id	author	title	date	pages	extension	mime	words	sentences	flesch	summary	cache	txt
cord-002169-7kwlteyr	Wu, Nicholas C	Adaptation in protein fitness landscapes is facilitated by indirect paths	2016-07-08		.txt	text/plain	9303	504	54	Previous empirical studies on combinatorially complete fitness landscapes have been limited to subgraphs of the sequence space consisting of only two amino acids at each site (2 L genotypes) (Weinreich et al., 2006; Lunzer et al., 2005; O'Maille et al., 2008; Lozovsky et al., 2009; Franke et al., 2011; Tan et al., 2011) . Our findings support the view that direct paths of protein adaptation are often constrained by pairwise epistasis on a rugged fitness landscape (Weinreich et al., 2005; Kondrashov and Kondrashov, 2015) . With our experimental data, we observed two distinct mechanisms of bypass, either using an extra amino acid at the same site or using an additional site, that allow proteins to continue adaptation when no direct paths were accessible due to reciprocal sign epistasis ( Figure 2 ). Our results suggest that higher-order epistasis can either increase or decrease the ruggedness induced by pairwise epistasis, which in turn determines the accessibility of direct paths in a rugged fitness landscape (Figure 3-figure supplement 6).	./cache/cord-002169-7kwlteyr.txt	./txt/cord-002169-7kwlteyr.txt