Data transferability from model organisms to human beings: insights from the functional genomics of the flightless region of Drosophila - PubMed (original) (raw)

Data transferability from model organisms to human beings: insights from the functional genomics of the flightless region of Drosophila

R Maleszka et al. Proc Natl Acad Sci U S A. 1998.

Abstract

At what biological levels are data from single-celled organisms akin to a Rosetta stone for multicellular ones? To examine this question, we characterized a saturation-mutagenized 67-kb region of the Drosophila genome by gene deletions, transgenic rescues, phenotypic dissections, genomic and cDNA sequencing, bio-informatic analysis, reverse transcription-PCR studies, and evolutionary comparisons. Data analysis using cDNA/genomic DNA alignments and bio-informatic algorithms revealed 12 different predicted proteins, most of which are absent from bacterial databases, half of which are absent from Saccharomyces cerevisiae, and nearly all of which have relatives in Caenorhabditis elegans and Homo sapiens. Gene order is not evolutionarily conserved; the closest relatives of these genes are scattered throughout the yeast, nematode, and human genomes. Most gene expression is pleiotropic, and deletion studies reveal that a morphological phenotype is seldom observed when these genes are removed from the genome. These data pinpoint some general bottlenecks in functional genomics, and they reveal the acute emerging difficulties with data transferability above the levels of genes and proteins, especially with complex human phenotypes. At these higher levels the Rosetta stone analogy has almost no applicability. However, newer transgenic technologies in Drosophila and Mus, combined with coherency pattern analyses of gene networks, and synthetic neural modeling, offer insights into organismal function. We conclude that industrially scaled robogenomics in model organisms will have great impact if it can be realistically linked to epigenetic analyses of human variation and to phenotypic analyses of human diseases in different genetic backgrounds.

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Figures

Figure 1

Figure 1

Cytogenetic and molecular characteristics of the approximately 2-megabase region at the base of the X chromosome of Drosophila melanogaster. Polytene subdivisions 19A through 19F and 20A through 20F are as shown. The 67-kb flightless region (in blue) is expanded to illustrate the 12 primary transcription units. The genomic transforming fragments used to rescue the mutant phenotypes are T1 through T8. The deficiencies used to uncover the mutant phenotypes are designated D1 through D8 (dotted lines represent the deficiency, and the approximate breakpoints are shown in orange). Deficiencies D1 through D8 correspond to deficiencies 17–257, GA104, GE263, 2/19B, JC77, 16–129, HM44, and Q539 (–8).

Figure 2

Figure 2

The intron–exon structures of the 12 transcription units, and the structures of the 12 predicted proteins. The domains, motifs, and repetitive regions are as shown, and their relatives in different phyla are traceable by accession numbers, references, or references in the text. They are as follows: tweety; flightless (6); dodo (7, 9); penguin (the repeats, P46061; the pum motif, X62589; the sperm-activating precursor 1, D38490); small optic lobes (2, 10); innocent bystander (11); bobby sox (12); sluggish (4); Helicase (3, 8); misato (8); and la costa (TESS motif, yeast glucoamylase, PO8640).

Figure 3

Figure 3

RT-PCR analyses of the Helicase (Upper) and misato (Lower) loci. The molecular weight markers in lane 1 are the 1018-bp and the 517/506-bp doublet of the Boehringer 1-kb ladder. The sources of the mRNA in the remaining lanes are as follows: 2, adult ovaries; 3, larval salivary glands; 4, larval fat bodies; 5, imaginal disks; 6, larval third-instar brains; 7, late pupal brains; 8 and 9, adult female and adult male brains respectively, less than 1 hr after emergence; 10 and 11, adult female and adult male brains at 5 days after emergence; 12 and 13, adult female and adult male brains at 20 days after emergence; and 14, adult thoraces.

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