Limited phenotypic consilience: Across our MO studies, many different phenotypes are affected by manipulation of candidate orthologs, with little consilience between species. Although mammalian and invertebrate nervous systems show extensive molecular and functional conservation (Bargmann, 1998; Brownlee and Fairweather, 1999) and many drugs mediate their behavioral effects through orthologous target proteins (Matthews and Kopczynski, 2001; Kaletta and Hengartner, 2006), phenotypic consilience and consistent direction of effect following manipulation of a specific gene are not always observed across species (e.g. manipulations of chloride intracellular channel 4 (Clic4) orthologs altered sensitivity in flies and mice but in different directions (Bhandari et al., 2012). There are also differences in ethanol-response measures available for different MOs (e.g. AFT has not been demonstrated in flies despite direct efforts to elicit this response (Chan et al., 2014)). Within species, we observe consilience across studies for effects of 1) Klf-3 and binding partner Ctbp1 on AFT and 2) genes influencing intracellular calcium levels on initial sensitivity in worms, and 2) Col6a3 on HIC in mice.
