Department of Biology, University of Prince Edward Island, Charlottetown, PEI, Canada.
PLoS One. 2019 Oct 29;14(10):e0222654. doi: 10.1371/journal.pone.0222654. eCollection 2019.
Leptin, a critical mediator of feeding, metabolism and diabetes, is expressed on an incidental basis according to satiety. The genetic regulation of leptin should similarly be episodic.
Data from three mouse cohorts hosted by the Jackson Laboratory- 402 (174F, 228M) F2 Dilute Brown non-Agouti (DBA/2)×DU6i intercrosses, 142 Non Obese Diabetic (NOD/ShiLtJ×(NOD/ShiLtJ×129S1/SvImJ.H2g7) N2 backcross females, and 204 male Nonobese Nondiabetic (NON)×New Zealand Obese (NZO/HlLtJ) reciprocal backcrosses-were used to test for loci associated with absolute residuals in plasma leptin and arcsin-transformed percent fat ('phenotypic dispersion'; PDpLep and PDAFP). Individual data from 1,780 mice from 43 inbred strains was also used to estimate genetic variances and covariances for dispersion in each trait.
Several loci for PDpLep were detected, including possibly syntenic Chr 17 loci, but there was only a single position on Chr 6 for PDAFP. Coding SNP in genes linked to the consensus Chr 17 PDpLep locus occurred in immunological and cancer genes, genes linked to diabetes and energy regulation, post-transcriptional processors and vomeronasal variants. There was evidence of intersexual differences in the genetic architecture of PDpLep. PDpLep had moderate heritability [Formula: see text] and PDAFP low heritability [Formula: see text]; dispersion in these traits was highly genetically correlated r = 0.8).
Greater genetic variance for dispersion in plasma leptin, a physiological trait, may reflect its more ephemeral nature compared to body fat, an accrued progressive character. Genetic effects on incidental phenotypes such as leptin might be effectively characterized with randomization-detection methodologies in addition to classical approaches, helping identify incipient or borderline cases or providing new therapeutic targets.
瘦素是一种关键的摄食、代谢和糖尿病介质，根据饱腹感表现出偶发性表达。瘦素的遗传调控也应该是偶发性的。
来自杰克逊实验室的三个小鼠队列的数据-402（174F，228M）稀释棕色非阿育王（DBA/2）×DU6i 杂交，142 非肥胖型糖尿病（NOD/ShiLtJ×（NOD/ShiLtJ×129S1/SvImJ.H2g7）N2 回交雌性，和 204 雄性非肥胖非糖尿病（NON）×新西兰肥胖（NZO/HlLtJ）相互回交-用于检测与血浆瘦素绝对残差相关的基因座和反正弦转换的脂肪百分比（“表型分散”；PDpLep 和 PDAFP）。来自 43 个近交系的 1780 只小鼠的个体数据也用于估计每个性状中分散的遗传方差和协方差。
检测到多个与 PDpLep 相关的基因座，包括可能是同源 Chr17 基因座，但 Chr6 上只有一个位置与 PDAFP 相关。与共识 Chr17 PDpLep 基因座相关的编码 SNP 发生在免疫和癌症基因、与糖尿病和能量调节相关的基因、转录后处理器和犁鼻器变体中。PDpLep 的遗传结构存在雌雄间差异的证据。PDpLep 的遗传力中等[公式：见文本]，PDAFP 的遗传力低[公式：见文本]；这些性状的分散性具有高度的遗传相关性（r=0.8）。
血浆瘦素生理性状的分散性具有更大的遗传方差，可能反映了其比体脂肪更短暂的性质，体脂肪是一种累积的渐进特征。除了经典方法外，随机化检测方法还可以有效地描述瘦素等偶发性表型的遗传效应，有助于识别初期或边缘病例，或提供新的治疗靶点。
