Current Genomics - Volume 9, Issue 2, 2008

There is an epistemological crisis in genomics. At issue is what constitutes scientific knowledge in genomic science, or systems biology in general. Does this crisis require a new perspective on knowledge heretofore absent from science or is it merely a matter of interpreting new scientific developments in an existing epistemological framework? This paper discusses the manner in which the experimental method, as developed and understood over recent centuries, leads naturally to a scientific epistemology grounded in an experimental-mathematical duality. It places genomics into this epistemological framework and examines the current situation in genomics. Meaning and the constitution of scientific knowledge are key concerns for genomics, and the nature of the epistemological crisis in genomics depends on how these are understood.

It is widely predicted that cost and efficiency gains in sequencing will usher in an era of personal genomics and personalized, predictive, preventive, and participatory medicine within a decade. I review the computational challenges ahead and propose general and specific directions for research and development. There is an urgent need to develop semantic ontologies that span genomics, molecular systems biology, and medical data. Although the development of such ontologies would be costly and difficult, the benefits will far outweigh the costs. I argue that availability of such ontologies would allow a revolution in web-services for personal genomics and medicine.

Domains are the building blocks of all globular proteins and present one of the most useful levels at which protein function can be understood. Through recombination and duplication of a limited set of domains, proteomes evolved and the collection of protein superfamilies in an organism formed. As such, the presence of a shared domain can be regarded as an indicator of similar function and evolutionary history, but it does not necessarily imply it since convergent evolution may give rise to similar gene functions as well as architectures. Through the wealth of sequences and annotation data brought about by genomics, evolutionary links can be sought for via homology relationships and comparative genomics, structural modeling and phylogenetics. The goal hereby is not only to predict the function of newly discovered proteins, but also to spell out their pathway of evolution and, possibly, identify their most likely origin. This can ultimately help to understand protein function and functional relationships of protein families. Additionally, through comparison with transcriptional data, evolutionary data can be linked to gene (and genome) activity and thus allow for the identification of common principles behind fast evolving proteins and relatively stable ones. In this review, we describe the basic principles of studying protein (domain) evolution and illustrate recent developments in molecular evolution and give valuable new insights in the field of comparative genomics. As an example, we include here molecular models of the multiple PDZ domain protein MUPP-1 and present a simple comparative genomic view on its structural course of evolution.

Cancer is currently a major public health problem and, as such, emerging research is making significant progress in identifying major players in its biology. One recent topic of interest involves microRNAs (miRNAs) which are small, non-coding RNA molecules that inhibit gene expression post-transcriptionally. They accomplish this by binding to the 3' untranslated region (3'UTR) of target messengerRNA (mRNA), resulting in either their degradation or inhibition of translation, depending on the degree of complementary base pairing. They are transcribed by RNA polymerase II and are formed into mature miRNAs via two steps, each catalyzed by a different ribonuclease III (RNaseIII). Cross-species comparisons demonstrate that miRNAs are evolutionarily conserved and play important roles in a wide array of normal biological processes. Importantly, aberrant miRNA expression is correlated with human disease, especially in the development of cancer. Recent research has identified targets and functions of miRNAs, illustrating that some are oncogenic in nature while others show tumor suppressor activity. The miRNAs have also been characterized as having high potential in the clinical arena and, as such, have been a target for exploitation toward cancer therapy. Not only has it been shown that miRNA expression profiles may prove useful as diagnostic and prognostic markers in cancer, various miRNA-based therapies show promise as well. It is anticipated that further research will elucidate the benefits of using miRNAs as clinical agents in the battle against cancer and other chronic diseases.

Ancestry informative markers (AIMs) are human polymorphisms that exhibit substantially allele frequency differences among populations. These markers can be useful to provide information about ancestry of samples which may be useful in predicting a perpetrator's ethnic origin to aid criminal investigations. Variations in human pigmentation are the most obvious phenotypes to distinguish individuals. It has been recently shown that the variation of a G in an A allele of the coding single-nucleotide polymorphism (SNP) rs1426654 within SLC24A5 gene varies in frequency among several population samples according to skin pigmentation. Because of these observations, the SLC24A5 locus has been evaluated as Ancestry Informative Region (AIR) by typing rs1426654 together with two additional intragenic markers (rs2555364 and rs16960620) in 471 unrelated individuals originating from three different continents (Africa, Asia and Europe). This study further supports the role of human SLC24A5 gene in skin pigmentation suggesting that variations in SLC24A5 haplotypes can correlate with human migration and ancestry. Furthermore, our data do reveal the utility of haplotype and combined unphased genotype analysis of SLC24A5 in predicting ancestry and provide a good example of usefulness of genetic characterization of larger regions, in addition to single polymorphisms, as candidates for population-specific sweeps in the ancestral population.

The Neuronal Ceroid Lipofuscinoses (NCLs) are the most common group of neurodegenerative disorders of childhood. While mutations in eight different genes have been shown to be responsible for these clinically distinct types of NCL, the NCLs share many clinical and pathological similarities. We have conducted an exhaustive Basic Local Alignment Search Tool (BLAST) analysis of the human protein sequences for each of the eight known NCL proteins- CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8 and CLN10. The number of homologous species per CLN-protein identified by BLAST searches varies depending on the parameters set for the BLAST search. For example, a lower threshold is able to pull up more homologous sequences whereas a higher threshold decreases this number. Nevertheless, the clade confines are consistent despite this variation in BLAST searching parameters. Further phylogenetic analyses on the appearance of NCL proteins through evolution reveals a different time line for the appearance of the CLN-proteins. Moreover, divergence of each protein shows a different pattern, providing important clues on the evolving role of these proteins. We present and review in-depth bioinformatic analysis of the NCL proteins and classify the CLN-proteins into families based on their structures and evolutionary relationships, respectively. Based on these analyses, we have grouped the CLN-proteins into common clades indicating a common evolving pathway within the evolutionary tree of life. CLN2 is grouped in Eubacteria, CLN1 and CLN10 in Viridiplantae, CLN3 in Fungi/ Metazoa, CLN7 in Bilateria and CLN5, CLN6 and CLN8 in Euteleostomi.