Genomics, gene expression and DNA arrays

Experimental genomics in combination with the growing body of sequence information promise to revolutionize the way cells and cellular processes are studied. Information on genomic sequence can be used experimentally with high-density DNA arrays that allow complex mixtures of RNA and DNA to be interrogated in a parallel and quantitative fashion. DNA arrays can be used for many different purposes, most prominently to measure levels of gene expression (messenger RNA abundance) for tens of thousands of genes simultaneously. Measurements of gene expression and other applications of arrays embody much of what is implied by the term 'genomics'; they are broad in scope, large in scale, and take advantage of all available sequence information for experimental design and data interpretation in pursuit of biological understanding.     

Genomic profiling of drug sensitivities via induced haploinsufficiency

Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analysed for drug sensitivity using high-density oligonucleotide arrays. Individual heterozygous strain analysis verified six known drug targets. Parallel analysis identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity observed in human populations.     

Lahontan cutthroat trout ( Oncorhynchus clarki henshawi ) spawning and downstream migration of juveniles into Summit Lake, Nevada

The only remaining self-sustaining native population of lacustrine Lahontan cutthroat trout ( Oncorhynchus clarki henshawi ) not affected by nonnative salmonids is in Summit Lake, Humboldt County, Nevada. Annual spawning runs in 1993 and 1994 were monitored at a fish trap on Mahogany Creek, the only spawning tributary for Summit Lake. Number of spawners was similar in both years, with 1290 upstream migrants observed in 1993 and 1255 in 1994. In 1993, 137 postspawners (10.6% of upstream migrants) returned to the lake, and in 1994, 434 postspawners (34.6% of upstream migrants) returned downstream through the fish trap. Two distinct groups of subadult Lahontan cutthroat trout were observed moving downstream in 1994. The first group passed downstream between 27 April and 29 July and included 1188 fish (average fork length = 90 mm). Between 1 August and 31 October, 1160 fish (average fork length = 42 mm) moved downstream. Size differences of these 2 groups suggest that the 1st group comprised fish that had overwintered in Mahogany Creek, while the 2nd group were probably young-of-the-year.     

Malaria research in the post-genomic era

For many pathogens the availability of genome sequence, permitting genome-dependent methods of research, can partially substitute for powerful forward genetic methods (genome-independent) that have advanced model organism research for decades. In 2002 the genome sequence of Plasmodium falciparum, the parasite causing the most severe type of human malaria, was completed, eliminating many of the barriers to performing state-of-the-art molecular biological research on malaria parasites. Although new, licensed therapies may not yet have resulted from genome-dependent experiments, they have produced a wealth of new observations about the basic biology of malaria parasites, and it is likely that these will eventually lead to new therapeutic approaches. This review will focus on the basic research discoveries that have depended, in part, on the availability of the Plasmodium genome sequences.