On the origin of the longhair mutation in cats Ali$AlHaid1,$B.$Gandolfi2,$L.$A.$Lyons2,$and$H.$Alhaddad1$1)  Department of Biological Science, Kuwait University, Kuwait

2)  College of Veterinary Medicine, University of Missouri-Columbia, Columbia, MO

Fig.2. Sample sizes of cat breeds and feral cat populations genotyped for FGF5 (C-475) mutation.

Introduction •  The fibroblast growth factor 5 (FGF5) is a gene expressed in mammals.

Mutations within FGF5 are responsible for longhair phenotype in cats [1-2] and other mammals.

•  In the domestic cat, six non-synonymous mutations are associated with longhair trait [1-2]. Four substitution and two InDel mutations are distributed through the three exons of FGF5 transcript (Fig.1).

Objectives 1.  Examine the frequency of the longhair (C-475) allele across cat

breeds.

2.  Investigate the frequency of the longhair (C-475) allele in world-wide feral populations.

3.  Infer the likely origin of the (C-475) mutation by testing Turkey and Iran as two focal origins.

Conclusion The FGF5 (c.475 A>C) mutation is the most prevalent longhair mutation in longhair breeds and likely to have originated in the Mediterranean/

Middle-east region and most likely in Turkey.

Dataset and Analyses •  A comprehensive dataset (n=2571) representing domestic (n=2503) and

non-domestic cats (n=68) was used. The domestic cat samples belong to 38 breeds (n=1832) and feral cats (n=671) sampled from 21 geographical locations, including Turkey and Iran (Fig.2).

Birman 312

Scottish Fold 164

Perisan 163Burmese 121

Bengal 98

Siamese 80

La Perm 66

Siberian 61

Ragdoll 60

Maine Coon 57

Abyssinian 56

Oriental 56

Munchkin 40

Sphynx 40

British Shorthair 40

Toyger 34

Peterbald 31Lykoi 27

Turkish Van 26Cornish Rex 26American Curl 25

Japanese Bobtail 22Selkirk Rex 22

Korat 22Tennesse REX 21

Egypt 115 Iran 104Israel 45

Turkey 42Kenya 36

South Korea 34Singapore 33

Cyprus 30India 30

Brazil 29

Italy 27Sri Lanka 23

Germany 22China 20Vietnam 19Lamu 18Dubai 10

European wild cat 59

Asian Leopard Cats 9

*Devon Rex 21Norweigian Forest Cat 20

Manx 20Egyptian Mau 18

American Shorthair 14Russian Blue 12

Turkish Angora 11Bombay 11

Chartreaux 11American Wirehair 9

Somali 6Ocicat 5

Havana Brown 4

**Hawaii 10Missouri-US 9

Pate 9Cornell-US 6

*

**

Fig.1. Illustration of cat FGF5 mature transcript and the positions of all non-synonymous mutations.

5' UTR 3' UTR

182 T>A

194 C>A

356 Ins T

406 C>T

474 Del T

475 A>C

1 bp 813 bpCat FGF5 Full Transcript

•  Most longhair breeds possess the (475) mutation in high frequencies with the exception of Ragdoll, Norwegian Forest Cats, and Maine Coon cats, which have (356), (406), and (474), respectively [1].

•  The missense (c.475 A>C) mutation substitutes threonine with proline in FGF5 protein (p.T159P).

•  The inheritance of longhair allele (C-475) is autosomal recessive and longhair phenotype is shown when the allele is homozygous or heterozygous with any of the other five FGF5 mutations.

•  Genotypes of FGF5-475 alleles were obtained from the 63K Feline Array Consortium and the feral population dataset from L.A. Lyons laboratory.

•  Allele and genotype frequencies were calculated using R package “genetics”.

•  Geographical locations of feral populations were used to calculate the distance from Turkey and Iran. The correlation between longhair (C-475) allele frequency and distance from an origin (Turkey, Iran) was tested using standard R.

Findings •  In agreement with previous studies [1], the majority of longhair breeds

exhibit the longhair phenotype through the (C-475) mutation with the exception of three breeds (Fig.3).

•  The high (C-475) allele frequency and high genotype frequency of (C/C) and (C/A) suggests that C-475 mutation is associated with “longhairness” in most longhair breeds either in a homozygous state or in a compound heterozygous state with other FGF5 mutations (Fig.3).

•  Breeds that are not defined by longhair and allow BOTH short and longhair varieties show high frequency of the (C-475) allele in homozygous and heterozygous genotypes, which suggests that longhair within such breeds is determined by the FGF5-475 mutation (Fig.3).

Fig.3. Frequencies of the Short/Long hair alleles and genotypes across cat breeds.

Frequency1.0 0.8 0.6 0.4 0.2 0.0

Shorthair Allele (475-A)

Frequency Frequency0.0 0.2 0.4 0.6 0.8 1.0

Longhair Allele (475-C)

Frequency

BirmanTurkish Angora

Turkish VanPerisanSiberianSomali

Maine CoonRagdoll

Norweigian Forest Cat La Perm

American CurlTennesse REXMunchkin

Selkirk RexJapanese Bobtail

Scottish FoldManxSphynxPeterbaldLykoiBombay

American ShorthairBritish Shorthair

Devon RexChartreauxOriental

American WirehairBengal

Cornish RexAbyssinianKorat

SiameseBurmese

Egyptian MauHavana Brown

ToygerOcicat

Russian BlueAsian Leopard CatEuropean Wild Cat

Frequency0.0 0.2 0.4 0.6 0.8 1.0

Longhair (C/C)

Frequency Frequency0.0 0.2 0.4 0.6 0.8 1.0

Longhair Carrier (C/A)

Frequency Frequency0.0 0.2 0.4 0.6 0.8 1.0

Shorthair (A/A)

Frequency

•  Excluding the locations in North and South America where cats were introduced anthropologically, 17 feral cat populations in the Mediterranean/Middle-east regions exhibit a relatively higher frequency of the Longhair (C-475) allele (Fig.4-Top).

•  Assuming that the C-475 mutation arose (1) once in the past, and (2) in a specific location and (3) that its frequency in the origin is high and decreases further away, two likely origins were tested (Turkey and Iran).

•  The correlation between C-475 frequency and distance from the origin was found to be more significant for Turkey (p < 2x10-5) compared to Iran (p = 0.0015) (Fig.4-Right).

BrazilBrazilBrazilBrazilBrazilBrazilBrazilBrazilBrazil

ChinaChinaChinaChinaChinaChinaChinaChinaChinaCornellCornellCornellCornellCornellCornellCornellCornellCornell CyprusCyprusCyprusCyprusCyprusCyprusCyprusCyprusCyprus

UAEUAEUAEUAEUAEUAEUAEUAEUAEEgyptEgyptEgyptEgyptEgyptEgyptEgyptEgyptEgypt

GermanyGermanyGermanyGermanyGermanyGermanyGermanyGermanyGermany

HawaiiHawaiiHawaiiHawaiiHawaiiHawaiiHawaiiHawaiiHawaii IndiaIndiaIndiaIndiaIndiaIndiaIndiaIndiaIndia

IranIranIranIranIranIranIranIranIran

ISRISRISRISRISRISRISRISRISR

ItalyItalyItalyItalyItalyItalyItalyItalyItaly

KenyaKenyaKenyaKenyaKenyaKenyaKenyaKenyaKenyaLamuLamuLamuLamuLamuLamuLamuLamuLamu

MissourriMissourriMissourriMissourriMissourriMissourriMissourriMissourriMissourri

PatePatePatePatePatePatePatePatePate

SingaporeSingaporeSingaporeSingaporeSingaporeSingaporeSingaporeSingaporeSingapore

South KoreaSouth KoreaSouth KoreaSouth KoreaSouth KoreaSouth KoreaSouth KoreaSouth KoreaSouth Korea

Sri LankaSri LankaSri LankaSri LankaSri LankaSri LankaSri LankaSri LankaSri Lanka

TurkeyTurkeyTurkeyTurkeyTurkeyTurkeyTurkeyTurkeyTurkey

VietnamVietnamVietnamVietnamVietnamVietnamVietnamVietnamVietnam

Short-hair AlleleLonghair AlleleShort-hair GenotypeShort/Long hair GenotypeLonghair Genotype

Distance from origin (Km)

Long

hair

Alle

le (C

) Fre

quen

cy

0 2000 4000 6000 8000 10000

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Turkey OriginIran OriginFig.4. Longhair (C-475) allele in relation to

the geographic location of feral cat populations. (Top): Short/Longhair allele and genotype frequencies in 21 geographic locations. (Right): Relationship between longhair (C-475) allele frequency and distance (Km) from a possible mutation origin (Turkey, Iran). Dots represent feral populations and lines represent the best fitting line of the correlation.

References 1.  Kehler et al., J. Hered 98, 555-566 (2007). 2.  Drogemuller et al., Anim Genet 38, 218-221 (2007).