However, it must be noted that the regulation of ASIP activity by CORIN p.H587Y alone (or along with the effect of the SLC45A2 mutation) does not seem sufficient to fully explain the pigmentation change of stripes in either golden or snow white tigers. Snow white tigers are double homozygotes for both SLC45A2 p.A477V and CORIN p.H587Y mutations, indicating that the white tiger causal mutation in conjunction with the golden tiger mutation may have diminished melanogenesis over the entire pelage. The p.H587Y mutation may have impaired the function of CORIN and elongated the working period of ASIP, resulting in the prolonged agouti band of the golden tiger hair. The fact that secreted extracellular ASIP was degraded in the presence of wild-type CORIN suggests that CORIN functions downstream of agouti expression and likely regulates the length of the functioning period of ASIP during hair growth cycles, regardless of whether ASIP is a direct substrate of CORIN or not. The same result was also observed in the conditioned media of cells co-transfected with ASIP and CORIN variants ( Figure 1F, right panel). The secreted ASIP was reduced in the presence of wild-type CORIN, but not the p.H587Y mutant CORIN, when the culture supernatant from ASIP-expressing cells was added to cells transfected with wild-type or mutant CORIN ( Figure 1G). No difference was detected between the expression level of wild-type CORIN and the p.H587Y mutant in cells ( Figure 1F, left panel). To determine the effect of p.H587Y on CORIN's function of regulating ASIP in the tiger, we transfected HEK293 cells with tiger ASIP and/or CORIN variants. The pheomelanin band in the agouti-patterned hairs is caused by a pulse of ASIP expression during hair growth, leading to a switch from eumelanin to pheomelanin production. MC1R is otherwise activated by melanocyte stimulating hormone (α-MSH), leading to eumelanogenesis. Wild-type CORIN regulates melanogenesis by suppressing the activity of ASIP, a paracrine signaling molecule that inhibits the binding of melanocortins to the transmembrane MC1R protein of melanocytes 7. Genotyping analyses of CORIN p.H587Y and SLC45A2 p.A477V in the same individuals confirmed that the individual or combined effect of the two mutations corresponded to the specific tiger coat color variations ( Figure 1E). The supposition holds that CORIN c.1759C >T (p.H587Y) causes the golden tiger pelage. All golden ( n = 16) and snow white ( n = 22) tigers were homozygous for CORIN c.1759C >T all orange ( n = 123) and white ( n = 36) tigers carried at least one copy of the wild-type allele ( Figure 1E). The residue H587 is located in the LDL receptor class A domain 6 of tiger CORIN, and it is evolutionarily conserved across vertebrates ( Figure 1D).Ī perfect correlation was detected between CORINc.1759C >T and the “wideband” phenotype among unrelated individuals from wild or captive tiger populations worldwide ( Figure 1E and Supplementary information, Table S1). CORIN c.1759C >T is a non-synonymous substitution resulting in a histidine-to-tyrosine substitution at amino acid residue 587 (p.H587Y). CORIN knockout mice with agouti backgrounds exhibit prolonged agouti bands in the hair shaft 7, resembling the hair pigmentation switch in the golden tiger. CORIN encodes a transmembrane serine protease and is known to participate in blood pressure regulation by activating natriuretic peptides and in pigment biosynthesis by suppressing the agouti pathway 7, 8. Scaffolds with a high level of association ( P T (scaffold1457:2829955 C>T) identified in the coding region of CORIN is specific to golden and snow white tigers. SNPs within every 500-Kb window are plotted in a single column. Tiger scaffolds are arranged and grouped into putative chromosomes (x axis) based on homology to the cat genome ( Felis_catus 6.2). (C) Genome-wide association plot of the tiger wideband gene. The length proportion of each component (black tip, agouti band and black base) of agouti hair is presented using Tukey's boxplots. (B) The pigmentation pattern difference in agouti zigzag hairs from orange and golden tigers. Schematics of tiger zigzag hairs from the background (upper) and stripes (lower) are shown for each morph. (A) The four coat color morphs known in tigers.
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