Data from: Use of a natural hybrid zone for genome-wide association mapping of craniofacial traits in the house mouse

The identification of the genes involved in morphological variation in nature is still a major challenge. Here we explore a new approach: we combine 178 samples from a natural hybrid zone between two subspecies of the house mouse (Mus musculus domesticus and Mus musculus musculus), and high coverage of the genome (~145K SNPs) to identify loci underlying craniofacial shape variation. Due to the long history of recombination in the hybrid zone, high mapping resolution is anticipated. The combination of genomes from subspecies allows the mapping of both, variation within subspecies and intersubspecific differences, thereby increasing the overall amount of causal genetic variation than can be detected. Skull and mandible shape were measured using 3D landmarks and geometric morphometrics. Using principle component axes as phenotypes, and a linear mixed model accounting for genetic relatedness in the mapping populations, we identified 9 genomic regions associated with skull and 10 with mandible shape. High mapping resolution (median size of significant regions = 148 kb) enabled identification of single or few candidate genes in most cases. Some of the genes act as regulators or modifiers of signaling pathways relevant for morphological development and bone formation, including several with known craniofacial phenotypes in mice and humans. The significant associations combined explain 13% and 7% of the skull and mandible shape variation. In addition, a positive correlation was found between chromosomal length and proportion of variation explained. Our results suggest a complex genetic architecture for shape traits, and support a polygenic model.在自然界中，鉴定参与形态变异的基因仍是一项核心挑战。本研究探索了一种全新的研究策略：我们整合了小家鼠（Mus musculus domesticus与Mus musculus musculus）两个亚种间天然杂交带的178份样本，结合全基因组高覆盖度的约14.5万个单核苷酸多态性（Single Nucleotide Polymorphism, SNP）位点，以鉴定调控颅面形状变异的基因座（locus，复数loci）。由于该杂交带中存在长期的重组历史，预期可获得较高的遗传定位分辨率。通过整合两个亚种的基因组数据，本研究既可定位亚种内部的形态变异，也可解析亚种间的表型差异，由此相较于单一亚种的研究，可检测到更多的因果遗传变异。 研究采用三维标志点与几何形态测量学（geometric morphometrics）对颅骨与下颌骨的形状进行量化表征。以主成分轴作为表型指标，结合考虑定位群体遗传亲缘关系的线性混合模型（Linear Mixed Model, LMM）进行关联分析，本研究最终鉴定到9个与颅骨形状相关的基因组区域，以及10个与下颌骨形状相关的基因组区域。较高的遗传定位分辨率（显著关联区域的中位数长度为148 kb）使得本研究在多数案例中可鉴定到单个或少量候选基因。部分候选基因可作为信号通路的调控因子或修饰因子，参与形态发育与骨形成过程，其中若干基因在小鼠与人类中已被证实存在已知的颅面表型。 上述所有显著关联的基因组区域总计可解释13%的颅骨形状变异与7%的下颌骨形状变异。此外，研究发现染色体长度与该区域解释的表型变异比例呈正相关。本研究结果表明，形状性状存在复杂的遗传结构，并支持多基因遗传模型。