Sittig Laura J, Carbonetto Peter, Engel Kyle A, Krauss Kathleen S, Barrios-Camacho Camila M, Palmer Abraham A
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA; Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
Neuron. 2016 Sep 21;91(6):1253-1259. doi: 10.1016/j.neuron.2016.08.013. Epub 2016 Sep 8.
Genome-wide association studies (GWASs) have identified numerous loci that influence risk for psychiatric diseases. Genetically engineered mice are often used to characterize genes implicated by GWASs. These studies are based on the assumption that observed genotype-phenotype relationships will generalize to humans, implying that the results would at least generalize to other inbred mouse strains. Given current concerns about reproducibility, we sought to directly test this assumption. We produced F1 crosses between male C57BL/6J mice heterozygous for null alleles of Cacna1c and Tcf7l2 and wild-type females from 30 inbred laboratory strains. We found extremely strong interactions with genetic background that sometimes supported diametrically opposing conclusions. These results do not negate the invaluable contributions of mouse genetics to biomedical science, but they do show that genotype-phenotype relationships cannot be reliably inferred by studying a single genetic background, and thus constitute a major challenge to the status quo. VIDEO ABSTRACT.
全基因组关联研究（GWAS）已经确定了许多影响精神疾病风险的基因座。基因工程小鼠常被用于表征GWAS所涉及的基因。这些研究基于这样一种假设，即观察到的基因型与表型之间的关系将推广到人类，这意味着结果至少会推广到其他近交小鼠品系。鉴于当前对可重复性的担忧，我们试图直接检验这一假设。我们让雄性C57BL/6J小鼠（其Cacna1c和Tcf7l2无效等位基因杂合）与来自30个近交实验室品系的野生型雌性小鼠进行F1杂交。我们发现与遗传背景存在极强的相互作用，有时会支持完全相反的结论。这些结果并没有否定小鼠遗传学对生物医学科学的宝贵贡献，但确实表明不能通过研究单一遗传背景可靠地推断基因型与表型之间的关系，因此对现状构成了重大挑战。视频摘要。
