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The era of "big data" presents immense opportunities for scientific discovery and technological progress, with the potential to have enormous impact on research and development in the public sector. In order to capitalize on these benefits, there are significant challenges to overcome in data analytics. The National Institute of Allergy and Infectious Diseases held a symposium entitled "Data Science: Unlocking the Power of Big Data" to create a forum for big data experts to present and share some of the creative and innovative methods to gleaning valuable knowledge from an overwhelming flood of biological data. A significant investment in infrastructure and tool development, along with more and better-trained data scientists, may facilitate methods for assimilation of data and machine learning, to overcome obstacles such as data security, data cleaning, and data integration., Competing Interests: Author Disclosure Statement No competing financial interests exist.

The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.

Recent developments in genome-wide transcript monitoring have led to a rapid accumulation of data from gene expression studies. Such projects highlight the need for methods to predict the molecular basis of transcriptional coregulation. A microarray project identified the 420 yeast transcripts whose synthesis displays cell cycle-dependent periodicity. We present here a statistical technique we developed to identify the sequence elements that may be responsible for this cell cycle regulation. Because most gene regulatory sites contain a short string of highly conserved nucleotides, any such strings that are involved in gene regulation will occur frequently in the upstream regions of the genes that they regulate, and rarely in the upstream regions of other genes. Our strategy therefore utilizes statistical procedures to identify short oligomers, five or six nucleotides in length, that are over-represented in upstream regions of genes whose expression peaks at the same phase of the cell cycle. We report, with a high level of confidence, that 9 hexamers and 12 pentamers are over-represented in the upstream regions of genes whose expression peaks at the early G(1), late G(1), S, G(2), or M phase of the cell cycle. Some of these sequence elements show a preference for a particular orientation, and others, through a separate statistical test, for a particular position upstream of the ATG start codon. The finding that the majority of the statistically significant sequence elements are located in late G(1) upstream regions correlates with other experiments that identified the late G(1)/early S boundary as a vital cell cycle control point. Our results highlight the importance of MCB, an element implicated previously in late G(1)/early S gene regulation, as most of the late G(1) oligomers contain the MCB sequence or variations thereof. It is striking that most MCB-like sequences localize to a specific region upstream of the ATG start codon. Additional sequences that we have identified may be important for regulation at other phases of the cell cycle.

Sequence-dependent DNA curvature is known to play an important role in initiation of transcription of many genes. We compared the distribution of predicted intrinsic curvature of Escherichia coli and human promoter sequences with the distribution of curvature of randomly selected coding and non-coding fragments from these organisms. Different methods of curvature calculation were found to yield mostly similar overall tendencies of DNA curvature in all groups of sequences. According to all methods of calculation, E. coli promoters were found to be more curved than coding sequences from the same genome and random sequences with the same nucleotide composition. By contrast, the average curvature of human promoter sequences was only marginally greater than the average curvature of human coding sequences. Non-coding intron sequences were found to be the most curved of the human sequences examined. Based on these observations, we hypothesize about the role of DNA curvature in promoter sequences.

Progression through the eukaryotic cell cycle is known to be both regulated and accompanied by periodic fluctuation in the expression levels of numerous genes. We report here the genome-wide characterization of mRNA transcript levels during the cell cycle of the budding yeast S. cerevisiae. Cell cycle-dependent periodicity was found for 416 of the 6220 monitored transcripts. More than 25% of the 416 genes were found directly adjacent to other genes in the genome that displayed induction in the same cell cycle phase, suggesting a mechanism for local chromosomal organization in global mRNA regulation. More than 60% of the characterized genes that displayed mRNA fluctuation have already been implicated in cell cycle period-specific biological roles. Because more than 20% of human proteins display significant homology to yeast proteins, these results also link a range of human genes to cell cycle period-specific biological functions.

The de novo protein albebetin has been engineered (J. Mol. Biol. 1992, 225, 927-931) to form a predesigned tertiary fold that has not yet been observed in natural proteins. Analysis of albebetin expressed in a cell-free system and in Escherichia coli revealed its compactness, relative stability, and the secondary structure close to the predesigned one. The blast-transforming biological activity of human interferon was grafted to albebetin by attachment of an eight amino acid interferon fragment to the N-terminus of albebetin next to its first methionine residue. The chimeric protein was expressed in a wheat germ cell-free translation system and tested for its structural properties, receptor binding, and biological activity. According to the tests, albebetin incorporating the active interferon fragment has a compact and relatively stable structure, and binds the murine thymocyte receptor effectively. It activates the blast transformation reaction of thymocyte cells even more efficiently than human interferon at low concentrations.

The de novo protein albebetin has been designed recently to form a predetermined tertiary fold that has not yet been observed in natural proteins. An eight amino acid fragment (131-138) of human interferon alpha(2) carrying the blast-transforming activity of the protein was attached to the N-terminus of albebetin next to its initiatory methionine residue. The gene of chimeric protein was expressed in a wheat germ cell-free translation system and synthesized protein was tested for its compactness and stability. Its ability for receptor binding was also studied. We have shown that albebetin with attached octapeptide is practically as compact as natural proteins of corresponding molecular weight and possesses high stability toward the urea-induced unfolding. It binds murine thymocyte receptor at a high affinity and activates the thymocyte blast transformation efficiently at a concentration of 10(-11) M.

An investigation of the functional topography of thermolysin was carried out using frequency analysis of its primary and tertiary structures. The statistical validity of this approach was estimated for the enzyme active site, the substrate-binding pocket, the inter-domain interface and calcium-binding sites' predictions. We showed that frequency analysis of primary structure could be employed to predict the localization of contiguous parts of the inter-domain interface. The same approach appears to be unsuitable to a search for conformation-dependent enzyme active sites and substrate-binding pockets. In contrast, frequency analysis of the spatial neighborhood is not effective for predicting the inter-domain interface as distinct from the active site, substrate-binding pocket and calcium-binding sites. These differences should be taken into account when investigating and understanding protein structure-function relationships.

Computer search for probable T-epitopes of hepatitis A virus capsid proteins was performed using an integrated set of programs. Eight segments of the VP1, VP2, VP3 and VP4 proteins were chosen and synthesised. Five peptides previously examined as probable B-epitopes were used as well. All the peptides were tested for their ability to stimulate proliferation of lymph node T-cells primed with synthetic peptides. Almost all predicted T-epitopes affected the T-cell proliferation. None of the peptides had mitogenic activity. We demonstrated that regions 17-33 and 276-298 of VP1 are possible immunodominant promiscuous sites activating lymphocytes of all mouse haplotypes.

Peptide (P6) representing amino acids 62-75 of HAV capsid protein VP3 was synthesized. Pure P6, octamer form of P6, and P6 conjugated to KLH were injected into rabbits. The sera against these preparations reacted with denaturized VP3 in immunoblotting tests; however, only anti-P6-KLH serum was capable of binding the native HAV.

A comparison of a new method of searching for functionally important sites in proteins and peptide hormones with a previously published method is presented. All methods are based on information theory that holds that rare oligomers contain much information and, thus, are likely to be important for specific functional activity. Twenty-five proteins and peptide hormones with known receptor-binding sites were studied; the new method showed good predictive ability. However, taking into account short-range sequential preferences in protein structures, the predictive ability of methods based on information theory, at least for the receptor-binding site predictions, was not greatly improved.

To determine whether hypotheses about the complementarity of amino acids based on the genetic code reflect the amino acid contact preferences found in natural proteins, the average contact probabilities for hypothetical complementary amino acid pairs were compared with those for all possible remaining pairs of the corresponding subset. A statistically significant preference was found for contact between amino acids with codons which had the same central nucleotide. Conversely, the contact probabilities for amino acids with complementary codons either did not exceed, or exceeded only insignificantly, the value for the corresponding remainder subset. The data obtained do not support the hypothesis for the complementarity of peptides coded by complementary RNA strands.

An essential part of structure-functional studies of proteins is the search for sites responsible for specific functional activity. The information theory can be of much help in such a search. According to this theory, rarely occurring oligomers contain more information and thus are more likely to take part in forming the active site. We used frequencies of occurrences of amino acids (mean and for each polypeptide) to search for clusters of highly informative amino acids by the moving window smoothing method. In 16 out of 19 peptide hormones such sequences were active sites known from literature.