High-resolution Genome-wide Analysis Research Articles

Plasmodium falciparum population dynamics in East Africa and genomic surveillance along the Kenya-Uganda border

East African countries accounted for ~ 10% of all malaria prevalence worldwide in 2022, with an estimated 23.8 million cases and > 53,000 deaths. Despite recent increases in malaria incidence, high-resolution genome-wide analyses of Plasmodium parasite populations are sparse in Kenya, Tanzania, and Uganda. The Kenyan-Ugandan border region is a particular concern, with Uganda confirming the emergence and spread of artemisinin resistant P. falciparum parasites. To establish genomic surveillance along the Kenyan-Ugandan border and analyse P. falciparum population dynamics within East Africa, we generated whole-genome sequencing (WGS) data for 38 parasites from Bungoma, Western Kenya. These sequences were integrated into a genomic analysis of available East African isolate data (n = 599) and revealed parasite subpopulations with distinct genetic structure and diverse ancestral origins. Ancestral admixture analysis of these subpopulations alongside isolates from across Africa (n = 365) suggested potential independent ancestral populations from other major African populations. Within isolates from Western Kenya, the prevalence of biomarkers associated with chloroquine resistance (e.g. Pfcrt K76T) were significantly reduced compared to wider East African populations and a single isolate contained the PfK13 V568I variant, potentially linked to reduced susceptibility to artemisinin. Overall, our work provides baseline WGS data and analysis for future malaria genomic surveillance in the region.

A budding yeast CAGE dataset comprising two cell types.

The budding yeast Saccharomyces cerevisiae is an excellent model organism for studying chromatin regulation with high-resolution genome-wide analyses. Since newly generated genome-wide data are often compared with publicly available datasets, expanding our dataset repertoire will be beneficial for the field. Information on transcription start sites (TSSs) determined at base pair resolution is essential for elucidating mechanisms of transcription and related chromatin regulation, yet no datasets that cover two different cell types are available. Here, we present a CAGE (cap analysis of gene expression) dataset for a-cells and α-cells grown in defined and rich media. Cell type-specific genes were differentially expressed as expected, ensuring the reliability of the data. Some of the differentially expressed TSSs were medium-specific or detected due to unrecognized chromosome rearrangement. By comparing the CAGE data with a high-resolution nucleosome map, major TSSs were primarily found in +1 nucleosomes, with a peak approximately 30 bp from the promoter-proximal end of the nucleosome. The dataset is available at DDBJ/GEA.

An integrated model for termination of RNA polymerase III transcription.

RNA polymerase III (RNAPIII) synthesizes essential and abundant noncoding RNAs such as transfer RNAs. Controlling RNAPIII span of activity by accurate and efficient termination is a challenging necessity to ensure robust gene expression and to prevent conflicts with other DNA-associated machineries. The mechanism of RNAPIII termination is believed to be simpler than that of other eukaryotic RNA polymerases, solely relying on the recognition of a T-tract in the nontemplate strand. Here, we combine high-resolution genome-wide analyses and in vitro transcription termination assays to revisit the mechanism of RNAPIII transcription termination in budding yeast. We show that T-tracts are necessary but not always sufficient for termination and that secondary structures of the nascent RNAs are important auxiliary cis-acting elements. Moreover, we show that the helicase Sen1 plays a key role in a fail-safe termination pathway. Our results provide a comprehensive model illustrating how multiple mechanisms cooperate to ensure efficient RNAPIII transcription termination.

High-resolution genome-wide analysis is essential for the identification of ambiguous Aeromonas strains.

Aeromonads are mainly opportunistic pathogens; however, many species are emerging as important human pathogens. Therefore, monitoring these bacteria and their accurate characterization of its species is highly important. Aeromonas Aer593 strain was recovered from a diarrhoea outbreak and did not group with any previously described Aeromonas species by housekeeping gene sequencing. To clarify the taxonomic position of Aer593, its genome was sequenced and analysed by multilocus phylogenetic analysis (MLPA), in silico DNA-DNA hybridization (isDDH), average nucleotide identity (ANI) and core genome-based phylogenetic analyzes. The MLPA with the housekeeping genes gyrB, rpoD, recA, dnaJ, gyrA and dnaX ranked the Aer593 isolate into an independent branch suggesting that it could represent a new species. However, the identity percentages of Aer593 to A. caviae strains using robust genomic analysis by isDDH and ANI were at least 81.3% and 97.8%, respectively, defining Aer593 as A. caviae. Multilocus sequence typing (MLST) presented an exact match against only a single allele (groL96) and the novel ST648 was assigned for this strain. The core genome-based phylogenetic analyses with a total of 863 orthologous genes also grouped the Aer593 isolate with A. caviae reference strains. These findings warn about the possibility of misidentification of some Aeromonas strains by MLPA and show that high-resolution genome-wide analysis is essential for the correct identification of ambiguous Aeromonas strains.

Genetic architecture of cold tolerance in rice (Oryza sativa) determined through high resolution genome-wide analysis.

Cold temperature is an important abiotic stress which negatively affects morphological development and seed production in rice (Oryza sativa L.). At the seedling stage, cold stress causes poor germination, seedling injury and poor stand establishment; and at the reproductive stage cold decreases seed yield. The Rice Diversity Panel 1 (RDP1) is a global collection of over 400 O. sativa accessions representing the five major subpopulations from the INDICA and JAPONICA varietal groups, with a genotypic dataset consisting of 700,000 SNP markers. The objectives of this study were to evaluate the RDP1 accessions for the complex, quantitatively inherited cold tolerance traits at the germination and reproductive stages, and to conduct genome-wide association (GWA) mapping to identify SNPs and candidate genes associated with cold stress at these stages. GWA mapping of the germination index (calculated as percent germination in cold divided by warm treatment) revealed 42 quantitative trait loci (QTLs) associated with cold tolerance at the seedling stage, including 18 in the panel as a whole, seven in temperate japonica, six in tropical japonica, 14 in JAPONICA, and nine in INDICA, with five shared across all subpopulations. Twenty-two of these QTLs co-localized with 32 previously reported cold tolerance QTLs. GWA mapping of cold tolerance at the reproductive stage detected 29 QTLs, including seven associated with percent sterility, ten with seed weight per panicle, 14 with seed weight per plant and one region overlapping for two traits. Fifteen co-localized with previously reported QTLs for cold tolerance or yield components. Candidate gene ontology searches revealed these QTLs were associated with significant enrichment for genes related to with lipid metabolism, response to stimuli, response to biotic stimuli (suggesting cross-talk between biotic and abiotic stresses), and oxygen binding. Overall the JAPONICA accessions were more tolerant to cold stress than INDICA accessions.

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration.

To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.

TINTIN, at the interface of chromatin, transcription elongation, and mRNA processing

Recent work including high-resolution genome-wide analysis uncovered a new trimeric complex involved in transcription elongation, both as an integral part of the NuA4 histone acetyltransferase and as an independent functional entity. The complex is conserved in eukaryotes and is named TINTIN, for Trimer Independent of NuA4 for transcription Interactions with Nucleosomes. This point of view covers the current knowledge regarding TINTIN's function in modulating chromatin structure and influencing transcription elongation in eukaryotes. It also points to several physical and functional links to co-transcriptional processes, including interactions with the mRNA splicing machinery and the nuclear exosome.

High-resolution genome-wide analysis identified recurrent genetic alterations in NK/T-cell lymphoma, nasal type, which are associated with disease progression.

Extranodal NK/T-cell lymphoma, nasal type, is an aggressive mature NK-cell/T-cell lymphoma. Using array-based comparative genomic hybridization (array CGH) assays, we screened genomic alterations and potential candidate genes implicated in pathogenesis, progression, and prognosis. Our array CGH analysis detected an average of 83 chromosomal aberrations in 13 cases, ranging from 0 to 387. There were 177 recurrent chromosomal gains and 35 recurrent losses. Eleven gains and 14 losses were detected in more than 30 % of the cases, including gains of 3q26.1, 7q34, and 8q24.3 and losses of 15q24.2, 19q13.32, 5p13.2, and 14q21.1. The most common losses were observed in the 15q24.2 and 19q13.32 regions (9 cases, 69.2 %, respectively). Loss of 8p11.23 was associated with significant poor survival (P = 0.024). Five out of six patients with the loss of 8p11.23 died within 8 months after initial diagnosis with a median survival of 6 months. Several candidate genes were identified in the regions with frequent chromosomal aberrations, including ADAM3A (8p11.23) and GSTT1 (22q11.23). In summary, our studies detected recurrent genetic alterations in NK/T-cell lymphoma, some of which are associated with adverse prognosis. Some candidate genes in these regions may be involved in the pathogenesis and disease progression.

細菌の発現制御機構をゲノムワイドに解析する

これまで，転写開始点や転写制御因子の結合部位を正確に決めるためには，個々の遺伝子ごとに，プライマー伸長法や DNase I フットプリントをしなければならなかった．ところが，次世代シーケンサーの登場で，それらの方法と同等の精度で，ゲノムワイドな解析ができるようになりつつある．これらの解析手法の登場で，細菌のゲノム解析は，どこまで分子メカニズムに迫れるだろう．最近，続々と発表された1～数塩基レベルの解像度をもつ網羅的解析手法について解説してみたい．

High‐resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignant pediatric brain tumor characterized by genetic alterations affecting the SMARCB1 (hSNF5/INI1) locus in chromosome band 22q11.2. To identify potential additional genetic alterations, high-resolution genome-wide analysis was performed using a molecular inversion probe single-nucleotide polymorphism (MIP SNP) assay (Affymetrix OncoScan formalin-fixed paraffin-embedded express) on DNA isolated from 18 formalin-fixed paraffin-embedded archival samples. Alterations affecting the SMARCB1 locus could be demonstrated by MIP SNP in 15 out of 16 evaluable cases (94%). These comprised five tumors with homozygous deletions, six tumors with heterozygous deletions, and four tumors with copy number neutral loss of heterozygosity (LOH) involving chromosome band 22q11.2. Remarkably, MIB SNP analysis did not yield any further recurrent chromosomal gains, losses, or copy neutral LOH. On MIP SNP screening for somatic mutations, the presence of a SMARCB1 mutation (c.472C>T p.R158X) was confirmed, but no recurrent mutations of other cancer relevant genes could be identified. Results of fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and SMARCB1 sequencing were highly congruent with that of the MIP SNP assay. In conclusion, these data further suggest the absence of recurrent genomic alterations other than SMARCB1 in AT/RT.

High-Resolution Genome-Wide Analysis of Irradiated (UV and γ-Rays) Diploid Yeast Cells Reveals a High Frequency of Genomic Loss of Heterozygosity (LOH) Events

In diploid eukaryotes, repair of double-stranded DNA breaks by homologous recombination often leads to loss of heterozygosity (LOH). Most previous studies of mitotic recombination in Saccharomyces cerevisiae have focused on a single chromosome or a single region of one chromosome at which LOH events can be selected. In this study, we used two techniques (single-nucleotide polymorphism microarrays and high-throughput DNA sequencing) to examine genome-wide LOH in a diploid yeast strain at a resolution averaging 1 kb. We examined both selected LOH events on chromosome V and unselected events throughout the genome in untreated cells and in cells treated with either γ-radiation or ultraviolet (UV) radiation. Our analysis shows the following: (1) spontaneous and damage-induced mitotic gene conversion tracts are more than three times larger than meiotic conversion tracts, and conversion tracts associated with crossovers are usually longer and more complex than those unassociated with crossovers; (2) most of the crossovers and conversions reflect the repair of two sister chromatids broken at the same position; and (3) both UV and γ-radiation efficiently induce LOH at doses of radiation that cause no significant loss of viability. Using high-throughput DNA sequencing, we also detected new mutations induced by γ-rays and UV. To our knowledge, our study represents the first high-resolution genome-wide analysis of DNA damage-induced LOH events performed in any eukaryote.

High-Resolution Genome-Wide Analysis of Irradiated (UV and -Rays) Diploid Yeast Cells Reveals a High Frequency of Genomic Loss of Heterozygosity (LOH) Events

High-Resolution Genome-Wide Analysis of Irradiated (UV and -Rays) Diploid Yeast Cells Reveals a High Frequency of Genomic Loss of Heterozygosity (LOH) Events

Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update

We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. A review of English literature on childhood acute leukemias from the past 5 years was performed. Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.

NF1 Alterations Are Common In AML with Complex Karyotype and Correlate with Specific Genomic Imbalances

AbstractAbstract 4179In acute myeloid leukemia (AML), complex karyotype is defined as the presence of three or more chromosome abnormalities in the absence of one of the recurrent genetic abnormalities as defined by the recent WHO classification. AML with complex karyotype (CK-AML) account for approximately 10 to 15% of all cases and are associated with preceding myelodysplasia (MDS) or exposure to toxic agents; the prognosis of patients is very poor. So far, little is known about the molecular mechanisms underlying initiation or progression of CK-AML.To identify genomic regions of potential pathogenic relevance, we used microarray-based techniques [array-comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) analysis] for high-resolution genome-wide analysis in 242 cases, including 171 (71%) cases enrolled on clinical protocols using intensive chemotherapy. Among other genomic imbalances, we identified loss of chromosome band 17q11.2 encompassing the NF1 locus in 55 (23%) of the 242 cases. Interestingly, three of these cases exhibited homozygous loss of NF1. Based on these findings and the fact that NF1 is recurrently altered in myeloid malignancies, we further investigated its role in CK-AML. Therefore, we analyzed 11 cases with heterozygous microdeletions of NF1 for mutations in the remaining allele by direct sequencing of exons 1 to 60 and identified 5 mutations in 4 cases; all of these mutations resulted in a premature stop codon (3 frameshift mutations, 2 nonsense mutations); one frameshift mutation (c.2033dupC) was recurrent. Combining the findings from array-based and mutation analyses, we so far identified 7 patients with biallelic NF1 gene alterations, i.e. homozygous loss or loss of one allele and at least one mutation in the remaining allele.Since correlation of NF1 alteration with data from array-based genomic profiling revealed a significant correlation with loss of chromosome band 17p13 encompassing TP53 (P < .001), we correlated NF1 alteration with the TP53 status (mutation and/or loss), which was available for all 242 cases, and found a positive correlation with both TP53 alteration (mutation and/or loss) and TP53 mutation (P < .001 each). In addition, NF1 alteration was significantly correlated with biallelic TP53 alterations (loss and mutation or homozygous mutations) (P < .001). We than further investigated the two genotypes NF1alteration/TP53alteration (n=50) and NF1no alteration/TP53alteration (n=109) with regard to their association with other genomic imbalances. The genotype NF1alteration/TP53alteration was significantly correlated to the total number of deletions (median 9 vs 7; P = .025), the genomic complexity as measured by the total number of aberrations per case (median 13 vs 11; P = .039), and the presence of 16q loss (50% [25/50] vs 29% [32/109], P = .014) when compared with the NF1no alteration/TP53alteration genotype. Notably, in a recently published murine model deficiency of ICSBP, located on 16q24, was shown to synergize with NF1 haplo-insufficiency in leukemogenesis.In conclusion, the NF1 gene is found to be recurrently altered in CK-AML. Being associated with specific genomic aberrations, NF1 alteration is likely cooperating in myeloid leukemogenesis or disease progression. One important co-player might be TP53 that has an important role in genomic stability. The exact mechanism of interaction between NF1 and TP53 or other concurrent genetic alterations have to be further investigated. Disclosures:Döhner:Pfizer: Research Funding.

High-resolution genome-wide analysis of chromosomal alterations in elastofibroma

Elastofibroma is a rare, benign fibrous proliferation that most commonly occur in periscapular soft tissues and is characterized by accumulated elastic fibers. Although the lesion is generally regarded as a reactive process, an unusual fibroblastic pseudotumor or as a fibroelastic tumor-like lesion, its etiology remains unknown. Cytogenetic studies in these lesions detected chromosomal instability and some recurrent clonal chromosomal changes, which raised the possibility that the lesion represents a neoplastic process. Here, we report the genomic alterations detected by array-based comparative genomic hybridization (aCGH) and by multiplex ligation-dependent probe amplification (MLPA) in two cases of elastofibroma. Both cases showed losses on 1p, 13q, 19p, and 22q by aCGH. In addition, deletion of CASR (3q21), GSTP1 (11q13), BRCA2 (13q12) and gains on APC (5q21) and PAH (12q23) were observed by MLPA in both samples. Genomic screening studies of this fibrous proliferation may lead to identify chromosomal regions containing genes involved in the development of elastofibromas.

A single parasite gene determines strain-specific protective immunity against malaria: The role of the merozoite surface protein I

Despite many decades of research, no registered vaccine against the pathogenic blood stages of the malaria parasite exists, translating into the loss of many hundreds of thousands of young lives each year in tropical Africa. Although many parasite proteins have been shown to induce immune responses in the host, proof for their induction of protective immunity is still lacking. We previously reported a novel genetic approach called linkage group selection (LGS) for rapid identification of target antigens of strain-specific protective immunity (SSPI) against malaria. In preliminary LGS experiments, we crossed two genetically distinct strains of Plasmodium chabaudi chabaudi and subjected their progeny to selection in strain-specifically immunised mice, measuring the effects of SSPI selection with low coverage/resolution genetic markers. In the present study, through application of high coverage/resolution, single nucleotide polymorphism (SNP) markers spanning all 14 parasite chromosomes, we analysed 35 SSPI selection events on different populations of progeny parasites. Here we report a comprehensive high resolution genome-wide analysis of the effects of strain-specific immune selection on blood stage parasites. Our analyses consistently identify a single genomic region spanning ∼79 kb on chromosome 8 as the region controlling SSPI. Within this region, one gene (that of merozoite surface protein 1, MSP-1) accounted for >60% of genetic polymorphism and was most frequently under greatest reduction under SSPI. These results, combined with those of an independent LGS analysis of a different genetic cross with different parental strains, demonstrate that more than any other locus, the gene for MSP-1 determines the effect of strain-specific protective immunity against malaria in these host-parasite combinations. Our results provide unique insight into the precise timing of the parasite killing immune response against progeny parasites carrying specific alleles of MSP-1; these findings pave the way for investigating which part(s) of this highly polymorphic molecule mediate the protective immune response.

An Arabidopsis jmjC domain protein protects transcribed genes from DNA methylation at CHG sites

Differential cytosine methylation of genes and transposons is important for maintaining integrity of plant genomes. In Arabidopsis, transposons are heavily methylated at both CG and non-CG sites, whereas the non-CG methylation is rarely found in active genes. Our previous genetic analysis suggested that a jmjC domain-containing protein IBM1 (increase in BONSAI methylation 1) prevents ectopic deposition of non-CG methylation, and this process is necessary for normal Arabidopsis development. Here, we directly determined the genomic targets of IBM1 through high-resolution genome-wide analysis of DNA methylation. The ibm1 mutation induced extensive hyper-methylation in thousands of genes. Transposons were unaffected. Notably, long transcribed genes were most severely affected. Methylation of genes is limited to CG sites in wild type, but CHG sites were also methylated in the ibm1 mutant. The ibm1-induced hyper-methylation did not depend on previously characterized components of the RNAi-based DNA methylation machinery. Our results suggest novel transcription-coupled mechanisms to direct genic methylation not only at CG but also at CHG sites. IBM1 prevents the CHG methylation in genes, but not in transposons.

High-Resolution Genome-Wide Profiling of DNA Copy Number Abnormalities and Gene Resequencing in Pediatric Acute Myeloid Leukemia (AML).

To define the complement of genetic lesions in pediatric AML, we performed high resolution genome-wide analysis on bone marrow blasts from 111 cases using Affymetrix 100K and 500K SNP microarrays and genomic resequencing. Cases included t(8;21) (N=20), inv(16) (N=16), t(15;17) (N=7), MLL rearranged (N=16), FAB-M7 (N=9), miscellaneous cytogenetic abnormalities (N=24) and normal karyotype (N=19). Germline DNA was available for 67 of the cases. The mean number of somatic copy number abnormalities (CNA) was 2.38 (range 0–45) with 1.32 gains (range 0–41) and 1.06 losses (range 0–12). Focal CNAs were detected at the breakpoints of known chromosomal translocations, most commonly in inv(16) cases (7/16) and t(8;21) cases (4/20). Based on this observation, we examined focal CNAs that affected the 5' or 3' regions of genes for their possible involvement in cryptic translocations. CNAs involving NUP98 and MLL led to the identification of two cases with t(5;11)[NUP98-NSD1], and two with t(6;11)[MLL-MLLT4] not evident on cytogenetic analysis. RT-PCR for these fusions identified two additional NUP98-NSD1 cases. Identification of focal CNAs are thus useful in identifying clinically significant translocations in AML. Other recurring somatic CNAs were uncommon. Twelve regions containing a single gene were identified, including amplification of EBF, PRDM5, CCDC26*, GDF10, ABCC4*, and deletion of FAM20C*, TUSC1, GPC5, A2BP1, INSR, BCOR* (* involved in N>2 cases). The most frequent abnormality was amplification of CCDC26 at 8q24.21 (N=15; focal in 4 cases, broad in 11) which encodes a putative mediator of retinoic acid receptor signaling. The focal amplifications are predicted to abolish expression of normal transcripts. Seventeen additional recurring CNAs involving 2 to 25 genes were identified, many of which contain known or putative tumor suppressor genes or oncogenes, including deletions of regions at 7q36, 9p21 (CDKN2A/B), 11p14-p12 (WT1, WIT1), and amplification at 19p13 (JUNB, LYL1). These regions showed significant correlation between copy number and local gene expression in an integrated analysis of CNA and Affymetrix U133A gene expression data. Copy-neutral LOH was uncommon and recurrent only with LOH of chromosome 13 in 3 cases. Sequence analysis has been completed for several genes involved in recurring CNAs (CCDC26, TUSC1, FBXW7) and for genes known to be mutated in AML (N/KRAS, PTPN11, BRAF, SOS1, FLT3, CEPBA, NPM1, AML1, CKIT, GATA1). No mutations were identified in CCDC26, TUSC1, FBXW7, BRAF, or SOS1. Marked differences in the combination of CNA and sequence mutation were identified across the different genetic subtypes of AML. FAB M7 cases had the highest frequency of CNA (mean 9.3 lesions/case) but had sequence mutations limited to GATA1. Mutations of FLT3, CEPBA and NPM1 were most frequent in cases with no or miscellaneous cytogenetic abnormalities, where as RAS mutations were most frequent in t(8;21) and inv(16) cases. Importantly, approximately 30% of the cases with recurring translocations had no other sequence or numerical abnormalities. These data demonstrated that, in contrast to pediatric ALL, AML is characterized by relatively few recurring CNAs, and that spectrum of CNA and sequence mutation is significantly associated with disease subtype.