Molecular evolutionary and structural analysis of human UCHL1 gene demonstrates the relevant role of intragenic epistasis in Parkinson’s disease and other neurological disorders

Table 1 Amino-acid replacements in UCHL1 during primate history

Position	Mammals ancestral residues	Replacement in ancestor of primates	Replacement in ancestor of simians	Replacement in ancestor of apes.	Neutral/Radical	Impact on protein stability	Location motif/domain
18	A		S		Radical (+ 1)	Decreased (−0.85)	Peptidase C12 domain
107	E		G		Radical (−2)	Decreased (−1.79)	Peptidase C12 domain
124	L	M			Radical (+ 2)	Decreased (−0.74)	Peptidase C12 domain
192	S		T		Radical (+ 1)	Decreased (−0.79)	Peptidase C12 domain
195	Q			K	Radical (+ 1)	Decreased (−1.45)	Peptidase C12 domain

After the divergence from mammal’s ancestor, one amino-acid change occurred in the root of primates, three replacements occurred specifically in the ancestor of Simians lineage whereas one replacement occurred in apes history. The 6th column depicts the putative physicochemical impact of each replacement on protein/structure function. The number within brackets is the log odds associated with changing the amino acids. Positive numbers imply a preferred change, zero implies a neutral change and negative numbers imply an un-preferred change. The 7th column depicts the putative impact of each replacement on stability of protein. The numbers within brackets are the confidence scores (i.e. from −1 to 1) associated with the impact on stability of protein structure by changing the amino acids. Positive numbers imply an increase in stability of protein structure. The bigger the score, the more confident the prediction is. Conversely, negative numbers imply a decrease in the stability of protein structure

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