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Zsofia K Stadler,
Diane Esposito,
Sohela Shah,
Joseph Vijai,
Boris Yamrom,
Dan Levy, Yoon-Ha Lee,
Jude Kendall,
Anthony Leotta,
Michael Ronemus, [......],
Robert J Klein,
Steven M Lipkin,
Rajmohan Murali,
Mark Robson,
Joel Sheinfeld,
Darren Feldman,
George Bosl,
Larry Norton,
Michael Wigler,
Kenneth Offit
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ABSTRACT: Although heritable factors are an important determinant of risk of early-onset cancer, the majority of these malignancies appear to occur sporadically without identifiable risk factors. Germline de novo copy-number variations (CNVs) have been observed in sporadic neurocognitive and cardiovascular disorders. We explored this mechanism in 382 genomes of 116 early-onset cancer case-parent trios and unaffected siblings. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were indeed found in 7% of 43 testicular germ cell tumor trios; this percentage exceeds background CNV rates and suggests a rare de novo genetic paradigm for susceptibility to some human malignancies.
The American Journal of Human Genetics 08/2012; 91(2):379-83. · 10.60 Impact Factor
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Ivan Iossifov,
Michael Ronemus,
Dan Levy,
Zihua Wang,
Inessa Hakker,
Julie Rosenbaum,
Boris Yamrom, Yoon-Ha Lee,
Giuseppe Narzisi,
Anthony Leotta, [......],
Robert S Fulton,
Vincent J Magrini,
Kenny Ye,
Jennifer C Darnell,
Robert B Darnell,
Elaine R Mardis,
Richard K Wilson,
Michael C Schatz,
W Richard McCombie,
Michael Wigler
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ABSTRACT: Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.
Neuron 04/2012; 74(2):285-99. · 14.74 Impact Factor
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Yoon-ha Lee,
Michael Ronemus,
Jude Kendall,
B Lakshmi,
Anthony Leotta,
Dan Levy,
Diane Esposito,
Vladimir Grubor,
Kenny Ye,
Michael Wigler,
Boris Yamrom
[show abstract]
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ABSTRACT: Genomic copy number variation underlies genetic disorders such as autism, schizophrenia, and congenital heart disease. Copy number variations are commonly detected by array based comparative genomic hybridization of sample to reference DNAs, but probe and operational variables combine to create correlated system noise that degrades detection of genetic events. To correct for this we have explored hybridizations in which no genetic signal is expected, namely "self-self" hybridizations (SSH) comparing DNAs from the same genome. We show that SSH trap a variety of correlated system noise present also in sample-reference (test) data. Through singular value decomposition of SSH, we are able to determine the principal components (PCs) of this noise. The PCs themselves offer deep insights into the sources of noise, and facilitate detection of artifacts. We present evidence that linear and piecewise linear correction of test data with the PCs does not introduce detectable spurious signal, yet improves signal-to-noise metrics, reduces false positives, and facilitates copy number determination.
Proceedings of the National Academy of Sciences 12/2011; 109(3):E103-10. · 9.68 Impact Factor
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Dan Levy,
Michael Ronemus,
Boris Yamrom, Yoon-ha Lee,
Anthony Leotta,
Jude Kendall,
Steven Marks,
B Lakshmi,
Deepa Pai,
Kenny Ye,
Andreas Buja,
Abba Krieger,
Seungtai Yoon,
Jennifer Troge,
Linda Rodgers,
Ivan Iossifov,
Michael Wigler
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ABSTRACT: To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited "ultrarare" duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence.
Neuron 06/2011; 70(5):886-97. · 14.74 Impact Factor
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Yoon-Ha Lee,
Michael Ronemus,
Jude Kendall,
B Lakshmi,
Anthony Leotta,
Dan Levy,
Diane Esposito,
Vladimir Grubor,
Kenny Ye,
Michael Wigler,
Boris Yamrom
[show abstract]
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ABSTRACT: Genomic copy number variation (CNV) is a large source of variation between
organisms, and its consequences include phenotypic differences and genetic
disorders. CNVs are commonly detected by hybridizing genomic DNA to microarrays
of nucleic acid probes. System noise caused by operational and probe
performance variability complicates the interpretation of these data. To
minimize the distortion of genetic signal by system noise, we have explored the
latter in an archive of hybridizations in which no genetic signal is expected.
This archive is obtained by comparative genomic hybridization (CGH) of a sample
in one channel to the same sample in the other channel, or 'self-self' data.
These self-self hybridizations trap a variety of system noise inherent in
sample-reference (test) data. Through singular value decomposition (SVD) of
self-self data, we have determined the principal components of system noise.
Assuming simple linear models of noise generation, the linear correction of
test data with self-self data -or 'system normalization'- reduces local and
long-range correlations and improves signal-to-noise metrics, yet does not
introduce detectable spurious signal. Using this method, 90% of hybridizations
displayed improved signal-to-noise ratios with an average increase of 7.0%, due
mainly to a reduced median average deviation (MAD). In addition, we have found
that principal component loadings correlate with specific probe variables
including array coordinates, base composition, and proximity to the 5' ends of
genes. The correlation of the principal component loadings with the test data
depends on operational variables, such as the temporal order of processing and
the localization of individual samples within 96-well plates.
05/2011;
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Shane E McCarthy,
Vladimir Makarov,
George Kirov,
Anjene M Addington,
Jon McClellan,
Seungtai Yoon,
Diana O Perkins,
Diane E Dickel,
Mary Kusenda,
Olga Krastoshevsky, [......],
Michael C O'Donovan,
Tamim H Shaikh,
Ezra Susser,
Lynn E Delisi,
Patrick F Sullivan,
Curtis K Deutsch,
Judith Rapoport,
Deborah L Levy,
Mary-Claire King,
Jonathan Sebat
[show abstract]
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ABSTRACT: Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Nature Genetics 11/2009; 41(11):1223-7. · 35.53 Impact Factor
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Vladimir Grubor,
Alex Krasnitz,
Jennifer E Troge,
Jennifer L Meth,
B Lakshmi,
Jude T Kendall,
Boris Yamrom,
Garrick Alex,
Deepa Pai,
Nicholas Navin,
Lisa A Hufnagel, Yoon-Ha Lee,
Kerry Cook,
Steven L Allen,
Kanti R Rai,
Rajendra N Damle,
Carlo Calissano,
Nicholas Chiorazzi,
Michael Wigler,
Diane Esposito
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ABSTRACT: We examined copy number changes in the genomes of B cells from 58 patients with chronic lymphocytic leukemia (CLL) by using representational oligonucleotide microarray analysis (ROMA), a form of comparative genomic hybridization (CGH), at a resolution exceeding previously published studies. We observed at least 1 genomic lesion in each CLL sample and considerable variation in the number of abnormalities from case to case. Virtually all abnormalities previously reported also were observed here, most of which were indeed highly recurrent. We observed the boundaries of known events with greater clarity and identified previously undescribed lesions, some of which were recurrent. We profiled the genomes of CLL cells separated by the surface marker CD38 and found evidence of distinct subclones of CLL within the same patient. We discuss the potential applications of high-resolution CGH analysis in a clinical setting.
Blood 11/2008; 113(6):1294-303. · 9.90 Impact Factor
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Jonathan Sebat,
B Lakshmi,
Dheeraj Malhotra,
Jennifer Troge,
Christa Lese-Martin,
Tom Walsh,
Boris Yamrom,
Seungtai Yoon,
Alex Krasnitz,
Jude Kendall, [......],
James S Sutcliffe,
Vaidehi Jobanputra,
Wendy Chung,
Dorothy Warburton,
Mary-Claire King,
David Skuse,
Daniel H Geschwind,
T Conrad Gilliam,
Kenny Ye,
Michael Wigler
[show abstract]
[hide abstract]
ABSTRACT: We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Science 05/2007; 316(5823):445-9. · 31.20 Impact Factor
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