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1.  Deep Resequencing and Association Analysis of Schizophrenia Candidate Genes 
Molecular psychiatry  2012;18(2):138-140.
PMCID: PMC3577417  PMID: 22472875
schizophrenia; sequencing; SNV; genetic; association; mutation; DISC1
2.  Exome sequencing of ion channel genes reveals complex variant profiles confounding personal risk assessment in epilepsy 
Cell  2011;145(7):1036-1048.
Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.
PMCID: PMC3131217  PMID: 21703448
3.  Whole-Genome Sequencing for Optimized Patient Management 
Science Translational Medicine  2011;3(87):87re3.
Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)–responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.
PMCID: PMC3314311  PMID: 21677200
4.  TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum 
Nature genetics  2011;43(3):189-196.
Ciliary dysfunction leads to a broad range of overlapping phenotypes, termed collectively as ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifying alleles to clinically distinct disorders. Here we show that mutations in TTC21B/IFT139, encoding a retrograde intraflagellar transport (IFT) protein, cause both isolated nephronophthisis (NPHP) and syndromic Jeune Asphyxiating Thoracic Dystrophy (JATD). Moreover, although systematic medical resequencing of a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations unmasked a significant enrichment of pathogenic alleles in cases, suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy patients. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies, as well as interact in trans with other disease-causing genes, and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of disorders.
PMCID: PMC3071301  PMID: 21258341
5.  A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies 
Nature genetics  2009;41(6):739-745.
Despite rapid advances in disease gene identification, the predictive power of the genotype remains limited, in part due 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 patients 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 229T-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.
PMCID: PMC2783476  PMID: 19430481
6.  Somatic mutations affect key pathways in lung adenocarcinoma 
Ding, Li | Getz, Gad | Wheeler, David A. | Mardis, Elaine R. | McLellan, Michael D. | Cibulskis, Kristian | Sougnez, Carrie | Greulich, Heidi | Muzny, Donna M. | Morgan, Margaret B. | Fulton, Lucinda | Fulton, Robert S. | Zhang, Qunyuan | Wendl, Michael C. | Lawrence, Michael S. | Larson, David E. | Chen, Ken | Dooling, David J. | Sabo, Aniko | Hawes, Alicia C. | Shen, Hua | Jhangiani, Shalini N. | Lewis, Lora R. | Hall, Otis | Zhu, Yiming | Mathew, Tittu | Ren, Yanru | Yao, Jiqiang | Scherer, Steven E. | Clerc, Kerstin | Metcalf, Ginger A. | Ng, Brian | Milosavljevic, Aleksandar | Gonzalez-Garay, Manuel L. | Osborne, John R. | Meyer, Rick | Shi, Xiaoqi | Tang, Yuzhu | Koboldt, Daniel C. | Lin, Ling | Abbott, Rachel | Miner, Tracie L. | Pohl, Craig | Fewell, Ginger | Haipek, Carrie | Schmidt, Heather | Dunford-Shore, Brian H. | Kraja, Aldi | Crosby, Seth D. | Sawyer, Christopher S. | Vickery, Tammi | Sander, Sacha | Robinson, Jody | Winckler, Wendy | Baldwin, Jennifer | Chirieac, Lucian R. | Dutt, Amit | Fennell, Tim | Hanna, Megan | Johnson, Bruce E. | Onofrio, Robert C. | Thomas, Roman K. | Tonon, Giovanni | Weir, Barbara A. | Zhao, Xiaojun | Ziaugra, Liuda | Zody, Michael C. | Giordano, Thomas | Orringer, Mark B. | Roth, Jack A. | Spitz, Margaret R. | Wistuba, Ignacio I. | Ozenberger, Bradley | Good, Peter J. | Chang, Andrew C. | Beer, David G. | Watson, Mark A. | Ladanyi, Marc | Broderick, Stephen | Yoshizawa, Akihiko | Travis, William D. | Pao, William | Province, Michael A. | Weinstock, George M. | Varmus, Harold E. | Gabriel, Stacey B. | Lander, Eric S. | Gibbs, Richard A. | Meyerson, Matthew | Wilson, Richard K.
Nature  2008;455(7216):1069-1075.
Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers—including NF1, APC, RB1 and ATM—and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
PMCID: PMC2694412  PMID: 18948947
7.  Characterizing the cancer genome in lung adenocarcinoma 
Nature  2007;450(7171):893-898.
Somatic alterations in cellular DNA underlie almost all human cancers1. The prospect of targeted therapies2 and the development of high-resolution, genome-wide approaches3–8 are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumors (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in ~12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
PMCID: PMC2538683  PMID: 17982442
8.  Deep resequencing reveals excess rare recent variants consistent with explosive population growth 
Nature Communications  2010;1:131-.
Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants.
To fully catalogue rare genetic variation in humans, many samples need to be examined. In this study, Coventry et al. resequenced two genes, KCNJ11 and HHEX, in 13,715 humans, and concluded that most of the sequence variation arose recently and that variation is greater than expected.
PMCID: PMC3060603  PMID: 21119644

Results 1-8 (8)