Zapata Isain, Serpell James A, Alvarez Carlos E
Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA.
Center for the Interaction of Animals and Society, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
BMC Genomics. 2016 Aug 8;17:572. doi: 10.1186/s12864-016-2936-3.
Fear/anxiety and anger/aggression greatly influence health, quality of life and social interactions. They are a huge burden to wellbeing, and personal and public economics. However, while much is known about the physiology and neuroanatomy of such emotions, little is known about their genetics - most importantly, why some individuals are more susceptible to pathology under stress.
We conducted genomewide association (GWA) mapping of breed stereotypes for many fear and aggression traits across several hundred dogs from diverse breeds. We confirmed those findings using GWA in a second cohort of partially overlapping breeds. Lastly, we used the validated loci to create a model that effectively predicted fear and aggression stereotypes in a third group of dog breeds that were not involved in the mapping studies. We found that i) known IGF1 and HMGA2 loci variants for small body size are associated with separation anxiety, touch-sensitivity, owner directed aggression and dog rivalry; and ii) two loci, between GNAT3 and CD36 on chr18, and near IGSF1 on chrX, are associated with several traits, including touch-sensitivity, non-social fear, and fear and aggression that are directed toward unfamiliar dogs and humans. All four genome loci are among the most highly evolutionarily-selected in dogs, and each of those was previously shown to be associated with morphological traits. We propose that the IGF1 and HMGA2 loci are candidates for identical variation being associated with both behavior and morphology. In contrast, we show that the GNAT3-CD36 locus has distinct variants for behavior and morphology. The chrX region is a special case due to its extensive linkage disequilibrium (LD). Our evidence strongly suggests that sociability (which we propose is associated with HS6ST2) and fear/aggression are two distinct GWA loci within this LD block on chrX, but there is almost perfect LD between the peaks for fear/aggression and animal size.
We have mapped many canine fear and aggression traits to single haplotypes at the GNAT3-CD36 and IGSF1 loci. CD36 is widely expressed, but areas of the amygdala and hypothalamus are among the brain regions with highest enrichment; and CD36-knockout mice are known to have significantly increased anxiety and aggression. Both of the other genes have very high tissue-specificity and are very abundantly expressed in brain regions that comprise the core anatomy of fear and aggression - the amygdala to hypothalamic-pituitary-adrenal (HPA) axis. We propose that reduced-fear variants at these loci may have been involved in the domestication process.
恐惧/焦虑和愤怒/攻击行为对健康、生活质量及社会交往有极大影响。它们给幸福安康以及个人和公共经济带来巨大负担。然而，尽管我们对这些情绪的生理学和神经解剖学了解颇多，但对其遗传学却知之甚少——最重要的是，为何有些人在压力下更容易出现病理状况。
我们对数百只不同品种犬的多种恐惧和攻击行为特征进行了全基因组关联（GWA）图谱分析，以确定品种刻板印象。我们在第二批部分重叠品种的犬中通过GWA证实了这些发现。最后，我们利用已验证的基因座创建了一个模型，该模型能有效预测第三组未参与图谱研究的犬品种中的恐惧和攻击行为刻板印象。我们发现：i）已知与小体型相关的IGF1和HMGA2基因座变异与分离焦虑、触觉敏感性、对主人的攻击行为及犬之间的竞争有关；ii）位于18号染色体上GNAT3和CD36之间以及X染色体上IGSF1附近的两个基因座与多种特征相关，包括触觉敏感性、非社交性恐惧以及针对陌生犬和人类的恐惧和攻击行为。这四个基因组基因座都是犬类中进化选择程度最高的，并且之前已证明每个基因座都与形态特征相关。我们提出IGF1和HMGA2基因座可能是与行为和形态都相关的相同变异的候选基因座。相比之下，我们表明GNAT3 - CD36基因座在行为和形态方面具有不同的变异。X染色体区域由于其广泛的连锁不平衡（LD）而情况特殊。我们的证据有力地表明社交性（我们认为与HS6ST2相关）和恐惧/攻击行为是X染色体上这个LD区域内两个不同的GWA基因座，但恐惧/攻击行为峰值与动物体型之间几乎完全连锁不平衡。
我们已将许多犬类的恐惧和攻击行为特征定位到GNAT3 - CD36和IGSF1基因座的单倍型上。CD36广泛表达，但杏仁核和下丘脑区域是大脑中表达最丰富的区域之一；已知CD36基因敲除小鼠的焦虑和攻击行为显著增加。另外两个基因都具有非常高的组织特异性，并且在构成恐惧和攻击行为核心解剖结构的大脑区域——从杏仁核到下丘脑 - 垂体 - 肾上腺（HPA）轴中大量表达。我们提出这些基因座上降低恐惧的变异可能参与了驯化过程。
