Full-genome Data Research Articles

Application of multicolor banding combined with heterochromatic and locus-specific probes identify evolutionary conserved breakpoints in Hylobates pileatus.

BackgroundThe question what makes Homo sapiens sapiens (HSA) special among other species is one of the basic questions of mankind. A small contribution to answer this question is to study the chromosomal constitution of HSA compared to other, closely related species. In order to check the types and extent of evolutionary conserved breakpoints we studied here for the first time the chromosomes of Hylobates pileatus (HPI) compared to HSA and Hylobates lar (HLA) by means of molecular cytogenetics.ResultsOverall, 68 new evolutionary conserved breakpoints compared to HSA could be characterized in this study. Interestingly, only seven of those were different compared to HLA. However, application of heterochromatic human DNA-probes provided evidence that observed high chromosomal rearrangement rates of gibbons in HPI happened rather in these repetitive elements than in euchromatin, even though most centromeric positions were preserved in HPI compared to HSA.ConclusionUnderstanding genomes of other species and comparing them to HSA needs full karyotypic and high resolution genomic data to approach both: euchromatic and heterochromatic regions of the studied chromosome-content. This study provides full karyotypic data and previously not available data on heterochromatin-syntenies of HPI and HSA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-016-0228-x) contains supplementary material, which is available to authorized users.

Fine Dissection of Human Mitochondrial DNA Haplogroup HV Lineages Reveals Paleolithic Signatures from European Glacial Refugia.

Genetic signatures from the Paleolithic inhabitants of Eurasia can be traced from the early divergent mitochondrial DNA lineages still present in contemporary human populations. Previous studies already suggested a pre-Neolithic diffusion of mitochondrial haplogroup HV*(xH,V) lineages, a relatively rare class of mtDNA types that includes parallel branches mainly distributed across Europe and West Asia with a certain degree of structure. Up till now, variation within haplogroup HV was addressed mainly by analyzing sequence data from the mtDNA control region, except for specific sub-branches, such as HV4 or the widely distributed haplogroups H and V. In this study, we present a revised HV topology based on full mtDNA genome data, and we include a comprehensive dataset consisting of 316 complete mtDNA sequences including 60 new samples from the Italian peninsula, a previously underrepresented geographic area. We highlight points of instability in the particular topology of this haplogroup, reconstructed with BEAST-generated trees and networks. We also confirm a major lineage expansion that probably followed the Late Glacial Maximum and preceded Neolithic population movements. We finally observe that Italy harbors a reservoir of mtDNA diversity, with deep-rooting HV lineages often related to sequences present in the Caucasus and the Middle East. The resulting hypothesis of a glacial refugium in Southern Italy has implications for the understanding of late Paleolithic population movements and is discussed within the archaeological cultural shifts occurred over the entire continent.

Analyzing the potential for incorrect haplotype calls with different pharmacogenomic assays in different populations: a simulation based on 1000 Genomes data.

Many currently available pharmacogenomic assays and algorithms interrogate a set of 'tag' polymorphisms for inferring haplotypes. We wanted to test the accuracy of such haplotype inferences across different populations. We simulated haplotype inferences made by existing pharmacogenomic assays for seven important pharmacogenes based on full genome data of 2504 persons in the 1000 Genomes dataset. A sizable fraction of samples did not match any of the haplotypes in the star allele nomenclature systems. We found no clear population bias in the accuracy of results of simulated assays. Haplotype nomenclatures and inference algorithms need to be improved to adequately capture pharmacogenomic diversity in human populations.

Complete genome sequence analysis of enterovirus 71 isolated from children with hand, foot, and mouth disease in Thailand, 2012-2014.

The complete genomic sequences of 14 enterovirus 71 (EV71) strains isolated from children with hand, foot, and mouth disease in Thailand from 2012 to 2014 were determined and compared to enterovirus group A prototypes. Phylogenetic analysis revealed that 13 strains resembled the B5 subgroup, while one strain from a fatal case designated THA_1219 belonged to the C4 subgroup. Similarity plot and bootscan analyses suggested that THA_1219 underwent recombination in the P2 and P3 regions. Full-genome data from this work will contribute to the study of evolution dynamics of EV71.

Ancestral population genomics using coalescence hidden Markov models and heuristic optimisation algorithms

With full genome data from several closely related species now readily available, we have the ultimate data for demographic inference. Exploiting these full genomes, however, requires models that can explicitly model recombination along alignments of full chromosomal length. Over the last decade a class of models, based on the sequential Markov coalescence model combined with hidden Markov models, has been developed and used to make inference in simple demographic scenarios. To move forward to more complex demographic modelling we need better and more automated ways of specifying these models and efficient optimisation algorithms for inferring the parameters in complex and often high-dimensional models.In this paper we present a framework for building such coalescence hidden Markov models for pairwise alignments and present results for using heuristic optimisation algorithms for parameter estimation. We show that we can build more complex demographic models than our previous frameworks and that we obtain more accurate parameter estimates using heuristic optimisation algorithms than when using our previous gradient based approaches.Our new framework provides a flexible way of constructing coalescence hidden Markov models almost automatically. While estimating parameters in more complex models is still challenging we show that using heuristic optimisation algorithms we still get a fairly good accuracy.

Abstract 4283: Whole genome sequencing is superior to cancer panels to aid in decision-making in patients with advanced malignancies

Abstract Background: It is increasingly common to use targeted cancer panels to assess for informative or actionable targets to guide cancer treatment. We compared the utility of information obtained from such a panel compared to whole genome and transcriptome sequencing. Methods: Eligible subjects with incurable cancers for whom there were limited or no standard chemotherapy options, have several samples analyzed: a fresh tumour biopsy; a blood sample for normal comparison; and archival tumours when available. Samples underwent both the Ion Torrent AmpliSeq cancer panel analysis and comprehensive DNA (80X) and RNA sequencing followed by in-depth bioinformatic analysis to identify somatic mutations, copy number alterations, structural rearrangements, and corresponding gene expression changes that may be cancer “drivers” or provide informative (diagnostic) or actionable/druggable targets. Aberrant pathways were matched to drug databases and manual literature reviews undertaken to identify drugs that may be useful or potentially contraindicated; a report is generated and discussed in a multidisciplinary team. Results: Between July 2012 - November 2013, 51 subjects have consented and 45 have been sequenced: 12 breast, 7 lung; 4 colorectal, 3 squamous, 3 adrenal; 2 pancreas; 2 sarcomas, and 1 of each of nasopharynx, primary unknown, CLL-peripheral mantle cell, parotid, anal, appendix, peripheral T-cell, prostate, ovary, endometrial, glioma, and mesothelioma. The median number of lines of chemo prior to sequencing was 3. Of the first 40 cases, the panel did not yield informative or actionable results in 60% of cases: 36% of the cases the panel did not detect any somatic variants and in a further 24% TP53 mutations were the only variants identified. In the other 40% of cases, the panel might have identified an informative abnormality but when put into context of the pathways that can be drawn with the whole genome and transcriptome data the detected panel abnormalities were not comprehensive enough to guide treatment decisions. Examples include: in two colon cancer patients the panel detected a KRAS mutation in one and a RET mutation in the other, however both were actually inactivating mutations and therefore unlikely to be good targets. In contrast, the full genomic data was informative in 70% of cases and treatments were delivered based on the results in 60%, in this heavily pretreated population. Conclusions: The future of cancer medicine lies in genomic profiling to assist therapeutic decision-making. The cancer panel has advantages in terms of speed and cost; however it has not been as informative for identifying candidate druggable driver events and it has missed critical genomic abnormalities that have changed diagnoses. Given the complexity of the cancer genome it is our observation that the panels do not provide the depth and context required to make treatment decisions for the majority of patients with cancer. Citation Format: Janessa J. Laskin, Yaoqing Shen, Howard Lim, Karen A. Gelmon, Daniel Renouf, Stephen Yip, David Huntsman, Anna Tinker, Cheryl Ho, Stephen Chia, Yvonne Li, Katayoon Kasaian, Peter Eirew, Sreeja Leelakumari, Richard Moore, Samuel Aparicio, Yusanne Ma, Steven Jones, Marco Marra. Whole genome sequencing is superior to cancer panels to aid in decision-making in patients with advanced malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4283. doi:10.1158/1538-7445.AM2014-4283

Chloroplast phylogenomic analyses resolve deep-level relationships of an intractable bamboo tribe Arundinarieae (poaceae).

The temperate woody bamboos constitute a distinct tribe Arundinarieae (Poaceae: Bambusoideae) with high species diversity. Estimating phylogenetic relationships among the 11 major lineages of Arundinarieae has been particularly difficult, owing to a possible rapid radiation and the extremely low rate of sequence divergence. Here, we explore the use of chloroplast genome sequencing for phylogenetic inference. We sampled 25 species (22 temperate bamboos and 3 outgroups) for the complete genome representing eight major lineages of Arundinarieae in an attempt to resolve backbone relationships. Phylogenetic analyses of coding versus noncoding sequences, and of different regions of the genome (large single copy and small single copy, and inverted repeat regions) yielded no well-supported contradicting topologies but potential incongruence was found between the coding and noncoding sequences. The use of various data partitioning schemes in analysis of the complete sequences resulted in nearly identical topologies and node support values, although the partitioning schemes were decisively different from each other as to the fit to the data. Our full genomic data set substantially increased resolution along the backbone and provided strong support for most relationships despite the very short internodes and long branches in the tree. The inferred relationships were also robust to potential confounding factors (e.g., long-branch attraction) and received support from independent indels in the genome. We then added taxa from the three Arundinarieae lineages that were not included in the full-genome data set; each of these were sampled for more than 50% genome sequences. The resulting trees not only corroborated the reconstructed deep-level relationships but also largely resolved the phylogenetic placements of these three additional lineages. Furthermore, adding 129 additional taxa sampled for only eight chloroplast loci to the combined data set yielded almost identical relationships, albeit with low support values. We believe that the inferred phylogeny is robust to taxon sampling. Having resolved the deep-level relationships of Arundinarieae, we illuminate how chloroplast phylogenomics can be used for elucidating difficult phylogeny at low taxonomic levels in intractable plant groups.

Biodiversity and multifunctionality in a microbial community: a novel theoretical approach to quantify functional redundancy

Ecosystems have a limited buffering capacity of multiple ecosystem functions against biodiversity loss (i.e. low multifunctional redundancy). We developed a novel theoretical approach to evaluate multifunctional redundancy in a microbial community using the microbial genome database (MBGD) for comparative analysis. In order to fully implement functional information, we defined orthologue richness in a community, each of which is a functionally conservative evolutionary unit in genomes, as an index of community multifunctionality (MF). We constructed a graph of expected orthologue richness in a community (MF) as a function of species richness (SR), fit the power function to SR (i.e. MF = cSRa), and interpreted the higher exponent a as the lower multifunctional redundancy. Through a microcosm experiment, we confirmed that MF defined by orthologue richness could predict the actual multiple functions. We simulated random and non-random community assemblages using full genomic data of 478 prokaryotic species in the MBGD, and determined that the exponent in microbial communities ranged from 0.55 to 0.75. This exponent range provided a quantitative estimate that a 6.6–8.9% loss limit in SR occurred in a microbial community for an MF reduction no greater than 5%, suggesting a non-negligible initial loss effect of microbial diversity on MF.

A unique DNA repair and recombination gene (recN) sequence for identification and intraspecific molecular typing of bacterial wilt pathogen Ralstonia solanacearum and its comparative analysis with ribosomal DNA sequences

Ribosomal gene sequences are a popular choice for identification of bacterial species and, often, for making phylogenetic interpretations. Although very popular, the sequences of 16S rDNA and 16-23S intergenic sequences often fail to differentiate closely related species of bacteria. The availability of complete genome sequences of bacteria, in the recent years, has accelerated the search for new genome targets for phylogenetic interpretations. The recently published full genome data of nine strains of R. solanacearum, which causes bacterial wilt of crop plants, has provided enormous genomic choices for phylogenetic analysis in this globally important plant pathogen. We have compared a gene candidate recN, which codes for DNA repair and recombination function, with 16S rDNA/16-23S intergenic ribosomal gene sequences for identification and intraspecific phylogenetic interpretations in R. solanacearum. recN gene sequence analysis of R. solanacearum revealed subgroups within phylotypes (or newly proposed species within plant pathogenic genus, Ralstonia), indicating its usefulness for intraspecific genotyping. The taxonomic discriminatory power of recN gene sequence was found to be superior to ribosomal DNA sequences. In all, the recN-sequence-based phylogenetic tree generated with the Bayesian model depicted 21 haplotypes against 15 and 13 haplotypes obtained with 16S rDNA and 16-23S rDNA intergenic sequences, respectively. Besides this, we have observed high percentage of polymorphic sites (S 23.04%), high rate of mutations (Eta 276) and high codon bias index (CBI 0.60), which makes the recN an ideal gene candidate for intraspecific molecular typing of this important plant pathogen.

Phylogenetic Signal Variation in the Genomes of Medicago (Fabaceae)

Genome-scale data offer the opportunity to clarify phylogenetic relationships that are difficult to resolve with few loci, but they can also identify genomic regions with evolutionary history distinct from that of the species history. We collected whole-genome sequence data from 29 taxa in the legume genus Medicago, then aligned these sequences to the Medicago truncatula reference genome to confidently identify 87 596 variable homologous sites. We used this data set to estimate phylogenetic relationships among Medicago species, to investigate the number of sites needed to provide robust phylogenetic estimates and to identify specific genomic regions supporting topologies in conflict with the genome-wide phylogeny. Our full genomic data set resolves relationships within the genus that were previously intractable. Subsampling the data reveals considerable variation in phylogenetic signal and power in smaller subsets of the data. Even when sampling 5000 sites, no random sample of the data supports a topology identical to that of the genome-wide phylogeny. Phylogenetic relationships estimated from 500-site sliding windows revealed genome regions supporting several alternative species relationships among recently diverged taxa, consistent with the expected effects of deep coalescence or introgression in the recent history of Medicago.

Phylogeography of Dengue Virus Serotype 4, Brazil, 2010–2011

Dengue virus serotype 4 (DENV-4) reemerged in Roraima State, Brazil, 28 years after it was last detected in the country in 1982. To study the origin and evolution of this reemergence, full-length sequences were obtained for 16 DENV-4 isolates from northern (Roraima, Amazonas, Pará States) and northeastern (Bahia State) Brazil during the 2010 and 2011 dengue virus seasons and for an isolate from the 1982 epidemic in Roraima. Spatiotemporal dynamics of DENV-4 introductions in Brazil were applied to envelope genes and full genomes by using Bayesian phylogeographic analyses. An introduction of genotype I into Brazil from Southeast Asia was confirmed, and full genome phylogeographic analyses revealed multiple introductions of DENV-4 genotype II in Brazil, providing evidence for >3 introductions of this genotype within the last decade: 2 from Venezuela to Roraima and 1 from Colombia to Amazonas. The phylogeographic analysis of full genome data has demonstrated the origins of DENV-4 throughout Brazil.

Genomic Evidence for Large, Long-Lived Ancestors to Placental Mammals

It is widely assumed that our mammalian ancestors, which lived in the Cretaceous era, were tiny animals that survived massive asteroid impacts in shelters and evolved into modern forms after dinosaurs went extinct, 65 Ma. The small size of most Mesozoic mammalian fossils essentially supports this view. Paleontology, however, is not conclusive regarding the ancestry of extant mammals, because Cretaceous and Paleocene fossils are not easily linked to modern lineages. Here, we use full-genome data to estimate the longevity and body mass of early placental mammals. Analyzing 36 fully sequenced mammalian genomes, we reconstruct two aspects of the ancestral genome dynamics, namely GC-content evolution and nonsynonymous over synonymous rate ratio. Linking these molecular evolutionary processes to life-history traits in modern species, we estimate that early placental mammals had a life span above 25 years and a body mass above 1 kg. This is similar to current primates, cetartiodactyls, or carnivores, but markedly different from mice or shrews, challenging the dominant view about mammalian origin and evolution. Our results imply that long-lived mammals existed in the Cretaceous era and were the most successful in evolution, opening new perspectives about the conditions for survival to the Cretaceous-Tertiary crisis.

Full-Genome Dissection of an Epidemic of Severe Invasive Disease Caused by a Hypervirulent, Recently Emerged Clone of Group A Streptococcus

Group A Streptococcus (GAS) causes an exceptionally broad range of infections in humans, from relatively mild pharyngitis and skin infections to life-threatening necrotizing fasciitis and toxic shock syndrome. An epidemic of severe invasive human infections caused by type emm59 GAS, heretofore an exceedingly rare cause of disease, spread west to east across Canada over a 3-year period (2006 to 2008). By sequencing the genomes of 601 epidemic, historic, and other emm59 organisms, we discovered that a recently emerged, genetically distinct emm59 clone is responsible for the Canadian epidemic. Using near-real-time genome sequencing, we were able to show spread of the Canadian epidemic clone into the United States. The extensive genome data permitted us to identify patterns of geographic dissemination as well as links between emm59 subclonal lineages that cause infections. Mouse and nonhuman primate models of infection demonstrated that the emerged clone is unusually virulent. Transmission of epidemic emm59 strains may have occurred primarily by skin contact, as suggested by an experimental model of skin transmission. In addition, the emm59 strains had a significantly impaired ability to persist in human saliva and to colonize the oropharynx of mice, and seldom caused human pharyngitis. Our study contributes new information to the rapidly emerging field of molecular pathogenomics of bacterial epidemics and illustrates how full-genome data can be used to precisely illuminate the landscape of strain dissemination during a bacterial epidemic.

Phylo-MCOA: A Fast and Efficient Method to Detect Outlier Genes and Species in Phylogenomics Using Multiple Co-inertia Analysis

Full genome data sets are currently being explored on a regular basis to infer phylogenetic trees, but there are often discordances among the trees produced by different genes. An important goal in phylogenomics is to identify which individual gene and species produce the same phylogenetic tree and are thus likely to share the same evolutionary history. On the other hand, it is also essential to identify which genes and species produce discordant topologies and therefore evolve in a different way or represent noise in the data. The latter are outlier genes or species and they can provide a wealth of information on potentially interesting biological processes, such as incomplete lineage sorting, hybridization, and horizontal gene transfers. Here, we propose a new method to explore the genomic tree space and detect outlier genes and species based on multiple co-inertia analysis (MCOA), which efficiently captures and compares the similarities in the phylogenetic topologies produced by individual genes. Our method allows the rapid identification of outlier genes and species by extracting the similarities and discrepancies, in terms of the pairwise distances, between all the species in all the trees, simultaneously. This is achieved by using MCOA, which finds successive decomposition axes from individual ordinations (i.e., derived from distance matrices) that maximize a covariance function. The method is freely available as a set of R functions. The source code and tutorial can be found online at http://phylomcoa.cgenomics.org.

Molecular characterisation of an avihepadnavirus isolated from Psittacula krameri (ring-necked parrot)

Avihepadnaviruses have been documented previously in ducks, herons, geese, storks and cranes. Here, we describe the full genome of a new avihepadnavirus isolated from Psittacula krameri (ring-necked parrot) in Poland. The parrot hepatitis B virus (PHBV) genome (3042 bp) shares <76% sequence identity with other avihepadnavirus isolates and is phylogenetically most closely related to heron and stork hepatitis B viruses isolates. PHBV has a genome organization similar to that of other hepadnaviruses and contains ORFs for a preC/C, preS/S and polyprotein. Additionally, we identified an X-like ORF in the genome of PHBV. The full-genome data will be useful in developing screening tools for avihepadnaviruses in parrots.

Domestication of olive fly through a multi-regional host shift to cultivated olives: Comparative dating using complete mitochondrial genomes

The evolutionary history of the olive fly, Bactrocera oleae, was reconstructed in a phylogenetic and coalescent framework using full mitochondrial genome data from 21 individuals covering the entire worldwide distribution of the species. Special attention was given to reconstructing the timing of the processes under study. The early subdivision of the olive fly reflects the Quaternary differentiation between Olea europea subsp. europea in the Mediterranean area and the two lineages of Olea europea subsp. cuspidata in Africa and Asia, pointing to an early and close association between the olive fly and its host. The geographic structure and timing of olive fly differentiation in the Mediterranean indicates a clear connection with the post-glacial recolonization of wild olives in the area, and is irreconcilable with the early historical process of domestication and spread of the cultivated olive from its Levantine origin. Therefore, we suggest an early co-history of the olive fly with its wild host during the Quaternary and post-glacial periods and a multi-regional shift of olive flies to cultivated olives as these cultivars gradually replaced wild olives in historical times.

Molecular complexity of successive bacterial epidemics deconvoluted by comparative pathogenomics

Understanding the fine-structure molecular architecture of bacterial epidemics has been a long-sought goal of infectious disease research. We used short-read-length DNA sequencing coupled with mass spectroscopy analysis of SNPs to study the molecular pathogenomics of three successive epidemics of invasive infections involving 344 serotype M3 group A Streptococcus in Ontario, Canada. Sequencing the genome of 95 strains from the three epidemics, coupled with analysis of 280 biallelic SNPs in all 344 strains, revealed an unexpectedly complex population structure composed of a dynamic mixture of distinct clonally related complexes. We discovered that each epidemic is dominated by micro- and macrobursts of multiple emergent clones, some with distinct strain genotype-patient phenotype relationships. On average, strains were differentiated from one another by only 49 SNPs and 11 insertion-deletion events (indels) in the core genome. Ten percent of SNPs are strain specific; that is, each strain has a unique genome sequence. We identified nonrandom temporal-spatial patterns of strain distribution within and between the epidemic peaks. The extensive full-genome data permitted us to identify genes with significantly increased rates of nonsynonymous (amino acid-altering) nucleotide polymorphisms, thereby providing clues about selective forces operative in the host. Comparative expression microarray analysis revealed that closely related strains differentiated by seemingly modest genetic changes can have significantly divergent transcriptomes. We conclude that enhanced understanding of bacterial epidemics requires a deep-sequencing, geographically centric, comparative pathogenomics strategy.

2× genomes - depth does matter

The use of low coverage genomes in comparative evolutionary analyses skews estimates of gene gains and losses.

From the Lab to the Clinic: Gene-Expression Profiles That Are Associated with Mek-Inhibitor Sensitivity In Vitro Are Coordinately Co-Expressed in Breast Cancer Biopsy Samples from the I-SPY Trial (CALGB 150007/150012, ACRIN 6657).

Abstract There is increasing appreciation that response to breast cancer therapy is dependent on the specific characteristics of each tumor, as has also been observed in the first analyses of 221 patients treated by standard neo-adjuvant chemotherapy in the I-SPY 1 TRIAL (CALGB 150007/150012, ACRIN 6657). I-SPY 1 has collected full-genome gene expression data on pre-treatment biopsies as well as outcome data for initial tumor response (pathological assessment) and 3-year outcome data. In addition, we have established an in vitro high-throughput system using 50 breast cancer cell lines that can be used to identify gene-expression patterns predictive of drug sensitivity using 'Adaptive Splines'. Though several groups are using cell lines to develop drug response predictors, there is understandable skepticism as to whether the cancer cell lines have retained sufficient similarity to in vivo tumors to make such an endeavor successful.Methods: We used the in vitro cell lines to identify molecular markers of sensitivity to the MEK inhibitor CI1040. We next used the molecular data collected in I-SPY 1, in particular Affymetrix U133A data from 121 patients, to see whether subgroups could be identified among the ISPY patients that vary according to the expression of genes in this signature. In addition, we used the network visualization tool, EGAN, to identify biological networks among the significant predictors of CI-1040 sensitivity or resistance.Results: Analysis of in vitro data using adaptive splines identified 406 genes predictive of response to CI1040, of which 135 and 271 were expressed more highly in CI1040-resistant or -sensitive cell lines respectively. EGAN analyses of these predictors revealed multiple subnetworks and pathways as important. Some of these expression patterns could be corroborated in additional datasets. When we clustered the gene expression data from biopsies using the best linear-classifier based gene predictors of CI1040 sensitivity, the genes and patients each divided into two classes. Notably, most of the genes expressed more highly in the CI-1040-resistant cell lines formed one cluster, while most of the genes expressed more highly in the sensitive cell lines formed another cluster (p&amp;lt;&amp;lt;0.001; Fisher Exact Test), a strong indicator that these genes are similarly co-expressed in both cell lines and tumor samples. Preliminary results indicate that roughly a third of patients show a pattern of gene-expression that is similar to the CI1040-sensitive cell lines.Conclusion: The expression of genes identified to associate with CI1040 sensitivity in vitro show a similar pattern of co-expression in I-SPY patient samples. These data suggest that this CI1040-sensitivity predictor should be tested for its ability to predict the therapeutic response among patients receiving CI1040 (or other drugs in this class). The I-SPY 2 trial will include phase II targeted drugs for which predictor gene sets will be derived from our in vitro system and prospectively tested in patients receiving that treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2042.

Data structures and compression algorithms for genomic sequence data

The continuing exponential accumulation of full genome data, including full diploid human genomes, creates new challenges not only for understanding genomic structure, function and evolution, but also for the storage, navigation and privacy of genomic data. Here, we develop data structures and algorithms for the efficient storage of genomic and other sequence data that may also facilitate querying and protecting the data. The general idea is to encode only the differences between a genome sequence and a reference sequence, using absolute or relative coordinates for the location of the differences. These locations and the corresponding differential variants can be encoded into binary strings using various entropy coding methods, from fixed codes such as Golomb and Elias codes, to variables codes, such as Huffman codes. We demonstrate the approach and various tradeoffs using highly variables human mitochondrial genome sequences as a testbed. With only a partial level of optimization, 3615 genome sequences occupying 56 MB in GenBank are compressed down to only 167 KB, achieving a 345-fold compression rate, using the revised Cambridge Reference Sequence as the reference sequence. Using the consensus sequence as the reference sequence, the data can be stored using only 133 KB, corresponding to a 433-fold level of compression, roughly a 23% improvement. Extensions to nuclear genomes and high-throughput sequencing data are discussed. Data are publicly available from GenBank, the HapMap web site, and the MITOMAP database. Supplementary materials with additional results, statistics, and software implementations are available from http://mammag.web.uci.edu/bin/view/Mitowiki/ProjectDNACompression.