Taking a functional genomics approach in molecular medicine

doi:10.1016/S1471-4914(01)02181-5

Trends in Molecular Medicine

Volume 7, Issue 11, 1 November 2001, Pages 494-501

https://doi.org/10.1016/S1471-4914(01)02181-5 Get rights and content

Abstract

The elucidation of genetic components of human diseases at the molecular level provides crucial information for developing future causal therapeutic intervention. High-throughput genome sequencing and systematic experimental approaches are fuelling strategic programs designed to investigate gene function at the biochemical, cellular and organism levels. Bioinformatics is one important tool in functional genomics, although showing clear limitations in predicting ab initio gene structures, gene function and protein folds from raw sequence data. Systematic large-scale data-set generation, using the same type of experiments that are used to decipher the function of single genes, are being applied on entire genomes. Comparative genomics, establishment of gene catalogues, and investigation of cellular and tissue molecular profiles are providing essential tools for understanding gene function in complex biological networks.

Section snippets

Genome analysis and sequence comparisons

With >50 microbial genomes sequenced, the microbiology community has pioneered comparative genomics as a lead to deduce molecular mechanisms underlying physiological characteristics of different bacterial strains, and to identify essential genes involved in infection. Sequencing of leading pathogens, including that of Streptococcus pneumoniae ³, enables the study of the biology of pathogens and host–pathogen relationships, knowledge that might contribute to future disease control. The

Systematic generation of phenotypes in invertebrate and vertebrate models

In many respects the most interesting aspect of the function of a gene is its function in the organism as a whole, requiring either the mutations of specific genes, followed by the analysis of the phenotype of the organisms carrying this mutation (gene-driven paradigm), or the identification of organisms with an interesting phenotype followed by the mapping of mutated genes (phenotype-driven paradigm). It was previously estimated that about one third of genes in yeast, worm, fly and mice is

Gene expression patterns by in situ hybridization

Systematic functional screens by in situ hybridization (ISH) reveal temporal and spatial gene expression patterns, which can contribute to the discovery of novel gene functions and synexpression groups leading to pathway identification. In gene-driven approaches, study of embryonic patterning using collections of random cDNA provides a direct link between DNA sequences and endogenous gene expression patterns. High-throughput whole-mount ISH developed for X.laevis and mouse embryos showed that

Proteome maps and phenotype analysis

Protein processing and modification can not be predicted from genomic information. In a given cell at a certain time point, up to 10 000–20 000 transcripts and 50 000–80 000 proteins could be expressed simultaneously, given estimates of about four isoforms per gene. Transcription levels do not necessarily correlate with those of proteins, particularly for rarely expressed genes ⁵³. In theory, array experiments should be mirrored with proteomics data for a full understanding of physiological

Proteomics and structural genomics

Structural information can provide a lead for protein function and drug action at the molecular level ⁶⁰. The Protein Data Bank ⁶¹ currently lists 14 150 protein structures, among which close to 3000 match the keyword ‘human’. World-wide efforts developing high-throughput structural genomics operations are setting up remarkably quickly (http://www.rcsb.org/pdb/strucgen.html). Structural genomics initiatives aim at resolving experimentally 10 000 protein structures within the next ten years,

Protein–protein interaction maps

The exploration of biological pathways and cellular functions builds upon knowledge of protein–protein interactions. Vertebrates made wide use of protein domain shuffling, increasing combinatorial diversity and the capacity to mediate protein–protein interactions, by adapting ancestral function or creating novel ones. The current gold standard for systematic search of protein-interaction partners is the yeast two-hybrid system ⁶⁴, whereby unknown partners (preys) can be screened against a bait

Lessons from model organisms and remaining challenges

Non-mammalian models will remain essential for tackling gene function in a systematic fashion, providing different contexts to assign function to many predicted genes that might have specialized or pleiotropic roles. Despite their value, mouse models are somewhat limiting owing to the relative paucity of mouse knockouts that give tractable phenotypes. It will be technically difficult and costly to generate most genes in the mouse genome and to study phenotypic outcomes even with standardized

Concluding remarks

This review explores highlights of ongoing efforts in functional genomics and illustrates how these approaches can be applied in biomedical research. Collectively, functional genomics approaches provide a matrix of information, allowing the ‘tagging’ of gene products with functional attributes and to reveal physiological pathways. Large data sets need to be archived, annotated, analyzed and made publicly available in a standardized and usable form to be best exploited. Integration with SNP

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Trends in Molecular Medicine

ReviewTaking a functional genomics approach in molecular medicine

Abstract

Section snippets

Genome analysis and sequence comparisons

Systematic generation of phenotypes in invertebrate and vertebrate models

Gene expression patterns by in situ hybridization

Proteome maps and phenotype analysis

Proteomics and structural genomics

Protein–protein interaction maps

Lessons from model organisms and remaining challenges

Concluding remarks

Cell

Mol. Med. Today

J. Biol. Chem.

Mech. Dev.

Cell

Dev. Biol.

Trends Genet.

Trends Genet.

Mech. Dev.

Trends Genet.

Trends Pharmacol. Sci.

Initial sequencing and analysis of the human genome

Nature

The sequence of the human genome

Science

Analysis of the complete nucleotide sequence and functional organization of the genome of Streptococcus pneumoniae bacteriophage Cp-1

J. Virol.

The COG database: new developments in phylogenetic classification of proteins from complete genomes

Nucleic Acids Res.

Comparative genomics of the eukaryotes

Science

Developmental rescue of Drosophila cephalic defects by the human Otx genes

Proc. Natl. Acad. Sci. U. S. A.

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Nat. Genet.

Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours

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Nat. Genet.

The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio

Development

Review
Taking a functional genomics approach in molecular medicine