Table 5.

Hypothesis-driven approaches to comparative genomic study design

Organism	Condition	Phenotype	References
S. cerevisiae	ubr2∆	Increased replicative lifespan	Kruegel et al. (2011)
S. cerevisiae	rpn4∆	Decreased replicative lifespan	Kruegel et al. (2011)
D. melanogaster	RPN11 overexpression	Increased lifespan	Tonoki et al. (2009)
C. elegans	Knockdown of rpn-1, rpn-3, rpn-6, rpn-7, rpn-8, rpn-9, rpn-11, rpt-1, rpt-4, rpt-5, rpt-6, pas-5, pas-6, pbs-2, pbs-3, pbs-4, pbs-5, or pbs-7	Decreased lifespan	Ghazi et al. (2007)
C. elegans	pbs-5 overexpression	Increased lifespan	Chondrogianni et al. (2015)
M. musculus	Pac1 knockout	Early embryonic lethality, decrease in free 20S proteasome, premature senescence	Sasaki et al. (2010)
M. musculus	Psmc1 knockdown in brain	Protein aggregation and neurodegeneration	Bedford et al. (2008)
H. sapiens (WI-38)	Lactacystin treatment	Reduces RLS	Torres et al. (2006)
H. glaber	Unknown	Unknown	Unknown

Perturbations to genes related to the proteasome, as well as the proteasome itself, result in changes to lifespan and healthspan of a variety of organisms, including yeasts, worms, flies, mice, and even humans. The long-lived naked mole-rat also has elevated proteasome activity, but we have little information about the genes involved. Thus, by interrogating the genome specifically for proteasome-related genes, we can study these genes more in depth and compare with other species, to identify beneficial (or detrimental) mutations or polymorphisms. Differences in gene/protein sequence can then be studied in vitro or in vivo to identify causal variants. [References in Table: Torres et al. (2006), Bedford et al. (2008), Sasaki et al. (2010), Chondrogianni et al. (2015)]