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Maximizing the potential of functional genomics

Key Points

  • Biology is entering an exciting era brought about by the increase in genome-wide information. Functional genomics in particular is making rapid progress in assigning biological meaning to genomic data.

  • One of the main challenges for the future for functional genomics lies in the transition of this technology, which is at present mainly carried out in a few dedicated centres, into individual laboratories — because this is where the biological expertise lies.

  • For this transition to be achieved, experiments must be miniaturized and costs must be lowered.

  • The three applications of genome technology that have achieved significant attention include gene knock-out approaches, gene-expression profiling and the genetic mapping of quantitative trait loci (QTLs).

  • Molecular barcoding provides tremendous power for the parallel phenotypic analysis of knock-outs in yeast and is among the most promising technologies for miniaturizing high-throughput approaches.

  • Gene-expression profiling has achieved high throughput, yet the technology and its interpretation are still problematic. Poor correlation with other functional parameters indicates that much insight can be gained from more rigorous study.

  • The genetic mapping of QTLs is plagued by both the lack of approaches that allow the scoring of thousands of markers in large numbers of samples and insufficient data to support statistical expectations. Functional studies in model organisms are needed to provide examples of the complexity that underlies quantitative traits.

  • High-throughput approaches show promise for revolutionizing disease diagnosis and treatment; however, the false-prediction rates of high-throughput approaches need to be eliminated.

  • Single-gene studies promise to remain essential.

Abstract

Geneticists have made tremendous progress in understanding the genetic basis of phenotypes, and genomics promises to bring further insights at a rapid pace. The progress in functional genomics has been driven primarily by the development of new techniques that are used in a few dedicated research centres. Focusing on selected advances in genomic technologies, we assess the results that have been obtained so far, highlight the challenges faced by these new tools and suggest ways in which they can be overcome. We argue that progress in functional genomics will depend on developing high-throughput technologies that can easily be moved away from dedicated centres and into individual laboratories.

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Figure 1: Assaying molecular barcode tags in yeast pools.
Figure 2: High-throughput development cycles.
Figure 3: Allelic switching with reciprocal hemizygosity.

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Acknowledgements

We would like to thank L. David and T. Neklesa for helpful comments on the manuscript.

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Correspondence to Lars M. Steinmetz.

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DATABASES

Entrez

LRPPRC

tetR

OMIM

Leigh syndrome

FURTHER INFORMATION

Arabidopsis Mutations

Human Gene Mutation Database

Yeast Deletion Database

Glossary

COMPLEX TRAITS

A trait that is determined by many genes, almost always interacting with environmental influences.

RNA INTERFERENCE

(RNAi). A process by which double-stranded RNA silences specifically the expression of homologous genes through degradation of their cognate mRNA.

SATURATION MUTAGENESIS

A mutagenesis screen that has reached a stage of saturation in which additional mutagenesis does not seem to recover mutations in new genes.

HAPLOINSUFFICIENCY

A gene dosage effect that occurs when a diploid requires both functional copies of a gene for a wild-type phenotype. An organism that is heterozygous for a haploinsufficient locus does not have a wild-type phenotype.

STOICHIOMETRIC

The molar ratio of interacting molecules.

TRANSFERRED DNA

 (T DNA). The segment of DNA in the Ti plasmid of Agrobacterium tumefaciens that is transferred to plant cells and inserted into the chromosomes of the plant.

CRE

Cre encodes a site-specific recombinase that recognizes and binds to specific sites called lox. Two lox sites recombine at nearly 100% efficiency in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

EPISOME

An independent DNA element, such as a plasmid, that can replicate extrachromosomally or that can be maintained by integrating into the genome of the host.

LOX SITE

A site to which Cre recombinase binds to mediate recombination, allowing DNA that is cloned between two such sites to be removed.

COMPLEMENTATION

One example is the use of partial diploids to determine whether two mutations affect the same or different genes. If the mutations are in the same gene, they generally fail to complement each other and the diploid retains the mutant phenotype. By contrast, mutations in different genes usually complement one another and restore a wild-type phenotype to the diploid. However, exceptions to both cases abound.

HEMIZYGOUS

A diploid genotype that has only one copy of a particular gene, as in X-chromosome genes in a male, or when the homologous chromosome carries a deletion.

EPISTASIS

An interaction between non-allelic genes, such that one gene masks, interferes with or enhances the effect of the other gene.

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Steinmetz, L., Davis, R. Maximizing the potential of functional genomics. Nat Rev Genet 5, 190–201 (2004). https://doi.org/10.1038/nrg1293

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