Four independent mutations in the feline fibroblast growth factor 5 gene determine the long-haired phenotype in domestic cats

Abstract

To determine the genetic regulation of "hair length" in the domestic cat, a whole-genome scan was performed in a multigenerational pedigree in which the "long-haired" phenotype was segregating. The 2 markers that demonstrated the greatest linkage to the long-haired trait (log of the odds > or = 6) flanked an estimated 10-Mb region on cat chromosome B1 containing the Fibroblast Growth Factor 5 (FGF5) gene, a candidate gene implicated in regulating hair follicle growth cycle in other species. Sequence analyses of FGF5 in 26 cat breeds and 2 pedigrees of nonbreed cats revealed 4 separate mutations predicted to disrupt the biological activity of the FGF5 protein. Pedigree analyses demonstrated that different combinations of paired mutant FGF5 alleles segregated with the long-haired phenotype in an autosomal recessive manner. Association analyses of more than 380 genotyped breed and nonbreed cats were consistent with mutations in the FGF5 gene causing the long-haired phenotype in an autosomal recessive manner. In combination, these genomic approaches demonstrated that FGF5 is the major genetic determinant of hair length in the domestic cat.

Figure 1

Figure 1A. Alignment of FGF5 Isoform 1 (full length form translated from 3 exons) for human, short-haired (SH) cat and long-haired (LH) cats with 4 putative recessive mutations. Residue changes after putative mutations are marked in bold. Figure 1B. Alignment of FGF5 Isoform 2 (translated from exon 1 spliced to exon 3) for human, short-haired cat and long-haired cats with 4 putative recessive mutations.

Figure 2

Three independent pedigrees demonstrating autosomal recessive inheritance of mutations 1, 2 and 4 in FGF5 with the long-haired trait. A= Two-generation portion of the non-breed Nestlé-Purina pedigree. B= Two-generation portion of the non-breed John Hopkins University pedigree. C= Three-generation pedigree of long-haired Ragdoll cats. Square = male, Circle = female. Open symbol = short-haired, filled = long-haired. The identification number of cats is written over top of individual symbols. Coded genotypes are listed in parentheses: N= no mutation, 2 = Mutation 2 (c.C>T406), 3=Mutation 3 (c.del474T), 4 = Mutation 4 (c.A>C475)

Figure A1

FGF5 isoform 1 coding exons and flanking sequence for a short-haired Abyssinian cat (A) Coding Exon 1 and flanks, (B) Coding Exon 2 and flanks, (C) Coding Exon 3 and flanks. Coding exon sequence is in bold. Sequence 5′ of exon 1 coding sequence represents 5′UTR and sequence 3′ of exon 3 coding sequence represent 3′UTR. The remaining non-bolded text represents intronic sequence. (D) Putative feline FGF5 mRNA with coding sequence in bold.

Figure A1

FGF5 isoform 1 coding exons and flanking sequence for a short-haired Abyssinian cat (A) Coding Exon 1 and flanks, (B) Coding Exon 2 and flanks, (C) Coding Exon 3 and flanks. Coding exon sequence is in bold. Sequence 5′ of exon 1 coding sequence represents 5′UTR and sequence 3′ of exon 3 coding sequence represent 3′UTR. The remaining non-bolded text represents intronic sequence. (D) Putative feline FGF5 mRNA with coding sequence in bold.

Figure A2

Conservation of sequence motif in region of Mutation 4 (T159P). Amino acids in bold are identical to cat FGF5. The asterisk indicates the position of Mutation 4 (T159 P).