Abstract
BackgroundDuring a search for obesity candidate genes in a small region of the mouse genome, we noticed that many genes when knocked out influence body weight. To determine whether this was a general feature of gene knockout or a chance occurrence, we surveyed the Jackson Laboratory Mouse Genome Database for knockout mouse strains and their phenotypes. Body weights were not available for all strains so we also obtained body weight information by contacting a random sample of investigators responsible for a knockout strain.ResultsWe classified each knockout mouse strain as (1) lighter and smaller, (2) larger and heavier, or (3) the same weight, relative to control mice. We excluded knockout strains that died early in life, even though this type of lethality is often associated with a small embryo or reduced body size. Based on a dataset of 1,977 knockout strains, we found that that 31% of viable knockout mouse strains weighed less and an additional 3% weighed more than did controls.ConclusionBody weight is potentially a latent variable in about a third of experiments that use knockout mice and should be considered in interpreting experimental outcomes, e.g., in studies of hypertension, drug and hormone metabolism, organ development, cell proliferation and apoptosis, digestion, heart rate, or atherosclerosis. If we assume that the knockout genes we surveyed are representative then upward of 6,000 genes are predicted to influence the size of a mouse. Body weight is highly heritable, and numerous quantitative trait loci have been mapped in mice, but "multigenic" is an insufficient term for the thousands of loci that could contribute to this complex trait.
Highlights
During a search for obesity candidate genes in a small region of the mouse genome, we noticed that many genes when knocked out influence body weight
Of the viable knockout strains with body weight information, 65.5% were reported to have no difference in body weight, 31.3% had reduced body weight, and 3.1% had increased body weight compared with a reference group ([EQ2 in Methods]; Table 1, Figure 1)
"nonviable" knockout strains often had small embryos or neonates, these are not included in the totals for reduced body weight
Summary
During a search for obesity candidate genes in a small region of the mouse genome, we noticed that many genes when knocked out influence body weight. To determine whether this was a general feature of gene knockout or a chance occurrence, we surveyed the Jackson Laboratory Mouse Genome Database for knockout mouse strains and their phenotypes. One way to do this is to study the effects on body weight of knocking out all mouse genes, one by one. We focused on the information that was available: the Mouse Genome Database (MGD), a database of knockout strains and their phenotypes created and maintained by the Jackson Laboratory [3,4]. We conducted a survey of the MGD, with the goal to estimate the proportion of genes in the mouse that contribute to body size
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