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Haplotype analysis in multiple crosses to identify a QTL gene - PubMed

. 2004 Sep;14(9):1767-72.

doi: 10.1101/gr.2668204. Epub 2004 Aug 12.

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Haplotype analysis in multiple crosses to identify a QTL gene

Xiaosong Wang et al. Genome Res. 2004 Sep.

Abstract

Identifying quantitative trait locus (QTL) genes is a challenging task. Herein, we report using a two-step process to identify Apoa2 as the gene underlying Hdlq5, a QTL for plasma high-density lipoprotein cholesterol (HDL) levels on mouse chromosome 1. First, we performed a sequence analysis of the Apoa2 coding region in 46 genetically diverse mouse strains and found five different APOA2 protein variants, which we named APOA2a to APOA2e. Second, we conducted a haplotype analysis of the strains in 21 crosses that have so far detected HDL QTLs; we found that Hdlq5 was detected only in the nine crosses where one parent had the APOA2b protein variant characterized by an Ala61-to-Val61 substitution. We then found that strains with the APOA2b variant had significantly higher (P < or = 0.002) plasma HDL levels than those with either the APOA2a or the APOA2c variant. These findings support Apoa2 as the underlying Hdlq5 gene and suggest the Apoa2 polymorphisms responsible for the Hdlq5 phenotype. Therefore, haplotype analysis in multiple crosses can be used to support a candidate QTL gene.

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Figures

Figure 1
Figure 1

APOA2 protein sequence comparison in eight mammal species. Amino acids that are identical to those in mice having APOA2a, APOA2b, APOA2c, APOA2d, and APOA2e are highlighted yellow, rose, light green, pale blue, and gray, respectively; those that are identical to APOA2 from human (lavender), chimpanzee (sky blue), monkey (green), horse (light turquoise), cattle (orange), and rat (tan) are also highlighted. Sources, with GenBank accession no. or reference: Human (Homo sapiens), NP_037244; Chimpanzee (Pan troglodyte), AAM49808; Cynomolgus monkey (Macaca fascicularis), P18656; Horse (Equus caballus), D. Puppione (pers. comm.); Cattle (Bos taurus), P81644; Pig (Sus scrofa), CAD91908; Rat (Rattus norvegicus), NP_037244.

Figure 2
Figure 2

HDL concentrations in inbred mouse strains with five types of APOA2. The 43 strains were separated into five types (24 “a,” 12 “b,” 4 “c,” 2 “d,” and 1 “e”) according to amino acids located at nine different APOA2 positions (see Table 1). Plasma HDL concentrations (mean ± SEM, mg/dL) were obtained from groups of 7- to 10-week-old males (A) and females (B) fasted for 4 h (all the strains in Table 1 except CASA, MRL, and NZO; Mouse Phenome Database). Each group consisted of between 10 and 40 mice (24 ± 7 males and 22 ± 6 females, mean ± SD). Plasma concentrations of HDL in male (C) and female (D) mice with Ala61 (all the strains except APOA2b mice) and those with Val61 (APOA2b mice) were also compared.

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WEB SITE REFERENCES

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