05 epitope completes coverage by neutralizing antibody of all major exposed regions of the prefusion closed trimer., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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44. Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center.
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Strongin A, Heller T, Doherty D, Glass IA, Parisi MA, Bryant J, Choyke P, Turkbey B, Daryanani K, Yildirimli D, Vemulapalli M, Mullikin JC, Malicdan MC, Vilboux T, Gahl WA, and Gunay-Aygun M
- Subjects
- Abnormalities, Multiple genetics, Abnormalities, Multiple physiopathology, Adolescent, Adult, Cerebellum physiopathology, Child, Child, Preschool, Disease Progression, Eye Abnormalities genetics, Eye Abnormalities physiopathology, Female, Humans, Infant, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic physiopathology, Liver Diseases congenital, Liver Diseases genetics, Liver Diseases physiopathology, Logistic Models, Male, Prospective Studies, Retina physiopathology, Young Adult, Abnormalities, Multiple diagnosis, Cerebellum abnormalities, Eye Abnormalities diagnosis, Kidney Diseases, Cystic diagnosis, Liver Diseases diagnosis, Retina abnormalities
- Abstract
Background and Aims: Joubert Syndrome (JS) is a rare, inherited, ciliopathy defined by cerebellar and brainstem malformations and is variably associated with liver, kidney, and ocular dysfunction. This study characterizes the hepatic findings in JS and identifies factors associated with probable portal hypertension., Methods: Hundred individuals with JS were prospectively evaluated at the National Institutes of Health Clinical Center. Laboratory tests, imaging, and DNA sequencing were performed. Patients were stratified based on the spleen length/patient height ratio as a marker of splenomegaly, used as a surrogate for probable portal hypertension., Results: Forty-three patients (43%) had liver involvement based on elevated liver enzymes and/or liver hyperechogenicity and/or splenomegaly. None of the patients had macroscopic liver cysts or bile duct dilatation. Based on the spleen length/patient height ratio, 13 patients were stratified into a probable portal hypertension group. We observed significant elevations in alkaline phosphatase (269 vs 169 U/L, P ≤ 0.001), alanine aminotransferase (92 vs 42 U/L, P = 0.004), aspartate aminotransferase (77 vs 40 U/L, P = 0.002), and gamma-glutamyl transferase (226 vs 51 U/L, P ≤ 0.001) in the probable portal hypertension group. Platelets were lower in the probable portal hypertension cohort (229 vs 299 × 10 cells/μL, P = 0.008), whereas synthetic function was intact in both groups. Probable portal hypertension was also more prevalent in patients with kidney disease (P = 0.001) and colobomas (P = 0.02), as well as mutations in the TMEM67 gene (P = 0.001)., Conclusions: In JS, probable portal hypertension is associated with abnormal hepatic enzymes, as well as presence of kidney disease, coloboma, and/or mutation in TMEM67. These findings may allow early identification of JS patients who have or are more likely to develop liver disease.
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- 2018
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45. A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families.
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Kimble DC, Lach FP, Gregg SQ, Donovan FX, Flynn EK, Kamat A, Young A, Vemulapalli M, Thomas JW, Mullikin JC, Auerbach AD, Smogorzewska A, and Chandrasekharappa SC
- Subjects
- Cell Line, Fanconi Anemia pathology, Fluorescent Antibody Technique, Humans, Fanconi Anemia genetics, Fanconi Anemia Complementation Group A Protein genetics, Mutation, Missense genetics
- Abstract
Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA-null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G > C and c.1565A > G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitting studies of genotype-phenotype correlations., (© Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)
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- 2018
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46. The Draft Genome Assembly of Dermatophagoides pteronyssinus Supports Identification of Novel Allergen Isoforms in Dermatophagoides Species.
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Randall TA, Mullikin JC, and Mueller GA
- Subjects
- Amino Acid Sequence, Animals, Dermatophagoides farinae immunology, Dermatophagoides pteronyssinus immunology, Genetic Markers, Protein Isoforms, Sequence Homology, Amino Acid, Whole Genome Sequencing, Allergens genetics, Antigens, Dermatophagoides genetics, Dermatophagoides farinae genetics, Dermatophagoides pteronyssinus genetics, Genome
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- 2018
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47. The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas.
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Le Gallo M, Rudd ML, Urick ME, Hansen NF, Merino MJ, Mutch DG, Goodfellow PJ, Mullikin JC, and Bell DW
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- Adenocarcinoma, Clear Cell genetics, Autoantigens genetics, Carcinoma, Endometrioid genetics, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases genetics, Endometrial Neoplasms genetics, F-Box-WD Repeat-Containing Protein 7 genetics, Female, Hepatocyte Nuclear Factor 3-beta genetics, Humans, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Microsatellite Instability, Mutation, Neoplasms, Cystic, Mucinous, and Serous genetics, Polymerase Chain Reaction, Protein Phosphatase 2 genetics, Sequence Analysis, DNA, Tumor Suppressor Protein p53 genetics, Carcinoma genetics, Carcinosarcoma genetics, Uterine Neoplasms genetics
- Abstract
Background: Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the current study was to identify novel somatically mutated genes in UCSs., Methods: We whole exome sequenced paired tumor and nontumor DNAs from 14 UCSs and orthogonally validated 464 somatic variants using Sanger sequencing. Fifteen genes that were somatically mutated in at least 2 tumor exomes were Sanger sequenced in another 39 primary UCSs., Results: Overall, among 53 UCSs in the current study, the most frequently mutated of these 15 genes were tumor protein p53 (TP53) (75.5%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (34.0%), protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A) (18.9%), F-box and WD repeat domain containing 7 (FBXW7) (18.9%), chromodomain helicase DNA binding protein 4 (CHD4) (17.0%), and forkhead box A2 (FOXA2) (15.1%). FOXA2 has not previously been implicated in UCSs and was predominated by frameshift and nonsense mutations. One UCS with a FOXA2 frameshift mutation expressed truncated FOXA2 protein by immunoblotting. Sequencing of FOXA2 in 160 primary endometrial carcinomas revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid, and 11.1% of mixed endometrial carcinomas, the majority of which were frameshift mutations., Conclusions: Collectively, the findings of the current study provide compelling genetic evidence that FOXA2 is a pathogenic driver gene in the etiology of primary uterine cancers, including UCSs. Cancer 2018;124:65-73. © 2017 American Cancer Society., (© 2017 American Cancer Society.)
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- 2018
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48. Prospective Evaluation of Kidney Disease in Joubert Syndrome.
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Fleming LR, Doherty DA, Parisi MA, Glass IA, Bryant J, Fischer R, Turkbey B, Choyke P, Daryanani K, Vemulapalli M, Mullikin JC, Malicdan MC, Vilboux T, Sayer JA, Gahl WA, and Gunay-Aygun M
- Subjects
- Abnormalities, Multiple diagnostic imaging, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Vesicular Transport, Adolescent, Adult, Age of Onset, Antigens, Neoplasm genetics, Cell Cycle Proteins genetics, Cerebellum diagnostic imaging, Cerebellum metabolism, Child, Child, Preschool, Cytoskeletal Proteins, Eye Abnormalities complications, Eye Abnormalities diagnostic imaging, Female, Genotype, Humans, Infant, Kidney Diseases, Cystic complications, Kidney Diseases, Cystic diagnostic imaging, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic metabolism, Kidney Failure, Chronic etiology, Magnetic Resonance Imaging, Male, Membrane Proteins genetics, Multicystic Dysplastic Kidney complications, Multicystic Dysplastic Kidney diagnostic imaging, Multicystic Dysplastic Kidney genetics, Mutation, Neoplasm Proteins genetics, Phenotype, Polycystic Kidney, Autosomal Recessive complications, Polycystic Kidney, Autosomal Recessive diagnostic imaging, Polycystic Kidney, Autosomal Recessive genetics, Prospective Studies, Proteins genetics, Retina diagnostic imaging, Retina metabolism, Ultrasonography, Prenatal, Young Adult, Abnormalities, Multiple genetics, Abnormalities, Multiple metabolism, Cerebellum abnormalities, Eye Abnormalities genetics, Eye Abnormalities metabolism, Kidney Diseases, Cystic congenital, Kidney Failure, Chronic genetics, Retina abnormalities
- Abstract
Background and Objectives: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center., Design, Setting, Participants, & Measurements: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing., Results: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67 , C5orf42 , CC2D2A , CEP290 , AHI1 , and KIAA0586 . Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD ( n =13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old)., Conclusions: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290 , TMEM67 , and AHI1 . Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype., (Copyright © 2017 by the American Society of Nephrology.)
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- 2017
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49. Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.
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Chandrasekharappa SC, Chinn SB, Donovan FX, Chowdhury NI, Kamat A, Adeyemo AA, Thomas JW, Vemulapalli M, Hussey CS, Reid HH, Mullikin JC, Wei Q, and Sturgis EM
- Subjects
- Adult, Age of Onset, BRCA2 Protein genetics, DNA Mutational Analysis, Fanconi Anemia Complementation Group D2 Protein genetics, Fanconi Anemia Complementation Group E Protein genetics, Fanconi Anemia Complementation Group L Protein genetics, Fanconi Anemia Complementation Group Proteins genetics, Female, Germ-Line Mutation, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Recombinases genetics, Sequence Analysis, DNA, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell genetics, Fanconi Anemia genetics, Head and Neck Neoplasms genetics
- Abstract
Background: Patients with Fanconi anemia (FA) have an increased risk for head and neck squamous cell carcinoma (HNSCC). The authors sought to determine the prevalence of undiagnosed FA and FA carriers among patients with HNSCC as well as an age cutoff for FA genetic screening., Methods: Germline DNA samples from 417 patients with HNSCC aged <50 years were screened for sequence variants by targeted next-generation sequencing of the entire length of 16 FA genes., Results: The sequence revealed 194 FA gene variants in 185 patients (44%). The variant spectrum was comprised of 183 nonsynonymous point mutations, 9 indels, 1 large deletion, and 1 synonymous variant that was predicted to effect splicing. One hundred eight patients (26%) had at least 1 rare variant that was predicted to be damaging, and 57 (14%) had at least 1 rare variant that was predicted to be damaging and had been previously reported. Fifteen patients carried 2 rare variants or an X-linked variant in an FA gene. Overall, an age cutoff for FA screening was not identified among young patients with HNSCC, because there were no significant differences in mutation rates when patients were stratified by age, tumor site, ethnicity, smoking status, or human papillomavirus status. However, an increased burden, or mutation load, of FA gene variants was observed in carriers of the genes FA complementation group D2 (FANCD2), FANCE, and FANCL in the HNSCC patient cohort relative to the 1000 Genomes population., Conclusions: FA germline functional variants offer a novel area of study in HNSCC tumorigenesis. FANCE and FANCL, which are components of the core complex, are known to be responsible for the recruitment and ubiquitination, respectively, of FANCD2, a critical step in the FA DNA repair pathway. In the current cohort, the increased mutation load of FANCD2, FANCE, and FANCL variants among younger patients with HNSCC indicates the importance of the FA pathway in HNSCC. Cancer 2017;123:3943-54. © 2017 American Cancer Society., (© 2017 American Cancer Society.)
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- 2017
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50. Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing.
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Le Gallo M, Rudd ML, Urick ME, Hansen NF, Zhang S, Lozy F, Sgroi DC, Vidal Bel A, Matias-Guiu X, Broaddus RR, Lu KH, Levine DA, Mutch DG, Goodfellow PJ, Salvesen HB, Mullikin JC, and Bell DW
- Subjects
- Adenocarcinoma, Clear Cell pathology, Aged, Cohort Studies, DNA Mutational Analysis, Endometrial Neoplasms pathology, Exome, Female, Genome-Wide Association Study, Humans, Immunoblotting methods, Microsatellite Instability, Middle Aged, Molecular Sequence Data, Prognosis, Adenocarcinoma, Clear Cell genetics, Endometrial Neoplasms genetics, Gene Expression Regulation, Neoplastic, Histone Acetyltransferases genetics, Mutation, TATA-Binding Protein Associated Factors genetics, Transcription Factor TFIID genetics
- Abstract
Background: The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases., Methods: We conducted whole exome sequencing of paired tumor-normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-of-interest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats., Results: Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC)., Conclusion: Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261-8. © 2017 American Cancer Society., (© 2017 American Cancer Society.)
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- 2017
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