A genotype-first approach identifies variants for orofacial clefts and other phenotypes in dogs. A genotype-first approach identifies variants for orofacial clefts and other phenotypes in dogs

Dog breeding promotes within-group homogeneity through conformation to strict breed standards and also drives between-group heterogeneity in pursuit of distinct morphological forms and characteristic breed traits. In this study, the genotype-first approach was adapted to the dog genome to investigate coding variation from over 2000 dogs, leading to discoveries of new mutations related to craniofacial morphology and stature. Breed enriched variants were prioritized according to gene constraint, which was calculated using a mutation model derived from trinucleotide substitution probabilities in the dog. Most priority variants were not associated with genomic signatures for breed differentiation, as these regions were enriched for constrained genes intolerant to nonsynonymous variation, suggesting a model of breed phenotype diversification based on regulatory changes to essential genes. Identification of trait-associated variants in dogs informs new biological roles of genes. Improved collection of breed disease risk data, along with increased breed representation, will drive further discoveries. Overall design: Dataset containing a total of 1,742 samples of which 1,434 are reanalyzed from GSM series, GSE83160, GSE83225, GSE90441, GSE96736, GSE121027, GSE123368, GSE193384, GSE213053, GSE241367. Remaining 308 samples are of various dog breeds, processed through GenomeStudio into a PLINK format for downstream analyses.

犬类繁育通过严格遵循品种标准，推动了群体内部的同质性；同时为塑造独特的形态特征与标志性品种性状，进一步加剧了群体间的异质性。本研究将基因型优先（genotype-first）研究方法适配至犬类基因组，对超过2000只犬的编码区变异展开探究，最终鉴定出与颅面形态及体型相关的全新突变。研究基于基因约束（gene constraint）对品种富集变异进行优先级排序，该约束值通过基于犬类三核苷酸替换概率构建的突变模型计算得到。多数优先级靠前的变异并未与品种分化的基因组特征存在关联，这是由于此类区域富集了对非同义变异不耐受的约束基因，由此提示了基于必需基因调控变化的品种表型多样化模型。鉴定犬类性状相关变异，可为解析基因的全新生物学功能提供重要参考。后续若能完善品种疾病风险数据的收集工作，并扩大品种的样本代表性，将助力更多研究发现的产出。整体设计：本数据集共包含1742份样本，其中1434份为重新分析的GSM系列数据集样本，涉及GSE83160、GSE83225、GSE90441、GSE96736、GSE121027、GSE123368、GSE193384、GSE213053、GSE241367。剩余308份样本源自多个不同犬品种，经GenomeStudio平台处理为PLINK格式，用于后续分析。