Genetics, Vol. 155, 785-792, June 2000, Copyright © 2000

Selective Genotyping With Epistasis Can Be Utilized for a Major Quantitative Trait Locus Mapping in Hypertension in Rats

Yoichi Ohnoa,b, Hisao Tanasec, Toru Nabikad, Keiichi Otsukab, Takayuki Sasakib, Taichi Suzawab, Toshiyuki Moriib, Yukio Yamorie, and Takao Sarutab
a Department of Internal Medicine, TEPCO Hospital, Tokyo 160, Japan,
b Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160, Japan,
c Laboratory Animal Science and Toxicology, Sankyo Co. Ltd., Shizuoka 437, Japan,
d Department of Laboratory Medicine, Shimane Medical University, Izumo 693, Japan,
e Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606, Japan

Corresponding author: Yoichi Ohno, Department of Internal Medicine, TEPCO Hospital, 9-2 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan., t0799791{at}pmail.tepco.co.jp (E-mail)

Communicating editor: S. TAVARÉ

Epistasis used to be considered an obstacle in mapping quantitative trait loci (QTL) despite its significance. Numerous epistases have proved to be involved in quantitative genetics. We established a backcross model that demonstrates a major QTL for hypertension (Ht). Seventy-eight backcrossed rats (BC), derived from spontaneously hypertensive rats (SHR) and normotensive Fischer 344 rats, showed bimodal distribution of systolic blood pressure (BP) values and a phenotypic segregation ratio consistent with 1:1. In this backcross analysis, sarco(endo)plasmic reticulum Ca2+-dependent ATPase (Serca) II heterozygotes showed widespread bimodality in frequency distribution of BP values and obviously demonstrated Ht. First, in genome-wide screening, Mapmaker/QTL analysis mapped Ht at a locus between D1Mgh8 and D1Mit4 near Sa in all 78 BC. The peak logarithm of the odds (LOD) score reached 5.3. Second, Serca II heterozygous and homozygous BC were analyzed separately using Mapmaker/QTL. In the 35 Serca II heterozygous BC, the peak LOD score was 3.8 at the same locus whereas it did not reach statistical significance in the 43 Serca II homozygotes. Third, to map Ht efficiently, we selected 18 Serca II heterozygous BC with 9 highest and 9 lowest BP values. In these 18 BC, the peak LOD score reached 8.1. In 17 of the 18, D1Mgh8 genotypes (homo or hetero) qualitatively cosegregated with BP phenotypes (high or low) (P < 0.0001, by chi-square analysis). In conclusion, selective genotyping with epistasis can be utilized for a major QTL mapping near Sa on chromosome 1 in SHR.




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