Quantitative trait locus (QTL) analyses of plasma cholesterol levels were carried out in three sets of F
2 mice that were formed in a `round-robin' manner from C57BL/6J, KK (
-Ay), and RR strains. Six QTLs were identified on chromosomes 1 (
Cq1, Cq2, and
Cq6), 3 (
Cq3), and 9 (
Cq4 and
Cq5); of these,
Cq2 colocalized with
Cq6, and
Cq4 colocalized with
Cq5. The major candidate gene for
Cq2 and
Cq6 is
Apoa2, and that for
Cq4 and
Cq5 is
Apoa4. The adequacy of polymorphisms in candidate genes as cause of QTLs was investigated in this study. For
Apoa2, three different alleles (
Apoa2a,
Apoa2b, and
Apoa2c) are known. Since there was no significant physiologic difference between
Apoa2a and
Apoa2c alleles, previous hypothesis that
Apoa2b was different from
Apoa2a and
Apoa2c in the ability to increase cholesterol levels was further supported. Presumably, G-to-A substitution at nucleotide 84 and/or C-to-T substitution at nucleotide 182 are crucial to make the
Apoa2b unique. On the other hand, for
Apoa4, the most striking polymorphism was the number of Glu-Gln-Ala/Val-Gln repeats in carboxyl end; however, this might not be responsible for QTLs. Instead, a silent mutation, C-to-T substitution at nucleotide 771, was shown to be completely correlated with the occurrence of QTLs in a total of six F
2 intercrosses. Provisionally, but reasonably, these base substitutions are qualified as primary causes that constitute QTL effect. The potential strategy for identifying genes and base substitutions underlying QTLs is discussed.
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