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4. Phenotypic and mutational spectrum of ROR2-related Robinow syndrome

Author

Lima, A.R., Ferreira, B.M., Zhang, C, Jolly, A., Du, H., White, J.J., Dawood, M., Lins, T.C., Chiabai, M.A., Beusekom, E. van, Cordoba, M.S., Rosa, E.C.C. Caldas, Kayserili, H., Kimonis, V., Wu, E., Mellado, C., Aggarwal, V., Richieri-Costa, A., Brunoni, D., Canó, T.M., Jorge, A.A.L., Kim, C.A., Honjo, R., Bertola, D.R., Dandalo-Girardi, R.M., Bayram, Y., Gezdirici, A., Yilmaz-Gulec, E., Gumus, E., Yilmaz, G.C., Okamoto, N., Ohashi, H., Coban-Akdemir, Z., Mitani, T., Jhangiani, S.N., Muzny, D.M., Regattieri, N.A.P., Pogue, R., Pereira, R.W., Otto, P.A., Gibbs, R.A., Ali, B.R., Bokhoven, H. van, Brunner, H.G., Sutton, V.R., Lupski, J.R., Vianna-Morgante, A.M., Carvalho, C.M., Mazzeu, J.F., Lima, A.R., Ferreira, B.M., Zhang, C, Jolly, A., Du, H., White, J.J., Dawood, M., Lins, T.C., Chiabai, M.A., Beusekom, E. van, Cordoba, M.S., Rosa, E.C.C. Caldas, Kayserili, H., Kimonis, V., Wu, E., Mellado, C., Aggarwal, V., Richieri-Costa, A., Brunoni, D., Canó, T.M., Jorge, A.A.L., Kim, C.A., Honjo, R., Bertola, D.R., Dandalo-Girardi, R.M., Bayram, Y., Gezdirici, A., Yilmaz-Gulec, E., Gumus, E., Yilmaz, G.C., Okamoto, N., Ohashi, H., Coban-Akdemir, Z., Mitani, T., Jhangiani, S.N., Muzny, D.M., Regattieri, N.A.P., Pogue, R., Pereira, R.W., Otto, P.A., Gibbs, R.A., Ali, B.R., Bokhoven, H. van, Brunner, H.G., Sutton, V.R., Lupski, J.R., Vianna-Morgante, A.M., Carvalho, C.M., and Mazzeu, J.F.

Abstract

Contains fulltext : 252015.pdf (Publisher’s version ) (Closed access), Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Published
2022

6. Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome

Author

Chen, N. Zhao, S. Jolly, A. Wang, L. Pan, H. Yuan, J. Chen, S. Koch, A. Ma, C. Tian, W. Jia, Z. Kang, J. Zhao, L. Qin, C. Fan, X. Rall, K. Coban-Akdemir, Z. Chen, Z. Jhangiani, S. Liang, Z. Niu, Y. Li, X. Yan, Z. Wu, Y. Dong, S. Song, C. Qiu, G. Zhang, S. Liu, P. Posey, J.E. Zhang, F. Luo, G. Wu, Z. Zhang, T.J. Wu, N. Wang, S. Liu, J. Liu, S. Zuo, Y. Liu, G. Yu, C. Liu, L. Shao, J. Zhao, H. Wang, H. Liu, B. Cheng, X. Lin, J. Du, H. Li, Y. Song, S. Xie, Z. Zhao, Z. Zhao, Z. Zheng, Z. Huang, Y. Su, J. Zhang, J. Chen, E.Y. Rouskas, K. Glentis, S. Bacopoulou, F. Deligeoroglou, E. Chrousos, G. Lyonnet, S. Polak, M. Rosenberg, C. Dingeldein, I. Bonilla, X. Borel, C. Gibbs, R.A. Dietrich, J.E. Dimas, A.S. Antonarakis, S.E. Brucker, S.Y. Lupski, J.R. Zhu, L. Deciphering Disorders Involving Scoliosis COmorbidities (DISCO) study group

Abstract

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E−06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects. © 2020 American Society of Human Genetics

Published
2021

7. High-depth African genomes inform human migration and health

Author

Choudhury, A., Aron, S., Botigué, Laura R., Sengupta, D., Botha, G., Bensellak, T., Wells, G., Kumuthini, J., Shriner, Daniel, Fakim, Y.J., Ghoorah, A.W., Dareng, E., Odia, T., Falola, O., Adebiyi, E., Hazelhurst, S., Mazandu, G., Nyangiri, O.A., Mbiyavanga, M., Benkahla, A., Kassim, S.K., Mulder, N., Adebamowo, S.N., Chimusa, E.R., Muzny, D., Metcalf, G., Gibbs, R.A., Rotimi, C., Ramsay, M., Adeyemo, A.A., Lombard, Z., Hanchard, N.A., TrypanoGEN Research Group, H3Africa Consortium, Choudhury, A., Aron, S., Botigué, Laura R., Sengupta, D., Botha, G., Bensellak, T., Wells, G., Kumuthini, J., Shriner, Daniel, Fakim, Y.J., Ghoorah, A.W., Dareng, E., Odia, T., Falola, O., Adebiyi, E., Hazelhurst, S., Mazandu, G., Nyangiri, O.A., Mbiyavanga, M., Benkahla, A., Kassim, S.K., Mulder, N., Adebamowo, S.N., Chimusa, E.R., Muzny, D., Metcalf, G., Gibbs, R.A., Rotimi, C., Ramsay, M., Adeyemo, A.A., Lombard, Z., Hanchard, N.A., TrypanoGEN Research Group, and H3Africa Consortium

Abstract

Altres ajuts: CERCA Programme/Generalitat de Catalunya, The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.

Published
2020

8. Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability

Author

Marom, R., Jain, M., Burrage, L.C., Song, I.W., Graham, B.H., Brown, C.W., Stevens, S.J.C., Stegmann, A.P.A., Gunter, A.T., Kaplan, J.D., Gavrilova, R.H., Shinawi, M., Rosenfeld, J.A., Bae, Y., Tran, A.A., Chen, Y, Lu, J.T., Gibbs, R.A., Eng, C., Yang, Y, Rousseau, J., Vries, B.B.A. de, Campeau, P.M., Lee, B., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
Male, Heterozygote, speech delay, Adolescent, Chromosomal Proteins, Non-Histone, Micrognathism, Mutation, Missense, Article, CHROMATIN-REMODELING COMPLEX, Humans, Exome, BAF complex, Child, HAPLOINSUFFICIENCY CAUSES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COFFIN-SIRIS SYNDROME, DNA Helicases, Nuclear Proteins, SWI/SNF COMPLEX, Chromatin Assembly and Disassembly, BARAITSER-WINTER SYNDROME, GENE, Actins, NUCLEAR ACTIN, DNA-Binding Proteins, ACTIN-RELATED PROTEINS, intellectual disability, DE-NOVO MUTATIONS, Face, Multiprotein Complexes, ACTL6A, Female, Hand Deformities, Congenital, MENTAL-RETARDATION, Protein Binding, Transcription Factors
Abstract

Item does not contain fulltext Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Published
2017
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9. Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing

Author

Floyd, J.S. (James S.), Bloch, K.M. (Katarzyna M.), Brody, J.A. (Jennifer A.), Maroteau, C. (Cyrielle), Siddiqui, M.K. (Moneeza K.), Gregory, R. (Richard), Carr, D.F. (Daniel F.), Molokhia, M. (Mariam), Liu, X. (Xiaoming), Bis, J.C. (Joshua), Ahmed, A. (Ammar), Liu, X. (Xuan), Hallberg, P. (Pär), Yue, Q. (Qunying), Magnusson, P.K. (Patrik), Brisson, D. (Diane), Wiggins, K.L. (Kerri L.), Morrison, A.C. (Alanna C.), Khoury, E. (Etienne), Mckeigue, P.M. (Paul), Stricker, B.H.Ch. (Bruno), Lapeyre-Mestre, M. (Maryse), Heckbert, S.R. (Susan), Gallagher, A.M. (Arlene M.), Chinoy, H. (Hector), Gibbs, R.A. (Richard), Bondon-Guitton, E. (Emmanuelle), Tracy, R.P. (Russell), Boerwinkle, E.A. (Eric), Gaudet, D. (Daniel), Conforti, A. (Anita), Staa, T.P. (Tjeerd) van, Sitlani, C.M. (Colleen M.), Rice, K.M. (Kenneth M.), Maitland-van der Zee, A-H. (Anke-Hilse), Wadelius, M. (Mia), Morris, A.P. (Andrew), Pirmohamed, M. (Munir), Palmer, C.A.N. (Colin A N), Psaty, B.M. (Bruce M.), Alfirevic, A. (Ana), Floyd, J.S. (James S.), Bloch, K.M. (Katarzyna M.), Brody, J.A. (Jennifer A.), Maroteau, C. (Cyrielle), Siddiqui, M.K. (Moneeza K.), Gregory, R. (Richard), Carr, D.F. (Daniel F.), Molokhia, M. (Mariam), Liu, X. (Xiaoming), Bis, J.C. (Joshua), Ahmed, A. (Ammar), Liu, X. (Xuan), Hallberg, P. (Pär), Yue, Q. (Qunying), Magnusson, P.K. (Patrik), Brisson, D. (Diane), Wiggins, K.L. (Kerri L.), Morrison, A.C. (Alanna C.), Khoury, E. (Etienne), Mckeigue, P.M. (Paul), Stricker, B.H.Ch. (Bruno), Lapeyre-Mestre, M. (Maryse), Heckbert, S.R. (Susan), Gallagher, A.M. (Arlene M.), Chinoy, H. (Hector), Gibbs, R.A. (Richard), Bondon-Guitton, E. (Emmanuelle), Tracy, R.P. (Russell), Boerwinkle, E.A. (Eric), Gaudet, D. (Daniel), Conforti, A. (Anita), Staa, T.P. (Tjeerd) van, Sitlani, C.M. (Colleen M.), Rice, K.M. (Kenneth M.), Maitland-van der Zee, A-H. (Anke-Hilse), Wadelius, M. (Mia), Morris, A.P. (Andrew), Pirmohamed, M. (Munir), Palmer, C.A.N. (Colin A N), Psaty, B.M. (Bruce M.), and Alfirevic, A. (Ana)

Abstract

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

Published
2019
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10. Correction: Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation (Molecular Psychiatry, (2018), 10.1038/s41380-018-0112-7)

Author

Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Cantwell, L.B. (Laura B.), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, P.K. (Paul K.), Crane, L.M.A., Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard), Goate, A. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Kunkle, B. (Brian), Perola, M. (Markus), Psaty, B.M. (Bruce), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Valladares, O. (Otto), Vardarajan, B.N. (Badri), Wang, L.S. (Li-San), Wang, W. (Weixin), Wijsman, E. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M.J. (Mark), Boerwinkle, E.A. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Martin, E.R., Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), Farrer, L.A. (Lindsay), Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Cantwell, L.B. (Laura B.), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, P.K. (Paul K.), Crane, L.M.A., Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard), Goate, A. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Kunkle, B. (Brian), Perola, M. (Markus), Psaty, B.M. (Bruce), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Valladares, O. (Otto), Vardarajan, B.N. (Badri), Wang, L.S. (Li-San), Wang, W. (Weixin), Wijsman, E. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M.J. (Mark), Boerwinkle, E.A. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Martin, E.R., Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), and Farrer, L.A. (Lindsay)

Abstract

Following publication, the authors noticed that ‘Laura Cantwell’, ‘Otto Valladares’, and ‘Li-San Wang’ were inadvertently omitted from the author list. These authors have now been added to the author list in 21st, 77th, and 79th position, respectively. This has been corrected in both the PDF and HTML versions of the article.

Published
2019
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13. SYT1-associated neurodevelopmental disorder: a case series

Author

Baker, K. (Kate), Gordon, S.L. (Sarah L.), Melland, H. (Holly), Bumbak, F. (Fabian), Scott, D.J. (Daniel J.), Jiang, T.J. (Tess J.), Owen, D. (David), Turner, B.J. (Bradley J.), Boyd, S.G. (Stewart G.), Rossi, M. (Mari), Al-Raqad, M. (Mohammed), Elpeleg, O. (Orly), Peck, D. (Dawn), Mancini, G.M.S. (Grazia), Wilke, M. (Martina), Zollino, M., Marangi, G. (Giuseppe), Weigand, H. (Heike), Borggraefe, I. (Ingo), Haack, T. (Tobias), Stark, Z. (Zornitza), Sadedin, S. (Simon), Tan, T.Y. (Tiong Yang), Jiang, Y. (Yunyun), Gibbs, R.A. (Richard A.), Ellingwood, S. (Sara), Amaral, M. (Michelle), Kelley, W. (Whitley), Kurian, M.A. (Manju A.), Cousin, M.A. (Michael A.), Raymond, F.L. (F. Lucy), Baker, K. (Kate), Gordon, S.L. (Sarah L.), Melland, H. (Holly), Bumbak, F. (Fabian), Scott, D.J. (Daniel J.), Jiang, T.J. (Tess J.), Owen, D. (David), Turner, B.J. (Bradley J.), Boyd, S.G. (Stewart G.), Rossi, M. (Mari), Al-Raqad, M. (Mohammed), Elpeleg, O. (Orly), Peck, D. (Dawn), Mancini, G.M.S. (Grazia), Wilke, M. (Martina), Zollino, M., Marangi, G. (Giuseppe), Weigand, H. (Heike), Borggraefe, I. (Ingo), Haack, T. (Tobias), Stark, Z. (Zornitza), Sadedin, S. (Simon), Tan, T.Y. (Tiong Yang), Jiang, Y. (Yunyun), Gibbs, R.A. (Richard A.), Ellingwood, S. (Sara), Amaral, M. (Michelle), Kelley, W. (Whitley), Kurian, M.A. (Manju A.), Cousin, M.A. (Michael A.), and Raymond, F.L. (F. Lucy)

Abstract

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human varian

Published
2018
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14. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Author

Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), Farrer, L.A. (Lindsay), Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), and Farrer, L.A. (Lindsay)

Abstract

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 contro

Published
2018
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16. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

Vogelaar, I.P., Post, R.S. van der, Krieken, J.H. van, Spruijt, L., Zelst-Stams, W.A.G. van, Kets, C.M., Lubinski, J., Jakubowska, A., Teodorczyk, U., Aalfs, C.M., Hest, L.P. van, Pinheiro, H., Oliveira, C. de, Jhangiani, S.N., Muzny, D.M., Gibbs, R.A., Lupski, J.R., Ligt, J. de, Vissers, L.E.L.M., Hoischen, A., Gilissen, C., Vorst, J.M. van de, Goeman, J.J., Schackert, H.K., Ranzani, G.N., Molinaro, V., Garcia, E.B., Hes, F.J., Holinski-Feder, E., Genuardi, M., Ausems, M., Sijmons, R.H., Wagner, A., Kolk, L.E. van der, Bjornevoll, I., Hoberg-Vetti, H., Geurts van Kessel, A.H.M., Kuiper, R.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Vogelaar, I.P., Post, R.S. van der, Krieken, J.H. van, Spruijt, L., Zelst-Stams, W.A.G. van, Kets, C.M., Lubinski, J., Jakubowska, A., Teodorczyk, U., Aalfs, C.M., Hest, L.P. van, Pinheiro, H., Oliveira, C. de, Jhangiani, S.N., Muzny, D.M., Gibbs, R.A., Lupski, J.R., Ligt, J. de, Vissers, L.E.L.M., Hoischen, A., Gilissen, C., Vorst, J.M. van de, Goeman, J.J., Schackert, H.K., Ranzani, G.N., Molinaro, V., Garcia, E.B., Hes, F.J., Holinski-Feder, E., Genuardi, M., Ausems, M., Sijmons, R.H., Wagner, A., Kolk, L.E. van der, Bjornevoll, I., Hoberg-Vetti, H., Geurts van Kessel, A.H.M., Kuiper, R.P., Ligtenberg, M.J.L., and Hoogerbrugge, N.

Abstract

Contains fulltext : 182216.pdf (publisher's version ) (Open Access), Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Published
2017

17. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

Vogelaar, I.P. (Ingrid P.), Van Der Post, R.S. (Rachel S.), Van Krieken, J.H. (J. Han), Spruijt, L. (Liesbeth), Zelst-Stams, W.A. van, Kets, C.M. (Marleen), Lubinski, J. (Jan), Jakubowska, A. (Anna), Teodorczyk, U. (Urszula), Aalfs, C.M. (Cora), Hest, L.P. (Liselotte) van, Pinheiro, H. (Hugo), Oliveira, C. (Carla), Jhangiani, S.N. (Shalini N.), Muzny, D. (Donna), Gibbs, R.A. (Richard A.), Lupski, J.R. (James R.), Ligt, J. (Joep) de, Vissers, L.E.L.M., Hoischen, A. (Alex), Gilissen, C. (Christian), Van De Vorst, M. (Maartje), Goeman, J.J. (Jelle), Schackert, H.K. (Hans), Ranzani, G.N. (Guglielmina N.), Molinaro, V. (Valeria), Garcia, E.B.G., Hes, F.J. (Frederik), Holinski-Feder, E. (Elke), Genuardi, M. (Maurizio), Ausems, M.G.E.M. (Margreet), Sijmons, R.H. (Rolf), Wagner, A. (Anja), Kolk, L.E. (Lizet) van der, Bjørnevoll, I. (Inga), Høberg Vetti, H. (Hildegunn), Geurts van Kessel, A.H.M. (Ad), Kuiper, R. (Ruud), Ligtenberg, M.J. (Marjolijn), Hoogerbrugge, N. (Nicoline), Vogelaar, I.P. (Ingrid P.), Van Der Post, R.S. (Rachel S.), Van Krieken, J.H. (J. Han), Spruijt, L. (Liesbeth), Zelst-Stams, W.A. van, Kets, C.M. (Marleen), Lubinski, J. (Jan), Jakubowska, A. (Anna), Teodorczyk, U. (Urszula), Aalfs, C.M. (Cora), Hest, L.P. (Liselotte) van, Pinheiro, H. (Hugo), Oliveira, C. (Carla), Jhangiani, S.N. (Shalini N.), Muzny, D. (Donna), Gibbs, R.A. (Richard A.), Lupski, J.R. (James R.), Ligt, J. (Joep) de, Vissers, L.E.L.M., Hoischen, A. (Alex), Gilissen, C. (Christian), Van De Vorst, M. (Maartje), Goeman, J.J. (Jelle), Schackert, H.K. (Hans), Ranzani, G.N. (Guglielmina N.), Molinaro, V. (Valeria), Garcia, E.B.G., Hes, F.J. (Frederik), Holinski-Feder, E. (Elke), Genuardi, M. (Maurizio), Ausems, M.G.E.M. (Margreet), Sijmons, R.H. (Rolf), Wagner, A. (Anja), Kolk, L.E. (Lizet) van der, Bjørnevoll, I. (Inga), Høberg Vetti, H. (Hildegunn), Geurts van Kessel, A.H.M. (Ad), Kuiper, R. (Ruud), Ligtenberg, M.J. (Marjolijn), and Hoogerbrugge, N. (Nicoline)

Abstract

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Published
2017
Full Text
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18. Erratum to: Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species

Author

Pearce, S.L., Clarke, D.F., East, P.D., Elfekih, S., Gordon, K.H.J., Jermiin, L.S., McGaughran, A., Oakeshott, J.G., Papanicolaou, A., Perera, O.P., Rane, R.V., Richards, S., Tay, W.T., Walsh, T.K., Anderson, A., Anderson, C.J., Asgari, S., Board, P.G., Bretschneider, A., Campbell, P.M., Chertemps, T., Christeller, J.T., Coppin, C.W., Downes, S.J., Duan, G., Farnsworth, C.A., Good, R.T., Han, L.B., Han, Y.C., Hatje, K., Horne, I., Huang, Y.P., Hughes, D.S.T., Jacquin-Joly, E., James, W., Jhangiani, S., Kollmar, M., Kuwar, S.S., Li, S., Liu, N-Y., Maibeche, M.T., Miller, J.R., Montagne, N., Perry, T., Qu, J., Song, S.V., Sutton, G.G., Vogel, H., Walenz, B.P., Xu, W., Zhang, H-J., Zou, Z., Batterham, P., Edwards, O.R., Feyereisen, R., Gibbs, R.A., Heckel, D.G., McGrath, A., Robin, C., Scherer, S.E., Worley, K.C., Wu, Y.D., Pearce, S.L., Clarke, D.F., East, P.D., Elfekih, S., Gordon, K.H.J., Jermiin, L.S., McGaughran, A., Oakeshott, J.G., Papanicolaou, A., Perera, O.P., Rane, R.V., Richards, S., Tay, W.T., Walsh, T.K., Anderson, A., Anderson, C.J., Asgari, S., Board, P.G., Bretschneider, A., Campbell, P.M., Chertemps, T., Christeller, J.T., Coppin, C.W., Downes, S.J., Duan, G., Farnsworth, C.A., Good, R.T., Han, L.B., Han, Y.C., Hatje, K., Horne, I., Huang, Y.P., Hughes, D.S.T., Jacquin-Joly, E., James, W., Jhangiani, S., Kollmar, M., Kuwar, S.S., Li, S., Liu, N-Y., Maibeche, M.T., Miller, J.R., Montagne, N., Perry, T., Qu, J., Song, S.V., Sutton, G.G., Vogel, H., Walenz, B.P., Xu, W., Zhang, H-J., Zou, Z., Batterham, P., Edwards, O.R., Feyereisen, R., Gibbs, R.A., Heckel, D.G., McGrath, A., Robin, C., Scherer, S.E., Worley, K.C., and Wu, Y.D.

Published
2017

19. Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species

Author

Pearce, S.L., Clarke, D.F., East, P.D., Elfekih, S., Gordon, K.H.J., Jermiin, L.S., McGaughran, A., Oakeshott, J.G., Papanikolaou, A., Perera, O.P., Rane, R.V., Richards, S., Tay, W.T., Walsh, T.K., Anderson, A., Anderson, C.J., Asgari, S., Board, P.G., Bretschneider, A., Campbell, P.M., Chertemps, T., Christeller, J.T., Coppin, C.W., Downes, S.J., Duan, G., Farnsworth, C.A., Good, R.T., Han, L.B., Han, Y.C., Hatje, K., Horne, I., Huang, Y.P, Hughes, D.S.T., Jacquin-Joly, E., James, W., Jhangiani, S., Kollmar, M., Kuwar, S.S., Li, S., Liu, N-Y., Maibeche, M.T., Miller, J.R., Montagne, N., Perry, T., Qu, J., Song, S.V., Sutton, G.G., Vogel, H., Walenz, B P., Xu, W., Zhang, H-J., Zou, Z., Batterham, P., Edwards, O.R., Feyereisen, R., Gibbs, R.A., Heckel, D.G., McGrath, A., Robin, C., Scherer, S.E., Worley, K.C., Wu, Y.D., Pearce, S.L., Clarke, D.F., East, P.D., Elfekih, S., Gordon, K.H.J., Jermiin, L.S., McGaughran, A., Oakeshott, J.G., Papanikolaou, A., Perera, O.P., Rane, R.V., Richards, S., Tay, W.T., Walsh, T.K., Anderson, A., Anderson, C.J., Asgari, S., Board, P.G., Bretschneider, A., Campbell, P.M., Chertemps, T., Christeller, J.T., Coppin, C.W., Downes, S.J., Duan, G., Farnsworth, C.A., Good, R.T., Han, L.B., Han, Y.C., Hatje, K., Horne, I., Huang, Y.P, Hughes, D.S.T., Jacquin-Joly, E., James, W., Jhangiani, S., Kollmar, M., Kuwar, S.S., Li, S., Liu, N-Y., Maibeche, M.T., Miller, J.R., Montagne, N., Perry, T., Qu, J., Song, S.V., Sutton, G.G., Vogel, H., Walenz, B P., Xu, W., Zhang, H-J., Zou, Z., Batterham, P., Edwards, O.R., Feyereisen, R., Gibbs, R.A., Heckel, D.G., McGrath, A., Robin, C., Scherer, S.E., Worley, K.C., and Wu, Y.D.

Abstract

Background: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. Results: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. Conclusions: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Published
2017

20. Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

Author

Dinckan, N., primary, Du, R., additional, Petty, L.E., additional, Coban-Akdemir, Z., additional, Jhangiani, S.N., additional, Paine, I., additional, Baugh, E.H., additional, Erdem, A.P., additional, Kayserili, H., additional, Doddapaneni, H., additional, Hu, J., additional, Muzny, D.M., additional, Boerwinkle, E., additional, Gibbs, R.A., additional, Lupski, J.R., additional, Uyguner, Z.O., additional, Below, J.E., additional, and Letra, A., additional

Published
2017
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21. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, J. Chu, A.Y. Willems, S.M. Wang, S. Yaghootkar, H. Brody, J.A. Dauriz, M. Hivert, M.-F. Raghavan, S. Lipovich, L. Hidalgo, B. Fox, K. Huffman, J.E. An, P. Lu, Y. Rasmussen-Torvik, L.J. Grarup, N. Ehm, M.G. Li, L. Baldridge, A.S. Stančáková, A. Abrol, R. Besse, C. Boland, A. Bork-Jensen, J. Fornage, M. Freitag, D.F. Garcia, M.E. Guo, X. Hara, K. Isaacs, A. Jakobsdottir, J. Lange, L.A. Layton, J.C. Li, M. Hua Zhao, J. Meidtner, K. Morrison, A.C. Nalls, M.A. Peters, M.J. Sabater-Lleal, M. Schurmann, C. Silveira, A. Smith, A.V. Southam, L. Stoiber, M.H. Strawbridge, R.J. Taylor, K.D. Varga, T.V. Allin, K.H. Amin, N. Aponte, J.L. Aung, T. Barbieri, C. Bihlmeyer, N.A. Boehnke, M. Bombieri, C. Bowden, D.W. Burns, S.M. Chen, Y. Chen, Y.-D. Cheng, C.-Y. Correa, A. Czajkowski, J. Dehghan, A. Ehret, G.B. Eiriksdottir, G. Escher, S.A. Farmaki, A.-E. Frånberg, M. Gambaro, G. Giulianini, F. Goddard, W.A. Goel, A. Gottesman, O. Grove, M.L. Gustafsson, S. Hai, Y. Hallmans, G. Heo, J. Hoffmann, P. Ikram, M.K. Jensen, R.A. Jørgensen, M.E. Jørgensen, T. Karaleftheri, M. Khor, C.C. Kirkpatrick, A. Kraja, A.T. Kuusisto, J. Lange, E.M. Lee, I.T. Lee, W.-J. Leong, A. Liao, J. Liu, C. Liu, Y. Lindgren, C.M. Linneberg, A. Malerba, G. Mamakou, V. Marouli, E. Maruthur, N.M. Matchan, A. McKean-Cowdin, R. McLeod, O. Metcalf, G.A. Mohlke, K.L. Muzny, D.M. Ntalla, I. Palmer, N.D. Pasko, D. Peter, A. Rayner, N.W. Renström, F. Rice, K. Sala, C.F. Sennblad, B. Serafetinidis, I. Smith, J.A. Soranzo, N. Speliotes, E.K. Stahl, E.A. Stirrups, K. Tentolouris, N. Thanopoulou, A. Torres, M. Traglia, M. Tsafantakis, E. Javad, S. Yanek, L.R. Zengini, E. Becker, D.M. Bis, J.C. Brown, J.B. Adrienne Cupples, L. Hansen, T. Ingelsson, E. Karter, A.J. Lorenzo, C. Mathias, R.A. Norris, J.M. Peloso, G.M. Sheu, W.H.-H. Toniolo, D. Vaidya, D. Varma, R. Wagenknecht, L.E. Boeing, H. Bottinger, E.P. Dedoussis, G. Deloukas, P. Ferrannini, E. Franco, O.H. Franks, P.W. Gibbs, R.A. Gudnason, V. Hamsten, A. Harris, T.B. Hattersley, A.T. Hayward, C. Hofman, A. Jansson, J.-H. Langenberg, C. Launer, L.J. Levy, D. Oostra, B.A. O'Donnell, C.J. O'Rahilly, S. Padmanabhan, S. Pankow, J.S. Polasek, O. Province, M.A. Rich, S.S. Ridker, P.M. Rudan, I. Schulze, M.B. Smith, B.H. Uitterlinden, A.G. Walker, M. Watkins, H. Wong, T.Y. Zeggini, E. Laakso, M. Borecki, I.B. Chasman, D.I. Pedersen, O. Psaty, B.M. Shyong Tai, E. Van Duijn, C.M. Wareham, N.J. Waterworth, D.M. Boerwinkle, E. Linda Kao, W.H. Florez, J.C. Loos, R.J.F. Wilson, J.G. Frayling, T.M. Siscovick, D.S. Dupuis, J. Rotter, J.I. Meigs, J.B. Scott, R.A. Goodarzi, M.O.

Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01mmoll-1, P=3.4 × 10-12), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035pmolinsulin mmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =6.8 × 10-6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004mmoll-1, P=1.3 × 10-8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. © 2015 Macmillan Publishers Limited. All rights reserved.

Published
2015

22. MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

Author

Eldomery, M.K., Akdemir, Z.C., Vogtle, F.N., Charng, W.L., Mulica, P., Rosenfeld, J.A., Gambin, T., Gu, S., Burrage, L.C., Shamsi, A. Al, Penney, S., Jhangiani, S.N., Zimmerman, H.H., Muzny, D.M., Wang, X., Tang, J., Medikonda, R., Ramachandran, P.V., Wong, L.J., Boerwinkle, E., Gibbs, R.A., Eng, C.M., Lalani, S.R., Hertecant, J., Rodenburg, R.J.T., Abdul-Rahman, O.A., Yang, Y, Xia, F., Wang, M.C., Lupski, J.R., Meisinger, C., Sutton, V.R., Eldomery, M.K., Akdemir, Z.C., Vogtle, F.N., Charng, W.L., Mulica, P., Rosenfeld, J.A., Gambin, T., Gu, S., Burrage, L.C., Shamsi, A. Al, Penney, S., Jhangiani, S.N., Zimmerman, H.H., Muzny, D.M., Wang, X., Tang, J., Medikonda, R., Ramachandran, P.V., Wong, L.J., Boerwinkle, E., Gibbs, R.A., Eng, C.M., Lalani, S.R., Hertecant, J., Rodenburg, R.J.T., Abdul-Rahman, O.A., Yang, Y, Xia, F., Wang, M.C., Lupski, J.R., Meisinger, C., and Sutton, V.R.

Abstract

Contains fulltext : 170911.pdf (publisher's version ) (Open Access), BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. CONCLUSIONS: Our findings reveal for the first time the role of th

Published
2016

23. DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome

Author

White, J.J., Mazzeu, J.F., Hoischen, A., Bayram, Y., Withers, M., Gezdirici, A., Kimonis, V., Steehouwer, M., Jhangiani, S.N., Muzny, D.M., Gibbs, R.A., Bon, B.W. van, Sutton, V.R., Lupski, J.R., Brunner, H.G., Carvalho, C.M., White, J.J., Mazzeu, J.F., Hoischen, A., Bayram, Y., Withers, M., Gezdirici, A., Kimonis, V., Steehouwer, M., Jhangiani, S.N., Muzny, D.M., Gibbs, R.A., Bon, B.W. van, Sutton, V.R., Lupski, J.R., Brunner, H.G., and Carvalho, C.M.

Abstract

Item does not contain fulltext, Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a -1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.

Published
2016

24. Association of the IGF1 gene with fasting insulin levels

Author

Willems, S.M. (Sara), Cornes, B.K. (Belinda), Brody, J.A. (Jennifer A.), Morrison, A.C. (Alanna), Lipovich, L. (Leonard), Dauriz, M. (Marco), Chen, Y. (Yuning), Liu, C.-T. (Ching-Ti), Rybin, D. (Denis), Gibbs, R.A. (Richard A), Muzny, D. (Donna), Pankow, J.S. (James), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Rotter, J.I. (Jerome I.), Siscovick, D.S. (David), Vasan, R.S. (Ramachandran S), Kaplan, R.C. (Robert C), Isaacs, A.J. (Aaron), Dupuis, J. (Josée), Duijn, C.M. (Cornelia) van, Meigs, J.B. (James), Willems, S.M. (Sara), Cornes, B.K. (Belinda), Brody, J.A. (Jennifer A.), Morrison, A.C. (Alanna), Lipovich, L. (Leonard), Dauriz, M. (Marco), Chen, Y. (Yuning), Liu, C.-T. (Ching-Ti), Rybin, D. (Denis), Gibbs, R.A. (Richard A), Muzny, D. (Donna), Pankow, J.S. (James), Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), Rotter, J.I. (Jerome I.), Siscovick, D.S. (David), Vasan, R.S. (Ramachandran S), Kaplan, R.C. (Robert C), Isaacs, A.J. (Aaron), Dupuis, J. (Josée), Duijn, C.M. (Cornelia) van, and Meigs, J.B. (James)

Abstract

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (F

Published
2016
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25. Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis

Author

Polfus, L.M. (Linda M.), Khajuria, R.K. (Rajiv K.), Schick, U.M. (Ursula), Pankratz, V.S. (Shane), Pazoki, R. (Raha), Brody, J.A. (Jennifer A.), Chen, M.-H. (Ming-Huei), Auer, P. (Paul), Floyd, J. (James), Huang, J. (Jian), Lange, L.A. (Leslie), Rooij, F.J.A. (Frank) van, Gibbs, R.A. (Richard), Metcalf, G.A. (Ginger A.), Muzny, D. (Donna), Veeraraghavan, N. (Narayanan), Walter, K. (Klaudia), Chen, L. (Lu), Yanek, L.R. (Lisa), Becker, L.C. (Lewis), Peloso, G.M. (Gina), Wakabayashi, A. (Aoi), Kals, M. (Mart), Metspalu, A. (Andres), Esko, T. (Tõnu), Fox, K. (Keolu), Wallace, R. (Robert), Franceshini, N. (Nora), Aleksic, N. (Nena), Rice, K.M. (Kenneth), Bartz, T.M. (Traci M.), Lyytikäinen, L.-P. (Leo-Pekka), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Raitakari, O.T. (Olli T.), Li-Gao, R. (Ruifang), Mook-Kanamori, D.O. (Dennis), Lettre, G. (Guillaume), Duijn, C.M. (Cornelia) van, Franco, O.H. (Oscar), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Uitterlinden, A.G. (André), Wilson, J.F. (James), Psaty, B.M. (Bruce), Soranzo, N. (Nicole), Dehghan, A. (Abbas), Boerwinkle, E.A. (Eric), Zhang, X. (Xiaoling), Johnson, A.D. (Andrew), O'Donnell, C.J. (Christopher), Johnsen, J.M. (Jill M.), Reiner, A. (Alexander), Ganesh, S.K. (Santhi), Sankaran, V.G. (Vijay G.), Polfus, L.M. (Linda M.), Khajuria, R.K. (Rajiv K.), Schick, U.M. (Ursula), Pankratz, V.S. (Shane), Pazoki, R. (Raha), Brody, J.A. (Jennifer A.), Chen, M.-H. (Ming-Huei), Auer, P. (Paul), Floyd, J. (James), Huang, J. (Jian), Lange, L.A. (Leslie), Rooij, F.J.A. (Frank) van, Gibbs, R.A. (Richard), Metcalf, G.A. (Ginger A.), Muzny, D. (Donna), Veeraraghavan, N. (Narayanan), Walter, K. (Klaudia), Chen, L. (Lu), Yanek, L.R. (Lisa), Becker, L.C. (Lewis), Peloso, G.M. (Gina), Wakabayashi, A. (Aoi), Kals, M. (Mart), Metspalu, A. (Andres), Esko, T. (Tõnu), Fox, K. (Keolu), Wallace, R. (Robert), Franceshini, N. (Nora), Aleksic, N. (Nena), Rice, K.M. (Kenneth), Bartz, T.M. (Traci M.), Lyytikäinen, L.-P. (Leo-Pekka), Kähönen, M. (Mika), Lehtimäki, T. (Terho), Raitakari, O.T. (Olli T.), Li-Gao, R. (Ruifang), Mook-Kanamori, D.O. (Dennis), Lettre, G. (Guillaume), Duijn, C.M. (Cornelia) van, Franco, O.H. (Oscar), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Uitterlinden, A.G. (André), Wilson, J.F. (James), Psaty, B.M. (Bruce), Soranzo, N. (Nicole), Dehghan, A. (Abbas), Boerwinkle, E.A. (Eric), Zhang, X. (Xiaoling), Johnson, A.D. (Andrew), O'Donnell, C.J. (Christopher), Johnsen, J.M. (Jill M.), Reiner, A. (Alexander), Ganesh, S.K. (Santhi), and Sankaran, V.G. (Vijay G.)

Abstract

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10−10) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10−27). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that pref

Published
2016
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29. The first myriapod genome sequence reveals conservative arthropod gene content in the centipede Strigamia maritima

Author

Chipman, A.D., Ferrier, D.E.K., Brena, C., Qu, J., Hughes, D.S.T., Schroeder, R., Torres-Oliva, M., Znassi, N., Jiang, H., Almeida, F.C., Alonso, C.R., Apostolou, Z., Aqrawi, P., Arthur, W., Barna, J.C.J., Blankenburg, K.P., Brites, D., Capella-Gutierrez, S., Coyle, M., Dearden, P.K., Du Pasquier, L., Duncan, E.J., Ebert, D., Eibner, C., Erikson, G., Evans, P.D., Extavour, C.G., Francisco, L., Gabaldon, T., Gillis, W.J., Goodwin-Horn, E.A., Green, J.E., Griffiths-Jones, S., Grimmelikhuijzen, C.J.P., Gubbala, S., Guigo, R., Han, Y., Hauser, F., Havlak, P., Hayden, L., Helbing, S., Holder, M., Hui, J.H.L., Hunn, J.P., Hunnekuhl, V.S., Jackson, L., Javaid, M., Jhangiani, S.N., Jiggins, F.M., Jones, T.E., Kaiser, T.S., Kalra, D., Kenny, N.J., Korchina, V., Kovar, C.L., Kraus, F.B., Lapraz, F., Lee, S.L., Lv, J., Mandapat, C., Manning, G., Mariotti, M., Mata, R., Mathew, T., Neumann, T., Newsham, I., Ngo, D.N., Ninova, M., Okwuonu, G., Ongeri, F., Palmer, W.J., Patil, S., Patraquim, P., Pham, C., Pu, L.L., Putman, N.H., Rabouille, C., Ramos, O.M., Rhodes, A.C., Robertson, H.E., Robertson, H.M., Ronshaugen, M., Rozas, J., Saada, N., Sanchez-Gracia, A., Scherer, S.E., Schurko, A.M., Siggens, K.W., Simmons, D., Stief, A., Stolle, E., Telford, M.J., Tessmar-Raible, K., Thornton, R., Zee, M. van der, Von Haeseler, A., Williams, J.M., Willis, J.H., Wu, Y., Zou, X., Lawson, D., Muzny, D.M., Worley, K.C., Gibbs, R.A., Akam, M., and Richards, S.

Published
2014

30. Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

Author

Delaneau O., Marchini J., McVeanh G.A., Donnelly P., Lunter G., Marchini J.L., Myers, S., Gupta-Hinch, A., Iqbal, Z., Mathieson I., Rimmer, A., Xifara, D.K., Kerasidou, A., Churchhouse, C., Altshuler, D.M., Gabriel, S.B., Lander, E.S., Gupta, N., Daly, M.J., DePristo, M.A., Banks, E., Bhatia G., Carneiro, M.O., Del Angel G., Genovese G., Handsaker, R.E., Hartl, C., McCarroll, S.A., Nemesh J.C., Poplin, R.E., Schaffner, S.F., Shakir, K., Sabeti P.C., Grossman, S.R., Tabrizi, S., Tariyal, R., Li H., Reich, D., Durbin, R.M., Hurles, M.E., Balasubramaniam, S., Burton J., Danecek P., Keane, T.M., Kolb-Kokocinski, A., McCarthy, S., Stalker J., Quail, M., Ayub Q., Chen, Y., Coffey, A.J., Colonna V., Huang, N., Jostins L., Scally, A., Walter, K., Xue, Y., Zhang, Y., Blackburne, B., Lindsay, S.J., Ning, Z., Frankish, A., Harrow J., Chris, T.-S., Abecasis G.R., Kang H.M., Anderson P., Blackwell, T., Busonero F., Fuchsberger, C., Jun G., Maschio, A., Porcu, E., Sidore, C., Tan, A., Trost, M.K., Bentley, D.R., Grocock, R., Humphray, S., James, T., Kingsbury, Z., Bauer, M., Cheetham, R.K., Cox, T., Eberle, M., Murray L., Shaw, R., Chakravarti, A., Clark, A.G., Keinan, A., Rodriguez-Flores J.L., De LaVega F.M., Degenhardt J., Eichler, E.E., Flicek P., Clarke L., Leinonen, R., Smith, R.E., Zheng-Bradley X., Beal, K., Cunningham F., Herrero J., McLaren W.M., Ritchie G.R.S., Barker J., Kelman G., Kulesha, E., Radhakrishnan, R., Roa, A., Smirnov, D., Streeter I., Toneva I., Gibbs, R.A., Dinh H., Kovar, C., Lee, S., Lewis L., Muzny, D., Reid J., Wang, M., Yu F., Bainbridge, M., Challis, D., Evani, U.S., Lu J., Nagaswamy, U., Sabo, A., Wang, Y., Yu J., Fowler G., Hale W., Kalra, D., Green, E.D., Knoppers, B.M., Korbel J.O., Rausch, T., Sttz, A.M., Lee, C., Griffin L., Hsieh, C.-H., Mills, R.E., Von Grotthuss, M., Zhang, C., Shi X., Lehrach H., Sudbrak, R., Amstislavskiy V.S., Lienhard, M., Mertes F., Sultan, M., Timmermann, B., Yaspo, M.L., Herwig, S.R., Mardis, E.R., Wilson, R.K., Fulton L., Fulton, R., Weinstock G.M., Chinwalla, A., Ding L., Dooling, D., Koboldt, D.C., McLellan, M.D., Wallis J.W., Wendl, M.C., Zhang Q., Marth G.T., Garrison, E.P., Kural, D., Lee W.-P., Leong W.F., Ward, A.N., Wu J., Zhang, M., Nickerson, D.A., Alkan, C., Hormozdiari F., Ko, A., Sudmant P.H., Schmidt J.P., Davies, C.J., Gollub J., Webster, T., Wong, B., Zhan, Y., Sherry, S.T., Xiao, C., Church, D., Ananiev V., Belaia, Z., Beloslyudtsev, D., Bouk, N., Chen, C., Cohen, R., Cook, C., Garner J., Hefferon, T., Kimelman, M., Liu, C., Lopez J., Meric P., Ostapchuk, Y., Phan L., Ponomarov, S., Schneider V., Shekhtman, E., Sirotkin, K., Slotta, D., Zhang H., Wang J., Fang X., Guo X., Jian, M., Jiang H., Jin X., Li G., Li J., Li, Y., Liu X., Lu, Y., Ma X., Tai, S., Tang, M., Wang, B., Wang G., Wu H., Wu, R., Yin, Y., Zhang W., Zhao J., Zhao, M., Zheng X., Lachlan H., Fang L., Li Q., Li, Z., Lin H., Liu, B., Luo, R., Shao H., Xie, Y., Ye, C., Yu, C., Zheng H., Zhu H., Cai H., Cao H., Su, Y., Tian, Z., Yang H., Yang L., Zhu J., Cai, Z., Albrecht, M.W., Borodina, T.A., Auton, A., Yoon, S.C., Lihm J., Makarov V., Jin H., Kim W., Kim, K.C., Gottipati, S., Jones, D., Cooper, D.N., Ball, E.V., Stenson P.D., Barnes, B., Kahn, S., Ye, K., Batzer, M.A., Konkel, M.K., Walker J.A., MacArthur, D.G., Lek, M., Shriver, M.D., Bustamante, C.D., Gravel, S., Kenny, E.E., Kidd J.M., Lacroute P., Maples, B.K., Moreno-Estrada, A., Zakharia F., Henn, B., Sandoval, K., Byrnes J.K., Halperin, E., Baran, Y., Craig, D.W., Christoforides, A., Izatt, T., Kurdoglu, A.A., Sinari, S.A., Homer, N., Squire, K., Sebat J., Bafna V., Burchard, E.G., Hernandez, R.D., Gignoux, C.R., Haussler, D., Katzman, S.J., Kent W.J., Howie, B., Ruiz-Linares, A., Dermitzakis, E.T., Lappalainen, T., Devine, S.E., Maroo, A., Tallon L.J., Rosenfeld J.A., Michelson L.P., Angius, A., Cucca F., Sanna, S., Bigham, A., Jones, C., Reinier F., Lyons, R., Schlessinger, D., Awadalla P., Hodgkinson, A., Oleksyk, T.K., Martinez-Cruzado J.C., Fu, Y., Xiong, M., Jorde L., Witherspoon, D., Xing J., Browning, B.L., Hajirasouliha I., Chen, K., Albers, C.A., Gerstein, M.B., Abyzov, A., Chen J., Habegger L., Harmanci, A.O., Mu X.J., Sisu, C., Balasubramanian, S., Jin, M., Khurana, E., Clarke, D., Michaelson J.J., OSullivan, C., Barnes, K.C., Gharani, N., Toji L.H., Gerry, N., Kaye J.S., Kent, A., Mathias, R., Ossorio P.N., Parker, M., Rotimi, C.N., Royal, C.D., Tishkoff, S., Via, M., Bodmer W., Bedoya G., Yang G., You, C.J., Garcia-Montero, A., Orfao, A., Dutil J., Brooks L.D., Felsenfeld, A.L., McEwen J.E., Clemm, N.C., Guyer, M.S., Peterson J.L., Duncanson, A., Dunn, M., Peltonen L., and 1000 Genomes Project Consortium

Subjects
haplotype, genetic association, genotype, General Physics and Astronomy, Genome-wide association study, genetic analysis, gene sequence, Biology, gene frequency, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, polymorphism, Gene Frequency, single nucleotide polymorphism, Humans, chromosome, human, 1000 Genomes Project, indel mutation, genome, Alleles, Genetic association, Genetics, Whole genome sequencing, Multidisciplinary, accuracy, Genome, Human, Haplotype, allele, article, reference database, General Chemistry, Microarray Analysis, chromosome 20, Haplotypes, Human genome, microarray analysis, Imputation (genetics), Algorithms, SNP array, Genome-Wide Association Study
Abstract

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved.

Published
2014
Full Text
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31. DOORS syndrome : phenotype, genotype and comparison with coffin-siris syndrome

Author

Campeau, Philippe M., Hennekam, Raoul C., Aftimos, A., Banka, S., Begleiter, M.L., Bilo, L., Blair, E., Burrage, L.C., Liu, D.S., De Bie, I., Félix, T.M., Giltay, J.C., Gibbs, R.A., Giuliano, F., Hadzsiev, K., Hori, M., Kariminejad, A., Kayserili, H., Kerr, B., Lee, B.H., Lu, J.T., Male, A., Meenakshi, G., Mey, A., Murray, M.L., Nair, L.D.V., Nampoothiri, S., Newman, W.G., Peluso, S., Peters, H., Powell, R., Repetto, G.M., Rump, P., Santos-Simarro, F., Stewart, F., Van Bever, Y., Van Den Ende, J., Wieczorek, Dagmar, Wisniewska, M., and Sisodiya, S.M.

Subjects
Medizin
Published
2014

32. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy

Author

McMichael, G., Bainbridge, M.N., Haan, E., Corbett, M., Gardner, A., Thompson, S., Bon, B.W.M. van, Eyk, C.L. van, Broadbent, J., Reynolds, C., O'Callaghan, M.E., Nguyen, L.S., Adelson, D.L., Russo, R., Jhangiani, S., Doddapaneni, H., Muzny, D.M., Gibbs, R.A., Gecz, J., MacLennan, A.H., McMichael, G., Bainbridge, M.N., Haan, E., Corbett, M., Gardner, A., Thompson, S., Bon, B.W.M. van, Eyk, C.L. van, Broadbent, J., Reynolds, C., O'Callaghan, M.E., Nguyen, L.S., Adelson, D.L., Russo, R., Jhangiani, S., Doddapaneni, H., Muzny, D.M., Gibbs, R.A., Gecz, J., and MacLennan, A.H.

Abstract

Contains fulltext : 154458.pdf (publisher's version ) (Closed access), Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Published
2015

33. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome

Author

White, J., Mazzeu, J.F., Hoischen, A., Jhangiani, S.N., Gambin, T., Alcino, M.C., Penney, S., Saraiva, J.M., Hove, H., Skovby, F., Kayserili, H., Estrella, E., Silfhout, A.T. van, Steehouwer, M., Muzny, D.M., Sutton, V.R., Gibbs, R.A., Lupski, J.R., Brunner, H.G., Bon, B.W. van, Carvalho, C.M., White, J., Mazzeu, J.F., Hoischen, A., Jhangiani, S.N., Gambin, T., Alcino, M.C., Penney, S., Saraiva, J.M., Hove, H., Skovby, F., Kayserili, H., Estrella, E., Silfhout, A.T. van, Steehouwer, M., Muzny, D.M., Sutton, V.R., Gibbs, R.A., Lupski, J.R., Brunner, H.G., Bon, B.W. van, and Carvalho, C.M.

Abstract

Item does not contain fulltext, Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.

Published
2015

34. The Matchmaker Exchange: a platform for rare disease gene discovery

Author

Philippakis, A.A., Azzariti, D.R., Beltran, S., Brookes, A.J., Brownstein, C.A., Brudno, M., Brunner, H.G., Buske, O.J., Carey, K., Doll, C., Dumitriu, S., Dyke, S.O.M., Dunnen, J.T. den, Firth, H.V., Gibbs, R.A., Girdea, M., Gonzalez, M., Haendel, M.A., Hamosh, A., Holm, I.A., Huang, L., Hurles, M.E., Hutton, B., Krier, J.B., Misyura, A., Mungall, C.J., Paschall, J., Paten, B., Robinson, P.N., Schiettecatte, F., Sobreira, N.L., Swaminathan, G.J., Taschner, P.E.M., Terry, S.F., Washington, N.L., Zuchner, S., Boycott, K.M., Rehm, H.L., Philippakis, A.A., Azzariti, D.R., Beltran, S., Brookes, A.J., Brownstein, C.A., Brudno, M., Brunner, H.G., Buske, O.J., Carey, K., Doll, C., Dumitriu, S., Dyke, S.O.M., Dunnen, J.T. den, Firth, H.V., Gibbs, R.A., Girdea, M., Gonzalez, M., Haendel, M.A., Hamosh, A., Holm, I.A., Huang, L., Hurles, M.E., Hutton, B., Krier, J.B., Misyura, A., Mungall, C.J., Paschall, J., Paten, B., Robinson, P.N., Schiettecatte, F., Sobreira, N.L., Swaminathan, G.J., Taschner, P.E.M., Terry, S.F., Washington, N.L., Zuchner, S., Boycott, K.M., and Rehm, H.L.

Abstract

Item does not contain fulltext, There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Published
2015

35. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome

Author

Burrage, L.C., Charng, W.L., Eldomery, M.K., Willer, J.R., Davis, E.E., Lugtenberg, D., Zhu, W., Leduc, M.S., Akdemir, Z.C., Azamian, M., Zapata, G., Hernandez, P.P., Schoots, J., Munnik, S.A. de, Roepman, R., Pearring, J.N., Jhangiani, S., Katsanis, N., Vissers, L.E.L.M., Brunner, H.G., Beaudet, A.L., Rosenfeld, J.A., Muzny, D.M., Gibbs, R.A., Eng, C.M., Xia, F., Lalani, S.R., Lupski, J.R., Bongers, E.M.H.F., Yang, Y, Burrage, L.C., Charng, W.L., Eldomery, M.K., Willer, J.R., Davis, E.E., Lugtenberg, D., Zhu, W., Leduc, M.S., Akdemir, Z.C., Azamian, M., Zapata, G., Hernandez, P.P., Schoots, J., Munnik, S.A. de, Roepman, R., Pearring, J.N., Jhangiani, S., Katsanis, N., Vissers, L.E.L.M., Brunner, H.G., Beaudet, A.L., Rosenfeld, J.A., Muzny, D.M., Gibbs, R.A., Eng, C.M., Xia, F., Lalani, S.R., Lupski, J.R., Bongers, E.M.H.F., and Yang, Y

Abstract

Item does not contain fulltext, Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6( *)) and c.35_38delTCAA (p.Ile12Lysfs( *)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

Published
2015

36. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, J. (Jennifer), Chu, A.Y. (Audrey Y), Willems, S.M. (Sara), Wang, S. (Shuai), Yaghootkar, H. (Hanieh), Brody, J.A. (Jennifer A.), Dauriz, M. (Marco), Hivert, M.-F. (Marie-France), Raghavan, S. (Sridharan), Lipovich, L. (Leonard), Hidalgo, B. (Bertha), Fox, K. (Keolu), Huffman, J.E. (Jennifer), An, P. (Ping), Lu, Y. (Yingchang), Rasmussen-Torvik, L.J. (Laura), Grarup, N. (Niels), Ehm, M.G. (Margaret G), L. Li, Baldridge, A.S. (Abigail S), Stancáková, A. (Alena), Abrol, R. (Ravinder), Besse, C. (Céline), Boland, A. (Anne), Bork-Jensen, J. (Jette), Fornage, M. (Myriam), Freitag, C.M. (Christine), Garcia, M. (Melissa), Guo, X. (Xiuqing), Hara, K. (Kazuo), Isaacs, A. (Aaron), Jakobsdottir, M. (Margret), Lange, L.A. (Leslie), Layton, J.C. (Jill C), Li, M. (Man), Zhao, J.H. (Jing Hua), Meidtner, K. (Karina), Morrison, A.C. (Alanna), Nalls, M.A. (Michael), Peters, M.J. (Marjolein), Sabater-Lleal, M. (Maria), Schurmann, C. (Claudia), Silveira, A. (Angela), Smith, A.V. (Davey), Southam, L. (Lorraine), Stoiber, M.H. (Marcus H), Strawbridge, R.J. (Rona), Taylor, K.D. (Kent), Varga, T.V. (Tibor V.), Allin, K.H. (Kristine H), Amin, N. (Najaf), Aponte, J.L. (Jennifer L), Aung, T. (Tin), Barbieri, C. (Caterina), Bihlmeyer, N.A. (Nathan A.), Boehnke, M. (Michael), Bombieri, C. (Cristina), Bowden, D.W. (Donald), Burns, S.M. (Sean M), Chen, Y. (Yuning), Chen, Y.-D. (Yii-Deri), Cheng, C-Y. (Ching-Yu), Correa, D.D., Czajkowski, J. (Jacek), Dehghan, A. (Abbas), Ehret, G.B. (Georg), Eiriksdottir, G. (Gudny), Escher, S.A. (Stefan A), Farmaki, A.-E. (Aliki-Eleni), Frånberg, M. (Mattias), Gambaro, G. (Giovanni), Giulianini, F. (Franco), Goddard, W.A. (William A), Goel, A. (Anuj), Gottesman, R.F. (Rebecca), Grove, M.L. (Megan), Gustafsson, S. (Stefan), Hai, Y. (Yang), Hallmans, G. (Göran), Heo, J. (Jiyoung), Hoffmann, P. (Per), Ikram, M.K. (Kamran), Jensen, R.A. (Richard), Jørgensen, M.E. (Marit), Jorgensen, T. (Torben), Karaleftheri, M. (Maria), Khor, C.C., Kirkpatrick, A. (Andrea), Kraja, A. (Aldi), Kuusisto, J. (Johanna), Lange, E.M. (Ethan), Lee, I.T., Lee, W.-J. (Wen-Jane), Leong, A. (Aaron), Liao, J. (Jie), Liu, C. (Chunyu), Liu, Y. (YongMei), Lindgren, C.M. (Cecilia), Linneberg, A. (Allan), Malerba, G. (Giovanni), Mamakou, V. (Vasiliki), Marouli, E. (Eirini), Maruthur, N.M. (Nisa M), Matchan, A. (Angela), McKean-Cowdin, R. (Roberta), McLeod, O. (Olga), Metcalf, G.A. (Ginger A.), Mohlke, K.L. (Karen), Muzny, D. (Donna), Ntalla, I. (Ioanna), Palmer, N.D. (Nicholette), Pasko, D. (Dorota), Peter, A. (Andreas), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rice, K.M. (Kenneth), Sala, C. (Cinzia), Sennblad, B. (Bengt), Serafetinidis, I. (Ioannis), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Speliotes, E.K. (Elizabeth), Stahl, E.A. (Eli), Stirrups, K. (Kathy), Tentolouris, N. (Nikos), Thanopoulou, A. (Anastasia), Torres, M. (Mina), Traglia, M. (Michela), Tsafantakis, E. (Emmanouil), Javad, S. (Sundas), Yanek, L.R. (Lisa), Zengini, E. (Eleni), Becker, D.M. (Diane), Bis, J.C. (Joshua), Brown, J.B. (James B), Cupples, L.A. (Adrienne), Hansen, T. (T.), Ingelsson, E. (Erik), Karter, A.J. (Andrew J), Lorenzo, C. (Carlos), Mathias, J. (Jasmine), Norris, J.M. (Jill M), Peloso, G.M. (Gina), Sheu, W.H.-H. (Wayne H.-H.), Toniolo, D. (Daniela), Vaidya, D. (Dhananjay), Varma, R. (Rohit), Wagenknecht, L.E. (Lynne), Boeing, H. (Heiner), Bottinger, E.P. (Erwin P.), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Ferrannini, E. (Ele), Franco, O.H. (Oscar), Franks, P.W. (Paul), Gibbs, R.A. (Richard A), Gudnason, V. (Vilmundur), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), Hofman, A. (Albert), Jansson, J.-H. (Jan-Håkan), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Levy, D. (Daniel), Oostra, B.A. (Ben), O'Donnell, C.J. (Christopher J.), O'Rahilly, S. (Stephen), Padmanabhan, S. (Sandosh), Pankow, J.S. (James), Polasek, O. (Ozren), Province, M.A. (Mike), Rich, S.S. (Stephen S.), Ridker, P.M. (Paul), Rudan, I. (Igor), Schulze, M.B. (Matthias B), Smith, B.H. (Blair), Uitterlinden, A.G. (André), Walker, M. (Mark), Watkins, H. (Hugh), Wong, T.Y. (Tien Yin), Zeggini, E. (Eleftheria), Laakso, M. (Markku), Borecki, I.B. (Ingrid), Chasman, D.I. (Daniel), Pedersen, O. (Oluf), Psaty, B.M. (Bruce), Shyong Tai, E., Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Waterworth, D.M. (Dawn), Boerwinkle, E.A. (Eric), Kao, W.H.L. (Wen), Florez, J.C. (Jose), Loos, R.J.F. (Ruth), Wilson, J.G. (James), Frayling, T.M. (Timothy M.), Siscovick, D.S. (David), Dupuis, J. (Josée), Rotter, J.I. (Jerome I.), Meigs, J.B. (James), Scott, R.A. (Robert), Goodarzi, M. (Mark), Wessel, J. (Jennifer), Chu, A.Y. (Audrey Y), Willems, S.M. (Sara), Wang, S. (Shuai), Yaghootkar, H. (Hanieh), Brody, J.A. (Jennifer A.), Dauriz, M. (Marco), Hivert, M.-F. (Marie-France), Raghavan, S. (Sridharan), Lipovich, L. (Leonard), Hidalgo, B. (Bertha), Fox, K. (Keolu), Huffman, J.E. (Jennifer), An, P. (Ping), Lu, Y. (Yingchang), Rasmussen-Torvik, L.J. (Laura), Grarup, N. (Niels), Ehm, M.G. (Margaret G), L. Li, Baldridge, A.S. (Abigail S), Stancáková, A. (Alena), Abrol, R. (Ravinder), Besse, C. (Céline), Boland, A. (Anne), Bork-Jensen, J. (Jette), Fornage, M. (Myriam), Freitag, C.M. (Christine), Garcia, M. (Melissa), Guo, X. (Xiuqing), Hara, K. (Kazuo), Isaacs, A. (Aaron), Jakobsdottir, M. (Margret), Lange, L.A. (Leslie), Layton, J.C. (Jill C), Li, M. (Man), Zhao, J.H. (Jing Hua), Meidtner, K. (Karina), Morrison, A.C. (Alanna), Nalls, M.A. (Michael), Peters, M.J. (Marjolein), Sabater-Lleal, M. (Maria), Schurmann, C. (Claudia), Silveira, A. (Angela), Smith, A.V. (Davey), Southam, L. (Lorraine), Stoiber, M.H. (Marcus H), Strawbridge, R.J. (Rona), Taylor, K.D. (Kent), Varga, T.V. (Tibor V.), Allin, K.H. (Kristine H), Amin, N. (Najaf), Aponte, J.L. (Jennifer L), Aung, T. (Tin), Barbieri, C. (Caterina), Bihlmeyer, N.A. (Nathan A.), Boehnke, M. (Michael), Bombieri, C. (Cristina), Bowden, D.W. (Donald), Burns, S.M. (Sean M), Chen, Y. (Yuning), Chen, Y.-D. (Yii-Deri), Cheng, C-Y. (Ching-Yu), Correa, D.D., Czajkowski, J. (Jacek), Dehghan, A. (Abbas), Ehret, G.B. (Georg), Eiriksdottir, G. (Gudny), Escher, S.A. (Stefan A), Farmaki, A.-E. (Aliki-Eleni), Frånberg, M. (Mattias), Gambaro, G. (Giovanni), Giulianini, F. (Franco), Goddard, W.A. (William A), Goel, A. (Anuj), Gottesman, R.F. (Rebecca), Grove, M.L. (Megan), Gustafsson, S. (Stefan), Hai, Y. (Yang), Hallmans, G. (Göran), Heo, J. (Jiyoung), Hoffmann, P. (Per), Ikram, M.K. (Kamran), Jensen, R.A. (Richard), Jørgensen, M.E. (Marit), Jorgensen, T. (Torben), Karaleftheri, M. (Maria), Khor, C.C., Kirkpatrick, A. (Andrea), Kraja, A. (Aldi), Kuusisto, J. (Johanna), Lange, E.M. (Ethan), Lee, I.T., Lee, W.-J. (Wen-Jane), Leong, A. (Aaron), Liao, J. (Jie), Liu, C. (Chunyu), Liu, Y. (YongMei), Lindgren, C.M. (Cecilia), Linneberg, A. (Allan), Malerba, G. (Giovanni), Mamakou, V. (Vasiliki), Marouli, E. (Eirini), Maruthur, N.M. (Nisa M), Matchan, A. (Angela), McKean-Cowdin, R. (Roberta), McLeod, O. (Olga), Metcalf, G.A. (Ginger A.), Mohlke, K.L. (Karen), Muzny, D. (Donna), Ntalla, I. (Ioanna), Palmer, N.D. (Nicholette), Pasko, D. (Dorota), Peter, A. (Andreas), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rice, K.M. (Kenneth), Sala, C. (Cinzia), Sennblad, B. (Bengt), Serafetinidis, I. (Ioannis), Smith, J.A. (Jennifer A), Soranzo, N. (Nicole), Speliotes, E.K. (Elizabeth), Stahl, E.A. (Eli), Stirrups, K. (Kathy), Tentolouris, N. (Nikos), Thanopoulou, A. (Anastasia), Torres, M. (Mina), Traglia, M. (Michela), Tsafantakis, E. (Emmanouil), Javad, S. (Sundas), Yanek, L.R. (Lisa), Zengini, E. (Eleni), Becker, D.M. (Diane), Bis, J.C. (Joshua), Brown, J.B. (James B), Cupples, L.A. (Adrienne), Hansen, T. (T.), Ingelsson, E. (Erik), Karter, A.J. (Andrew J), Lorenzo, C. (Carlos), Mathias, J. (Jasmine), Norris, J.M. (Jill M), Peloso, G.M. (Gina), Sheu, W.H.-H. (Wayne H.-H.), Toniolo, D. (Daniela), Vaidya, D. (Dhananjay), Varma, R. (Rohit), Wagenknecht, L.E. (Lynne), Boeing, H. (Heiner), Bottinger, E.P. (Erwin P.), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Ferrannini, E. (Ele), Franco, O.H. (Oscar), Franks, P.W. (Paul), Gibbs, R.A. (Richard A), Gudnason, V. (Vilmundur), Hamsten, A. (Anders), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Hayward, C. (Caroline), Hofman, A. (Albert), Jansson, J.-H. (Jan-Håkan), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Levy, D. (Daniel), Oostra, B.A. (Ben), O'Donnell, C.J. (Christopher J.), O'Rahilly, S. (Stephen), Padmanabhan, S. (Sandosh), Pankow, J.S. (James), Polasek, O. (Ozren), Province, M.A. (Mike), Rich, S.S. (Stephen S.), Ridker, P.M. (Paul), Rudan, I. (Igor), Schulze, M.B. (Matthias B), Smith, B.H. (Blair), Uitterlinden, A.G. (André), Walker, M. (Mark), Watkins, H. (Hugh), Wong, T.Y. (Tien Yin), Zeggini, E. (Eleftheria), Laakso, M. (Markku), Borecki, I.B. (Ingrid), Chasman, D.I. (Daniel), Pedersen, O. (Oluf), Psaty, B.M. (Bruce), Shyong Tai, E., Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Waterworth, D.M. (Dawn), Boerwinkle, E.A. (Eric), Kao, W.H.L. (Wen), Florez, J.C. (Jose), Loos, R.J.F. (Ruth), Wilson, J.G. (James), Frayling, T.M. (Timothy M.), Siscovick, D.S. (David), Dupuis, J. (Josée), Rotter, J.I. (Jerome I.), Meigs, J.B. (James), Scott, R.A. (Robert), and Goodarzi, M. (Mark)

Published
2015
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38. A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.

Author

Yamamoto, S., Jaiswal, M., Charng, W.L., Gambin, T., Karaca, E., Mirzaa, G., Wiszniewski, W., Sandoval, H., Haelterman, N.A., Xiong, B., Zhang, K., Bayat, V., David, G., Li, T., Chen, K., Gala, U., Harel, T., Pehlivan, D., Penney, S., Vissers, L.E.L.M., Ligt, J. de, Jhangiani, S.N., Xie, Y., Tsang, S.H., Parman, Y., Sivaci, M., Battaloglu, E., Muzny, D., Wan, Y.W., Liu, Z., Lin-Moore, A.T., Clark, R.D., Curry, C.J., Link, N., Schulze, K.L., Boerwinkle, E., Dobyns, W.B., Allikmets, R., Gibbs, R.A., Chen, R., Lupski, J.R., Wangler, M.F., Bellen, H.J., Yamamoto, S., Jaiswal, M., Charng, W.L., Gambin, T., Karaca, E., Mirzaa, G., Wiszniewski, W., Sandoval, H., Haelterman, N.A., Xiong, B., Zhang, K., Bayat, V., David, G., Li, T., Chen, K., Gala, U., Harel, T., Pehlivan, D., Penney, S., Vissers, L.E.L.M., Ligt, J. de, Jhangiani, S.N., Xie, Y., Tsang, S.H., Parman, Y., Sivaci, M., Battaloglu, E., Muzny, D., Wan, Y.W., Liu, Z., Lin-Moore, A.T., Clark, R.D., Curry, C.J., Link, N., Schulze, K.L., Boerwinkle, E., Dobyns, W.B., Allikmets, R., Gibbs, R.A., Chen, R., Lupski, J.R., Wangler, M.F., and Bellen, H.J.

Abstract

Item does not contain fulltext

Published
2014

39. NR2F1 Mutations Cause Optic Atrophy with Intellectual Disability

Author

Bosch, D.G.M., Boonstra, F.N., Gonzaga-Jauregui, C., Xu, M., Ligt, J. de, Jhangiani, S., Wiszniewski, W., Muzny, D.M., Yntema, H.G., Pfundt, R.P., Vissers, L.E.L.M., Spruijt, L., Blokland, E.A.W., Chen, C.A., Lewis, R.A., Tsai, S.Y., Gibbs, R.A., Tsai, M.J., Lupski, J.R., Zoghbi, H.Y., Cremers, F.P.M., Vries, B. de, Schaaf, C.P., et al., Bosch, D.G.M., Boonstra, F.N., Gonzaga-Jauregui, C., Xu, M., Ligt, J. de, Jhangiani, S., Wiszniewski, W., Muzny, D.M., Yntema, H.G., Pfundt, R.P., Vissers, L.E.L.M., Spruijt, L., Blokland, E.A.W., Chen, C.A., Lewis, R.A., Tsai, S.Y., Gibbs, R.A., Tsai, M.J., Lupski, J.R., Zoghbi, H.Y., Cremers, F.P.M., Vries, B. de, Schaaf, C.P., and et al.

Abstract

Item does not contain fulltext, Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

Published
2014

40. Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Author

Bis, J.C. (Joshua), DeStefano, A.L. (Anita), Liu, X. (Xiaoming), Brody, J.A. (Jennifer A.), Choi, S.-H. (Seung-Hoan), Verhaaren, B.F.J. (Benjamin), Debette, S. (Stéphanie), Ikram, M.A. (Arfan), Shahar, E. (Eyal), Butler Jr., K.R. (Kenneth), Gottesman, R.F. (Rebecca), Muzny, D. (Donna), Kovar, C.L. (Christie), Psaty, B.M. (Bruce), Hofman, A. (Albert), Lumley, T. (Thomas), Gupta, M. (Mayetri), Wolf, P.A. (Philip), Duijn, C.M. (Cornelia) van, Gibbs, R.A. (Richard), Mosley, T.H. (Thomas), Longstreth Jr., W.T., Boerwinkle, E.A. (Eric), Seshadri, S. (Sudha), Fornage, M. (Myriam), Bis, J.C. (Joshua), DeStefano, A.L. (Anita), Liu, X. (Xiaoming), Brody, J.A. (Jennifer A.), Choi, S.-H. (Seung-Hoan), Verhaaren, B.F.J. (Benjamin), Debette, S. (Stéphanie), Ikram, M.A. (Arfan), Shahar, E. (Eyal), Butler Jr., K.R. (Kenneth), Gottesman, R.F. (Rebecca), Muzny, D. (Donna), Kovar, C.L. (Christie), Psaty, B.M. (Bruce), Hofman, A. (Albert), Lumley, T. (Thomas), Gupta, M. (Mayetri), Wolf, P.A. (Philip), Duijn, C.M. (Cornelia) van, Gibbs, R.A. (Richard), Mosley, T.H. (Thomas), Longstreth Jr., W.T., Boerwinkle, E.A. (Eric), Seshadri, S. (Sudha), and Fornage, M. (Myriam)

Abstract

Background: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. Methods and Results: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). Conclusion: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

Published
2014
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41. The genome of Apis mellifera : dialog between linkage map and sequence assembly

Author

Solignac, M., Zhang, L., Mougel, F., Li, B., Vautrin, D., Monnerot, M., Cornuet, J.-M., C. Worley, K., M. Weinstock, G., Gibbs, R.A., Simonneau, Evelyne, Laboratoire Evolution, Génomes et Spéciation (LEGS), and Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology
Published
2007

43. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

Author

Baud, A., Hermsen, R., Guryev, V., Stridh, P., Graham, D., McBride, M.W., Foroud, T., Calderari, S., Diez, M., Ockinger, J., Beyeen, A.D., Gillett, A., Abdelmagid, N., Guerreiro-Cacais, A.O., Jagodic, M., Tuncel, J., Norin, U., Beattie, E., Huynh, N., Miller, W.H., Koller, D.L., Alam, I., Falak, S., Osborne-Pellegrin, M., Martinez-Membrives, E., Canete, T., Blazquez, G., Vicens-Costa, E., Mont-Cardona, C., Diaz-Moran, S., Tobena, A., Hummel, O., Zelenika, D., Saar, K., Patone, G., Bauerfeind, A., Bihoreau, M.T., Heinig, M., Lee, Y.A., Rintisch, C., Schulz, H., Wheeler, D.A., Worley, K.C., Muzny, D.M., Gibbs, R.A., Lathrop, M., Lansu, N., Toonen, P., Ruzius, F.P., de Bruijn, E., Hauser, H., Adams, D.J., Keane, T., Atanur, S.S., Aitman, T.J., Flicek, P., Malinauskas, T., Jones, E.Y., Ekman, D., Lopez-Aumatell, R., Dominiczak, A.F., Johannesson, M., Holmdahl, R., Olsson, T., Gauguier, D., Hubner, N., Fernandez-Teruel, A., Cuppen, E., Mott, R., Flint, J., Baud, A., Hermsen, R., Guryev, V., Stridh, P., Graham, D., McBride, M.W., Foroud, T., Calderari, S., Diez, M., Ockinger, J., Beyeen, A.D., Gillett, A., Abdelmagid, N., Guerreiro-Cacais, A.O., Jagodic, M., Tuncel, J., Norin, U., Beattie, E., Huynh, N., Miller, W.H., Koller, D.L., Alam, I., Falak, S., Osborne-Pellegrin, M., Martinez-Membrives, E., Canete, T., Blazquez, G., Vicens-Costa, E., Mont-Cardona, C., Diaz-Moran, S., Tobena, A., Hummel, O., Zelenika, D., Saar, K., Patone, G., Bauerfeind, A., Bihoreau, M.T., Heinig, M., Lee, Y.A., Rintisch, C., Schulz, H., Wheeler, D.A., Worley, K.C., Muzny, D.M., Gibbs, R.A., Lathrop, M., Lansu, N., Toonen, P., Ruzius, F.P., de Bruijn, E., Hauser, H., Adams, D.J., Keane, T., Atanur, S.S., Aitman, T.J., Flicek, P., Malinauskas, T., Jones, E.Y., Ekman, D., Lopez-Aumatell, R., Dominiczak, A.F., Johannesson, M., Holmdahl, R., Olsson, T., Gauguier, D., Hubner, N., Fernandez-Teruel, A., Cuppen, E., Mott, R., and Flint, J.

Abstract

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species., Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

Published
2013

44. A systematic survey of loss-of-function variants in human protein-coding genes

Author

MacArthur, D.G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J.K., Montgomery, S.B., Albers, C.A., Zhang, Z.D., Conrad, D.F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M.A., Banks, E., Hu, M., Handsaker, R.E., Rosenfeld, J.A., Fromer, M., Jin, M., Mu, X.J., Khurana, E., Ye, K., Kay, M., Saunders, G.I., Suner, M.M., Hunt, T., Barnes, I.H., Amid, C., Carvalho-Silva, D.R., Bignell, A.H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D.N., Xue, Y., Romero, I.G., Genomes Project, C., Wang, J, Li, Y., Gibbs, R.A., McCarroll, S.A., Dermitzakis, E.T., Pritchard, J.K., Barrett, J.C., Harrow, J., Hurles, M.E., Gerstein, M.B., Tyler-Smith, C., MacArthur, D.G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J.K., Montgomery, S.B., Albers, C.A., Zhang, Z.D., Conrad, D.F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M.A., Banks, E., Hu, M., Handsaker, R.E., Rosenfeld, J.A., Fromer, M., Jin, M., Mu, X.J., Khurana, E., Ye, K., Kay, M., Saunders, G.I., Suner, M.M., Hunt, T., Barnes, I.H., Amid, C., Carvalho-Silva, D.R., Bignell, A.H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D.N., Xue, Y., Romero, I.G., Genomes Project, C., Wang, J, Li, Y., Gibbs, R.A., McCarroll, S.A., Dermitzakis, E.T., Pritchard, J.K., Barrett, J.C., Harrow, J., Hurles, M.E., Gerstein, M.B., and Tyler-Smith, C.

Abstract

Item does not contain fulltext, Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

Published
2012

45. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.

Author

Khanna, H., Davis, E.E., Murga-Zamalloa, C.A., Estrada-Cuzcano, A., Lopez, I., Hollander, A.I. den, Zonneveld-Vrieling, M.N., Othman, M.I., Waseem, N., Chakarova, C., Maubaret, C., Diaz-Font, A., Macdonald, I., Muzny, D.M., Wheeler, D.A., Morgan, M., Lewis, L.R., Logan, C.V., Tan, P.L., Beer, M.A., Inglehearn, C.F., Lewis, R.A., Jacobson, S.G., Bergmann, C., Beales, P.L., Attie-Bitach, T., Johnson, C.A., Otto, E.A., Bhattacharya, S.S., Hildebrandt, F., Gibbs, R.A., Koenekoop, R.K., Swaroop, A., Katsanis, N., Khanna, H., Davis, E.E., Murga-Zamalloa, C.A., Estrada-Cuzcano, A., Lopez, I., Hollander, A.I. den, Zonneveld-Vrieling, M.N., Othman, M.I., Waseem, N., Chakarova, C., Maubaret, C., Diaz-Font, A., Macdonald, I., Muzny, D.M., Wheeler, D.A., Morgan, M., Lewis, L.R., Logan, C.V., Tan, P.L., Beer, M.A., Inglehearn, C.F., Lewis, R.A., Jacobson, S.G., Bergmann, C., Beales, P.L., Attie-Bitach, T., Johnson, C.A., Otto, E.A., Bhattacharya, S.S., Hildebrandt, F., Gibbs, R.A., Koenekoop, R.K., Swaroop, A., and Katsanis, N.

Abstract

Contains fulltext : 81600.pdf (publisher's version ) (Closed access), Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.

Published
2009

46. Initial sequencing and analysis of the human genome

Author

Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA, Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA, Sanger Ctr, Hinxton CB10 1RQ, Cambs, England, Washington Univ, Genome Sequencing Ctr, St Louis, MO 63108 USA, US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA, Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA, Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA, Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA, Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77225 USA, RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan, Genoscope, F-91057 Evry, France, CNRS, UMR 8030, F-91057 Evry, France, Genome Therapeut Corp, GTC Sequencing Ctr, Waltham, MA 02453 USA, Inst Mol Biotechnol, Dept Genome Anal, D-07745 Jena, Germany, Chinese Acad Sci, Inst Genet, Ctr Human Genome, Beijing Genom Inst, Beijing 100101, Peoples R China, So China Natl Human Genome Res Ctr, Shanghai 201203, Peoples R China, No China Natl Human Genome Res Ctr, Beijing 100176, Peoples R China, Inst Syst Biol, Multimegabase Sequencing Ctr, Seattle, WA 98105 USA, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA, Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA, Stanford Univ, Stanford Human Genome Ctrr, Sch Med, Stanford, CA 94305 USA, Univ Washington, Genome Ctr, Seattle, WA 98195 USA, Keio Univ, Sch Med, Dept Biol Mol, Shinjuku Ku, Tokyo 1608582, Japan, Univ Texas, SW Med Ctr, Dallas, TX 75235 USA, Univ Oklahoma, Adv Ctr Genome Technol, Dept Chem & Biochem, Norman, OK 73019 USA, Max Planck Inst Mol Genet, D-14195 Berlin, Germany, Cold Spring Harbor Lab, Lita Annenberg Hazen Genome Ctr, Cold Spring Harbor, NY 11724 USA, GBF, German Res Ctr Biotechnol, D-38124 Braunschweig, Germany, NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA, Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA, Univ Hosp Cleveland, Cleveland, OH 44106 USA, EMBL, European Bioinformat Inst, Cambridge CB10 1SD, England, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany, MIT, Dept Biol, Cambridge, MA 02139 USA, Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA, Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA, Affymetrix Inc, Berkeley, CA 94710 USA, RIKEN, Yokoham Inst, Genom Sci Ctr, Genom Explorat Res Grp, Tsurumi Ku, Kanagawa 2300045, Japan, Univ Calif Santa Cruz, Dept Comp Sci, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA, Univ Dublin Trinity Coll, Dept Genet, Smurfit Inst, Dublin 2, Ireland, Compaq Comp Corp, Cambridge Res Lab, Cambridge, MA 02142 USA, MIT, Genome Ctr, Cambridge, MA 02142 USA, Univ Calif Santa Cruz, Dept Math, Santa Cruz, CA 95064 USA, Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA, Weizmann Inst Sci, Crown Human Genet Ctr, IL-71600 Rehovot, Israel, Weizmann Inst Sci, Dept Mol Genet, IL-71600 Rehovot, Israel, Univ Oxford, Dept Human Anat & Genet, MRC, Funct Genet Unit, Oxford OX1 3QX, England, Inst Syst Biol, Seattle, WA 98105 USA, NHGRI, NIH, Bethesda, MD 20892 USA, US Dept Energy, Off Sci, Germantown, MD 20874 USA, Wellcome Trust, London NW1 2BE, England, Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., 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, J.P., 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, J.C., Mungall, A., Plumb, R., Ross, M., Shownkeen, R., Sims, S., Waterston, R.H., Wilson, R.K., Hillier, L.W., McPherson, John D., Marra, M.A., Mardis, E.R., Fulton, L.A., Chinwalla, A.T., Pepin, K.H., Gish, W.R., Chissoe, S.L., Wendl, M.C., Delehaunty, K.D., Miner, T.L., Delehaunty, A., Kramer, J.B., Cook, L.L., Fulton, R.S., Johnson, D.L., Minx, P.J., Clifton, S.W., Hawkins, T., Branscomb, E., Predki, P., Richardson, P., Wenning, S., Slezak, T., Doggett, N., Cheng, J.F., Olsen, A., Lucas, S., Elkin, C., Uberbacher, E.C., Frazier, M., Gibbs, R.A., Muzny, D.M., Scherer, S.E., Bouck, J.B., Sodergren, E.J., Worley, K.C., Rives, C.M., Gorrell, J.H., Metzker, M.L., Naylor, S.L., Kucherlapati, R.S., Nelson, D.L., Weinstock, G.M., 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., Rosenthal, A., Platzer, M., Nyakatura, G., Taudien, S., Rump, A., Yang, H.M., Yu, J., Wang, J., Huang, G.Y., Gu, J., Hood, L., Rowen, L., Madan, A., Qin, S.Z., Davis, R.W., Federspiel, N.A., Abola, A.P., Proctor, M.J., Myers, R.M., Schmutz, J., Dickson, M., Grimwood, J., Cox, D.R., Olson, M.V., Kaul, R., Shimizu, N., Kawasaki, K., Minoshima, S., Evans, G.A., Athanasiou, M., Schultz, R., Roe, B.A., Chen, F., Pan, H.Q., Ramser, J., Lehrach, H., Reinhardt, R., McCombie, W.R., De la Bastide, M., Dedhia, N., Blocker, H., Hornischer, K., Nordsiek, G., Agarwala, R., Aravind, L., Bailey, J.A., Bateman, A., Batzoglou, S., Birney, E., Bork, P., Brown, D.G., Burge, C.B., Cerutti, L., Chen, H.C., Church, D., Clamp, M., Copley, R.R., Doerks, T., Eddy, S.R., Eichler, E.E., Furey, T.S., Galagan, J., Gilbert, Jgr, Harmon, C., Hayashizaki, Y., Haussler, D., Hermjakob, H., Hokamp, K., Jang, W.H., Johnson, L.S., Jones, T.A., Kasif, S., Kaspryzk, A., Kennedy, S., Kent, W.J., Kitts, P., Koonin, E.V., Korf, I., Kulp, D., Lancet, D., Lowe, T.M., McLysaght, A., Mikkelsen, T., Moran, J.V., Mulder, N., Pollara, V.J., Ponting, C.P., Schuler, G., Schultz, J.R., Slater, G., Smit, A.F.A., Stupka, E., Szustakowki, J., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Wallis, J., Wheeler, R., Williams, A., Wolf, Y.I., Wolfe, K.H., Yang, S.P., Yeh, R.F., Collins, F., Guyer, M.S., Peterson, J., Felsenfeld, A., Wetterstrand, K.A., Patrinos, A., Morgan, M.J., Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA, Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA, Sanger Ctr, Hinxton CB10 1RQ, Cambs, England, Washington Univ, Genome Sequencing Ctr, St Louis, MO 63108 USA, US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA, Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA, Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA, Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA, Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77225 USA, RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan, Genoscope, F-91057 Evry, France, CNRS, UMR 8030, F-91057 Evry, France, Genome Therapeut Corp, GTC Sequencing Ctr, Waltham, MA 02453 USA, Inst Mol Biotechnol, Dept Genome Anal, D-07745 Jena, Germany, Chinese Acad Sci, Inst Genet, Ctr Human Genome, Beijing Genom Inst, Beijing 100101, Peoples R China, So China Natl Human Genome Res Ctr, Shanghai 201203, Peoples R China, No China Natl Human Genome Res Ctr, Beijing 100176, Peoples R China, Inst Syst Biol, Multimegabase Sequencing Ctr, Seattle, WA 98105 USA, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA, Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA, Stanford Univ, Stanford Human Genome Ctrr, Sch Med, Stanford, CA 94305 USA, Univ Washington, Genome Ctr, Seattle, WA 98195 USA, Keio Univ, Sch Med, Dept Biol Mol, Shinjuku Ku, Tokyo 1608582, Japan, Univ Texas, SW Med Ctr, Dallas, TX 75235 USA, Univ Oklahoma, Adv Ctr Genome Technol, Dept Chem & Biochem, Norman, OK 73019 USA, Max Planck Inst Mol Genet, D-14195 Berlin, Germany, Cold Spring Harbor Lab, Lita Annenberg Hazen Genome Ctr, Cold Spring Harbor, NY 11724 USA, GBF, German Res Ctr Biotechnol, D-38124 Braunschweig, Germany, NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA, Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA, Univ Hosp Cleveland, Cleveland, OH 44106 USA, EMBL, European Bioinformat Inst, Cambridge CB10 1SD, England, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany, MIT, Dept Biol, Cambridge, MA 02139 USA, Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA, Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA, Affymetrix Inc, Berkeley, CA 94710 USA, RIKEN, Yokoham Inst, Genom Sci Ctr, Genom Explorat Res Grp, Tsurumi Ku, Kanagawa 2300045, Japan, Univ Calif Santa Cruz, Dept Comp Sci, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA, Univ Dublin Trinity Coll, Dept Genet, Smurfit Inst, Dublin 2, Ireland, Compaq Comp Corp, Cambridge Res Lab, Cambridge, MA 02142 USA, MIT, Genome Ctr, Cambridge, MA 02142 USA, Univ Calif Santa Cruz, Dept Math, Santa Cruz, CA 95064 USA, Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA, Weizmann Inst Sci, Crown Human Genet Ctr, IL-71600 Rehovot, Israel, Weizmann Inst Sci, Dept Mol Genet, IL-71600 Rehovot, Israel, Univ Oxford, Dept Human Anat & Genet, MRC, Funct Genet Unit, Oxford OX1 3QX, England, Inst Syst Biol, Seattle, WA 98105 USA, NHGRI, NIH, Bethesda, MD 20892 USA, US Dept Energy, Off Sci, Germantown, MD 20874 USA, Wellcome Trust, London NW1 2BE, England, Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., 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, J.P., 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, J.C., Mungall, A., Plumb, R., Ross, M., Shownkeen, R., Sims, S., Waterston, R.H., Wilson, R.K., Hillier, L.W., McPherson, John D., Marra, M.A., Mardis, E.R., Fulton, L.A., Chinwalla, A.T., Pepin, K.H., Gish, W.R., Chissoe, S.L., Wendl, M.C., Delehaunty, K.D., Miner, T.L., Delehaunty, A., Kramer, J.B., Cook, L.L., Fulton, R.S., Johnson, D.L., Minx, P.J., Clifton, S.W., Hawkins, T., Branscomb, E., Predki, P., Richardson, P., Wenning, S., Slezak, T., Doggett, N., Cheng, J.F., Olsen, A., Lucas, S., Elkin, C., Uberbacher, E.C., Frazier, M., Gibbs, R.A., Muzny, D.M., Scherer, S.E., Bouck, J.B., Sodergren, E.J., Worley, K.C., Rives, C.M., Gorrell, J.H., Metzker, M.L., Naylor, S.L., Kucherlapati, R.S., Nelson, D.L., Weinstock, G.M., 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., Rosenthal, A., Platzer, M., Nyakatura, G., Taudien, S., Rump, A., Yang, H.M., Yu, J., Wang, J., Huang, G.Y., Gu, J., Hood, L., Rowen, L., Madan, A., Qin, S.Z., Davis, R.W., Federspiel, N.A., Abola, A.P., Proctor, M.J., Myers, R.M., Schmutz, J., Dickson, M., Grimwood, J., Cox, D.R., Olson, M.V., Kaul, R., Shimizu, N., Kawasaki, K., Minoshima, S., Evans, G.A., Athanasiou, M., Schultz, R., Roe, B.A., Chen, F., Pan, H.Q., Ramser, J., Lehrach, H., Reinhardt, R., McCombie, W.R., De la Bastide, M., Dedhia, N., Blocker, H., Hornischer, K., Nordsiek, G., Agarwala, R., Aravind, L., Bailey, J.A., Bateman, A., Batzoglou, S., Birney, E., Bork, P., Brown, D.G., Burge, C.B., Cerutti, L., Chen, H.C., Church, D., Clamp, M., Copley, R.R., Doerks, T., Eddy, S.R., Eichler, E.E., Furey, T.S., Galagan, J., Gilbert, Jgr, Harmon, C., Hayashizaki, Y., Haussler, D., Hermjakob, H., Hokamp, K., Jang, W.H., Johnson, L.S., Jones, T.A., Kasif, S., Kaspryzk, A., Kennedy, S., Kent, W.J., Kitts, P., Koonin, E.V., Korf, I., Kulp, D., Lancet, D., Lowe, T.M., McLysaght, A., Mikkelsen, T., Moran, J.V., Mulder, N., Pollara, V.J., Ponting, C.P., Schuler, G., Schultz, J.R., Slater, G., Smit, A.F.A., Stupka, E., Szustakowki, J., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Wallis, J., Wheeler, R., Williams, A., Wolf, Y.I., Wolfe, K.H., Yang, S.P., Yeh, R.F., Collins, F., Guyer, M.S., Peterson, J., Felsenfeld, A., Wetterstrand, K.A., Patrinos, A., and Morgan, M.J.

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.

Published
2009

47. Genome-wide detection and characterization of positive selection in human populations

Author

Sabeti, P.C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E.H., McCarroll, S.A., Gaudet, R., Schaffner, S.F., Rotimi, C.N., Adebamowo, C.A., Ajayi, I., Aniagwu, T., Marshall, P.A., Nkwodimmah, C., Royal, C.D.M., Leppert, M.F., Dixon, M., Boudreau, A., Taillon-Miller, P., Peiffer, A., Qiu, R., Kent, A., Kato, K., Niikawa, N., Adewole, I.F., Knoppers, B.M., Foster, M.W., Clayton, E.W., Watkin, J., Xiao, M., Hardenbol, P., Muzny, D., Nazareth, L., Sodergren, E., Weinstock, G.M., Yakub, I., Birren, B.W., Wilson, R.K., Fulton, L.L., Rogers, J., Tsui, L.C., Burton, J., Leal, S.M., Carter, N.P., Clee, C.M., Griffiths, M., Jones, M.C., McLay, K., Plumb, R.W., Ross, M.T., Sims, S.K., Mak, W., Willey, D.L., Chen, Z., Pasternak, S., Han, H., Kang, L., Godbout, M., Wallenburg, J.C., L'Archevêque, P., Bellemare, G., Saeki, K., You, Q.S., Wang, H., An, D., Fu, H., Wheeler, D.A., Li, Q., Wang, Z., Wang, R., Holden, A.L., Brooks, L.D., McEwen, J.E., Tam, P.K.H., Guyer, M.S., Wang, V.O., Peterson, J.L., Shi, M., Willis, T.D., Spiegel, J., Sung, L.M., Zacharia, L.F., Collins, F.S., Kennedy, K., Nakamura, Y., Jamieson, R., Stewart, J., Yu, F., Yang, H., Zeng, C., Gao, Y., Hu, H., Hu, W., Li, C., Lin, W., Kawaguchi, T., Liu, S., Pan, H., Tang, X., Wang, J., Wang, W., Yu, J., Zhang, B., Zhang, Q., Zhao, H., Kitamoto, T., Zhou, J., Gabriel, S.B., Barry, R., Blumenstiel, B., Camargo, A., Defelice, M., Faggart, M., Goyette, M., Gupta, S., Moore, J., Morizono, T., Nguyen, H., Onofrio, R.C., Parkin, M., Roy, J., Stahl, E., Winchester, E., Ziaugra, L., Altshuler, D., Shen, Y., Yao, Z., Lander, E.S., Huang, W., Chu, X., He, Y., Jin, L., Liu, Y., Sun, W., Wang, Y., Nagashima, A., Xiong, X., Xu, L., Waye, M.M.Y., Tsui, S.K.W., Xue, H., Wong, J.T.F., Galver, L.M., Fan, J.B., Gunderson, K., Murray, S.S., Ohnishi, Y., Oliphant, A.R., Chee, M.S., Montpetit, A., Chagnon, F., Ferretti, V., Leboeuf, M., Olivier, J.F., Phillips, M.S., Roumy, S., Sallée, C., Sekine, A., Verner, A., Hudson, T.J., Kwok, P.Y., Cai, D., Koboldt, D.C., Miller, R.D., Pawlikowska, L., Tanaka, T., Tsunoda, T., Deloukas, P., Bird, C.P., Delgado, M., Dermitzakis, E.T., Gwilliam, R., Frazer, K.A., Hunt, S., Morrison, J., Powell, D., Stranger, B.E., Whittaker, P., Bentley, D.R., Daly, M.J., De Bakker, P.I.W., Barrett, J., Chretien, Y.R., Ballinger, D.G., Maller, J., McCarroll, S., Patterson, N., Pe'Er, I., Price, A., Purcell, S., Richter, D.J., Saxena, R., Sham, P.C., Stein, L.D., Cox, D.R., Krishnan, L., Smith, A.V., Tello-Ruiz, M.K., Thorisson, G.A., Chakravarti, A., Chen, P.E., Cutler, D.J., Kashuk, C.S., Lin, S., Abecasis, G.R., Hinds, D.A., Guan, W., Li, Y., Munro, H.M., Qin, Z.S., Thomas, D.J., McVean, G., Auton, A., Bottolo, L., Cardin, N., Eyheramendy, S., Stuve, L.L., Freeman, C., Marchini, J., Myers, S., Spencer, C., Stephens, M., Donnelly, P., Cardon, L.R., Clarke, G., Evans, D.M., Morris, A.P., Gibbs, R.A., Weir, B.S., Johnson, T.A., Mullikin, J.C., Sherry, S.T., Feolo, M., Skol, A., Zhang, H., Matsuda, I., Fukushima, Y., MacEr, D.R., Belmont, J.W., Suda, E., Sabeti, P.C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E.H., McCarroll, S.A., Gaudet, R., Schaffner, S.F., Rotimi, C.N., Adebamowo, C.A., Ajayi, I., Aniagwu, T., Marshall, P.A., Nkwodimmah, C., Royal, C.D.M., Leppert, M.F., Dixon, M., Boudreau, A., Taillon-Miller, P., Peiffer, A., Qiu, R., Kent, A., Kato, K., Niikawa, N., Adewole, I.F., Knoppers, B.M., Foster, M.W., Clayton, E.W., Watkin, J., Xiao, M., Hardenbol, P., Muzny, D., Nazareth, L., Sodergren, E., Weinstock, G.M., Yakub, I., Birren, B.W., Wilson, R.K., Fulton, L.L., Rogers, J., Tsui, L.C., Burton, J., Leal, S.M., Carter, N.P., Clee, C.M., Griffiths, M., Jones, M.C., McLay, K., Plumb, R.W., Ross, M.T., Sims, S.K., Mak, W., Willey, D.L., Chen, Z., Pasternak, S., Han, H., Kang, L., Godbout, M., Wallenburg, J.C., L'Archevêque, P., Bellemare, G., Saeki, K., You, Q.S., Wang, H., An, D., Fu, H., Wheeler, D.A., Li, Q., Wang, Z., Wang, R., Holden, A.L., Brooks, L.D., McEwen, J.E., Tam, P.K.H., Guyer, M.S., Wang, V.O., Peterson, J.L., Shi, M., Willis, T.D., Spiegel, J., Sung, L.M., Zacharia, L.F., Collins, F.S., Kennedy, K., Nakamura, Y., Jamieson, R., Stewart, J., Yu, F., Yang, H., Zeng, C., Gao, Y., Hu, H., Hu, W., Li, C., Lin, W., Kawaguchi, T., Liu, S., Pan, H., Tang, X., Wang, J., Wang, W., Yu, J., Zhang, B., Zhang, Q., Zhao, H., Kitamoto, T., Zhou, J., Gabriel, S.B., Barry, R., Blumenstiel, B., Camargo, A., Defelice, M., Faggart, M., Goyette, M., Gupta, S., Moore, J., Morizono, T., Nguyen, H., Onofrio, R.C., Parkin, M., Roy, J., Stahl, E., Winchester, E., Ziaugra, L., Altshuler, D., Shen, Y., Yao, Z., Lander, E.S., Huang, W., Chu, X., He, Y., Jin, L., Liu, Y., Sun, W., Wang, Y., Nagashima, A., Xiong, X., Xu, L., Waye, M.M.Y., Tsui, S.K.W., Xue, H., Wong, J.T.F., Galver, L.M., Fan, J.B., Gunderson, K., Murray, S.S., Ohnishi, Y., Oliphant, A.R., Chee, M.S., Montpetit, A., Chagnon, F., Ferretti, V., Leboeuf, M., Olivier, J.F., Phillips, M.S., Roumy, S., Sallée, C., Sekine, A., Verner, A., Hudson, T.J., Kwok, P.Y., Cai, D., Koboldt, D.C., Miller, R.D., Pawlikowska, L., Tanaka, T., Tsunoda, T., Deloukas, P., Bird, C.P., Delgado, M., Dermitzakis, E.T., Gwilliam, R., Frazer, K.A., Hunt, S., Morrison, J., Powell, D., Stranger, B.E., Whittaker, P., Bentley, D.R., Daly, M.J., De Bakker, P.I.W., Barrett, J., Chretien, Y.R., Ballinger, D.G., Maller, J., McCarroll, S., Patterson, N., Pe'Er, I., Price, A., Purcell, S., Richter, D.J., Saxena, R., Sham, P.C., Stein, L.D., Cox, D.R., Krishnan, L., Smith, A.V., Tello-Ruiz, M.K., Thorisson, G.A., Chakravarti, A., Chen, P.E., Cutler, D.J., Kashuk, C.S., Lin, S., Abecasis, G.R., Hinds, D.A., Guan, W., Li, Y., Munro, H.M., Qin, Z.S., Thomas, D.J., McVean, G., Auton, A., Bottolo, L., Cardin, N., Eyheramendy, S., Stuve, L.L., Freeman, C., Marchini, J., Myers, S., Spencer, C., Stephens, M., Donnelly, P., Cardon, L.R., Clarke, G., Evans, D.M., Morris, A.P., Gibbs, R.A., Weir, B.S., Johnson, T.A., Mullikin, J.C., Sherry, S.T., Feolo, M., Skol, A., Zhang, H., Matsuda, I., Fukushima, Y., MacEr, D.R., Belmont, J.W., and Suda, E.

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.

Published
2007

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