,1,2,6, 李彩霞,3The effect of EDARV370A on facial and ear morphologies in Uyghur population
Yi Li1,2, Wenting Zhao3, Dan Li4, Xianming Tao1,2, Ziyi Xiong1,2, Jing Liu3, Wei Zhang3, Haibo Liu5, Anquan Ji3, Kun Tang4, Fan Liu,1,2,6, Caixia Li,3通讯作者:
编委: 谢小冬
收稿日期:2018-09-19修回日期:2018-11-1网络出版日期:2018-11-20
| 基金资助: |
Received:2018-09-19Revised:2018-11-1Online:2018-11-20
| Fund supported: |
作者简介 About authors
李祎,硕士研究生,专业方向：生物信息学E-mail:liyi@big.ac.cn。
赵雯婷,博士,副主任法医师,研究方向：法医遗传学E-mail:wtzhao@sibs.ac.cn，李祎和赵雯婷并列第一作者。
摘要
关键词：
Abstract
Keywords：
PDF (826KB)元数据多维度评价相关文章导出EndNote|Ris|Bibtex收藏本文
本文引用格式
李祎, 赵雯婷, 李丹, 陶现明, 熊子义, 刘京, 张微, 刘海渤, 季安全, 唐鲲, 刘凡, 李彩霞. EDARV370A对新疆维吾尔族人群面部及耳朵形态的效应[J]. 遗传, 2018, 40(11): 1024-1032 doi:10.16288/j.yczz.18-268
Yi Li, Wenting Zhao, Dan Li, Xianming Tao, Ziyi Xiong, Jing Liu, Wei Zhang, Haibo Liu, Anquan Ji, Kun Tang, Fan Liu, Caixia Li.
EDARV370A(rs3827760)是外异蛋白A受体基因(ectodysplasinA receptor, EDAR)上的一个错义突变,其衍生等位基因370A (G)的获得使EDAR的一个高度保守的缬氨酸改变为丙氨酸,影响了外异蛋白A (EDA)与其受体的结合效率,进而影响EDA通路下游的功能[1]。该突变发生在约3万年前并且在东亚地区经历了较强的正向自然选择[2,3,4],其衍生等位基因370A在东亚有极高的频率(0.873),而在欧洲和非洲人群中频率极低(0.011; 0.003)[3,4,5,6],因而造成了这些人群许多外胚层发育衍生表型的差异,如东亚人中常见的较直[7]且厚[8, 9]的头发[10]、较多的外泌汗腺[2]、女性较小的乳房[2]、铲形门齿[11,12,13]、下巴后缩[14]及耳垂附着[15, 16]等。
研究EDARV370A对外胚层衍生表型的作用有助于对外胚层发育相关疾病的理解,如少汗性外胚层发育不良症等,有助于理解外胚层衍生表型在东亚人群中的进化。同时,EDARV370A作为影响多个人类外貌表型的分子标记,在法医学上具有潜在的应用价值,例如,利用该基因作为分子标记可实现对DNA检材进行所属外貌等重要个人信息的推断,增加刑侦工作的主动性和智能性。
人类面部和耳朵是由外胚层发育衍生而来,其形态差异代表多组不同程度相关且具有高遗传度的人类复杂表型。近期,彭倩倩等[17]在以维吾尔族为代表的亚欧混合人群中进行了面部和耳朵形态的EDAR候选基因研究。其研究依据人类学测量标准从二维头面部照片中对面部形态和耳朵形态进行了人工分类,发现370A等位基因对下巴后缩和三角形耳垂的形成有显著作用,同时发现EDARV370A与一些其他面部形态表型存在建议性弱相关。这些结果证实EDARV370A对人类外胚层衍生表型的作用具有多效性。
由于EDARV370A在亚欧混合人群中的多态性最高,维吾尔族群体作为一个典型的东亚和欧洲混合的群体,是研究EDARV370A及其关联特征的理想对象,因此本研究进一步对715例新疆维吾尔族样本进行了面部和耳朵形态的EDARV370A候选基因研究。为揭示EDARV370A对人类面部形态的影响,本研究利用三维头面部高清照片和本课题组近期研发的面部特征点自动标点技术更系统地对多维面部形态表型进行了精准量化,期待提升统计效能并对EDARV370A的效应进行详细的直观描述。同时,还对耳朵形态表型进行了详细的人工分类,并进一步分析了EDARV370A与耳朵形态相关表型的关联性。
1 材料和方法
1.1 人群样本
样本采集自新疆维吾尔自治区图木舒克市,共计715例维吾尔族无关个体,其中男性688例,女性27例。年龄为16~59岁,平均年龄35.5岁。纳入研究的个体均符合以下要求：(1) 父母及祖父母均为维吾尔族;(2) 没有接受激素治疗;(3) 未患有甲状腺疾病,脑垂体疾病或肿瘤;(4) 没有因药物作用引起的生长发育问题,例如侏儒症,巨人症或肢端肥大症。研究人员通过手持Artec Spider扫描仪(Artec,卢森堡)结合相应软件对被要求保持中性表情的志愿者进行扫描获取三维面部数据,通过佳能EOS 5D Mark II照相机(Canon,日本)对固定位置的保持中性表情的志愿者拍摄获得正面和左右两侧的二维照片。本研究已通过公安部物证鉴定中心伦理委员会审查,所有受测者都签署了知情同意书。1.2 面部特征和耳朵特征的获取
首先对三维照片进行质控,去除合成错误和不完整的样本照片。利用本课题组近期发表的三维高清头面部照片自动化提取地标点坐标的方法对照片进行了分析[18]。该方法首先定位鼻尖特征地标点并进行姿势的标准化,随后对于较易获得的6个特征地标点定位,再通过主成分分析以及启发式定位的方法对其余的10个地标点定位。1位研究人员检查了全部经地标点标注的照片并对定位不准确的地标点进行了人工纠正,最终获得了17个面部特征地标点的三维坐标(图1)。对获取的地标点坐标数据进行广义普鲁克分析(generalized procrustes analysis)以校正由于移位、转置、大小导致的偏差,进而得到17个地标点两两之间共136组的欧几里德距离(Euclidean distance)。用Z-score转化进一步对欧几里德距离数据进行标准化处理,并以正负3倍标准差为阈值进行异常值处理,最终得到用于后续分析的表型数据。图1
新窗口打开|下载原图ZIP|生成PPT图117个面部地标点的位置和定义
Fig. 1Position and definition of the 17 facial landmarks
7个面部和耳朵形态定序分类表型包括1个下巴表型和6个耳朵表型,依据文献报道方法[14, 17],制订表型的分类标准。分类等级均为3类(表1),图2展示了耳垂附着表型的分类标准。对于有遮挡的无法判断表型的样本记为缺失,不参与后续分析。为了保证分类结果的客观性和准确性,共有3个评级者同时对于同一张二维照片进行独立观察并记录分类等级。在观察之前会对所有评级者依据随机挑选的100张照片进行表型分类训练,以保证评级者对表型定义理解的一致。除耳垂类型使用3个评级者评分等级的众数作为表型之外,其他表型均使用3个评级者评分等级的均值作为表型参与后续的分析。
Table 1
表1
表1 7个面部和耳朵形态定序分类表型的分类标准和数据特性
Table 1
| 表型 | 有效样本(例) | 分类1 (频率) | 分类2 (频率) | 分类3 (频率) |
|---|---|---|---|---|
| 耳垂附着 | 705 | 无(0.10) | 中等(0.54) | 显著(0.36) |
| 耳廓外展程度 | 707 | 外展(0.16) | 中等(0.68) | 紧贴(0.16) |
| 下巴类型 | 686 | 后缩(0.05) | 正常(0.46) | 凸出(0.49) |
| 耳垂类型 | 705 | 圆形(0.37) | 方形(0.23) | 三角形(0.40) |
| 耳垂大小 | 709 | 小(0.06) | 中等(0.83) | 大(0.11) |
| 对耳屏大小 | 697 | 微弱(0.13) | 中等(0.46) | 显著(0.23) |
| 耳轮脚延伸程度 | 707 | 微弱(0.08) | 中等(0.81) | 显著(0.11) |
新窗口打开|下载CSV
图2
新窗口打开|下载原图ZIP|生成PPT图2耳垂附着表型的分类标准
Fig. 2The classification criterion of earlobe attachment
1.3 基因分型
DNA样本来源于外周静脉血,用EDTA-Vacutainer试管收集放置于-20℃下保存。根据标准程序,使用IlluminaInfinium Global Screening Array 650K型号(GSA) (Illumina,美国)对样品进行基因分型。SNP质量控制包括分型成功率>0.9,符合哈德温伯格平衡(P>0.001),和低频等位基因频率(MAF)>1%。本研究共有700 078个常染色体SNPs的基因分型通过质检,其中包括2号染色体EDARV370A (rs3827760)。1.4 统计分析
(1) 利用一般线性回归模型(general linear model, GLM)进行EDARV370A与各表型的关联分析。基因型的赋值按照加性模型,该模型假设个体携带的突变型等位基因370A的数量与某特征的出现有累积效应。校正体重指数(body mass index, BMI)、性别和年龄等因素决定的表型差异,本研究使用基于加性模型假设的一般线性回归模型,如公式(1)所示：其中,yi表示个体的某项头面部特征,α表示固定效应,βADD表示个体携带的基因型对相关表型的效应,βBMI表示个体体重指数(BMI)对相关表型的效应,βAGE表示个体年龄对相关表型的效应,βSEX表示个体性别对相关表型的效应,βPC1、βPC2和βPC3表示来自基因型数据的前3个主成分对头面部特征的效应,εi表示残差,Gi表示个体的基因型,BMI表示个体体重指数,AGE表示个体年龄,SEX表示个体性别,PC1、PC2和PC3表示来自基因型数据的前3个主成分。基因型和性别赋值方法分别如公式(2)和(3)所示：
(2) 为进行多重检验校正,对面部定量表型和耳朵相关表型分别使用有效的独立变量数构建了Bonferroni校正,其中的独立变量数通过矩阵谱分解(matSpD)的方法进行评估[19]。
(3) 使用多元线性回归的方法评估了EDARV370A可以解释的经过性别,年龄,BMI以及前3个主成分校正的表型方差比例。使用模型如公式(5)所示：
其中,Trait代表某表型,Model1$residuals代表模型1的残差,Gi代表个体的基因型。
(4) 通过对370A纯合等位基因以及370V纯合等位基因个体的三维照片数据取平均值获得平均脸并使用R语言代码绘制三维脸图。
(5) 用R语言代码对来自千人基因组计划的2054例个体的EDARV370A基因型信息根据个体来源的26个采样地的坐标绘制了该突变的的全球频率分布图。
2 结果与分析
2.1EDARV370A在不同群体中的频率分布
全部715例亚欧混合维吾尔族样本获得了EDARV370A基因分型,其3个基因型的频率分别为0.40 (370V/370V)、0.48 (370V/370A)和0.12 (370A/370A),满足哈德温伯格平衡(P>0.05)。本研究使用千人基因组计划数据库中26个人群2054名个体的EDARV370A基因型信息,绘制了EDARV370A全球频率分布(图3),显示等位基因370A在东亚人群中有较高的频率(0.873),在欧洲人群中频率较低(0.011),在非洲人群中频率极低(0.003)。该等位基因在本研究亚欧混合维吾尔族样本中的频率为0.36,介于欧洲和东亚群体的频率之间,符合预期。图3
新窗口打开|下载原图ZIP|生成PPT图3EDARV370A的全球频率分布
Fig.3The global distribution of EDARV370A
2.2 EDARV370A与面部定量表型的关联分析
本研究共有612例维吾尔族样本的三维面部照片通过质控,包括590例男性,22例女性,平均年龄为34.9岁(标准差：9.72;附图1A),平均体重指数(BMI)为24.11 (标准差：3.93;附图1A)。性别、年龄和体重指数(BMI)均显示对多组面部形态定量表型显著相关。其中最显著的关联包括：女性鼻翼到鼻下点的距离比男性显著短(P<1.23×10-12),鼻子到上唇点的距离随年龄显著增加(7.84×10-14<P<2.03× 10-17),左右两耳根下点距离随体重指数(BMI)的增加显著增加(P = 4.34×10-114)。附图1
新窗口打开|下载原图ZIP|生成PPT附图1新疆维吾尔族样本(612例和709例)的年龄和体重指数的分布图
A：面部定量表型分析使用612例样本的年龄和体重指数分布；B：面部和耳朵定性表型分析使用709例样本的年龄和体重指数分布。
对于136组面部定量表型,由matSpD方法评估其共有39个有效的独立变量,Bonferroni校正后阈值为(0.05/39 = 1.28×10-3)。线性回归分析显示,等位基因370A和8个面部定量表型的距离增加显著相关(图4)。其中,等位基因370A对眼外角点到耳根下点的两个距离有最显著的增加效应,包括左眼外角点到左耳根下点和右眼外角点到右耳根下点(ExL-ObiL和ExR-ObiR, P=2.39×10-5; P=2.49× 10-5)。其中EDARV370A最高可以解释经性别、年龄、体重指数和基因组前3个主成分校正后的左外眼角点到左耳根下点距离表型方差的2.86% (表2)。通过比较纯合等位基因370V个体和纯合等位基因370A个体的平均脸中右眼外角到右耳根下点距离,发现纯合等位基因370A个体平均脸中该距离长于纯合等位基因370V个体的平均脸,同时,370A也对2组左右对称的共4个面部定量表型有显著增加的效应：左眼内角点到左耳根下点(EnL-ObiL)、右眼内角点到右耳根下点(EnR-ObiR)、右鼻翼点到口裂点(AlR-Sto)和左鼻翼点到口裂点(AlL-Sto)。另外,370A对另2个面部定量表型也有显著增加的效应：鼻根点到右耳根下点的距离和右鼻翼点到下唇点的距离(N-ObiR和AlR-Li)。
图4
新窗口打开|下载原图ZIP|生成PPT图4EDARV370A对维族人群面部形态定量表型的影响效应
A：纯合等位基因370V个体的平均脸;B：纯合等位基因370A个体的平均脸;C：EDARV370A对面部定量表型的影响效应。红线为纯合370V个体的右眼外角点和右耳根下点分别所处的水平线,蓝线为纯合370A个体的平均脸右眼外角点和右耳根下点分别所处的水平线。
Fig. 4The effect of EDARV370A on facial quantitative phenotypes in Uyghurs
Table 2
表2
表2 EDARV370A对维吾尔族人群面部定量表型的相关性
Table 2
| 表型 | 简写 | 均值±标准差 | Beta值 | 标准误 | P值 | R2(%) | 平均距离差(mm) |
|---|---|---|---|---|---|---|---|
| 左眼外角点到左耳根下点 | ExL-ObiL | 92.34±5.18 | 0.21 | 0.05 | 2.39E-05 | 2.86 | 3.25 |
| 右眼外角点到右耳根下点 | ExR-ObiR | 92.99±5.45 | 0.20 | 0.05 | 2.49E-05 | 2.85 | 3.26 |
| 左眼内角点到左耳根下点 | EnL-ObiL | 106.57±5.25 | 0.18 | 0.05 | 6.30E-05 | 2.58 | 3.21 |
| 右鼻翼点到口裂点 | AlR-Sto | 38.93±2.46 | 0.20 | 0.05 | 2.05E-04 | 2.22 | 1.60 |
| 右眼内角点到右耳根下点 | EnR-ObiR | 106.74±5.53 | 0.17 | 0.04 | 2.20E-04 | 2.20 | 2.93 |
| 左鼻翼点到口裂点 | AlL-Sto | 38.95±2.44 | 0.19 | 0.05 | 3.85E-04 | 2.03 | 1.39 |
| 鼻根点到右耳根下点 | N-ObiR | 128.5±5.83 | 0.15 | 0.05 | 9.45E-04 | 1.76 | 2.73 |
| 右鼻翼点到下唇点 | AlR-Li | 46.43±3.41 | 0.19 | 0.06 | 1.24E-03 | 1.68 | 1.74 |
新窗口打开|下载CSV
男性和女性样本的分组分析发现EDARV370A的效应在男女组中基本一致,并由于男性样本量较大,EDARV370A的效应在男性组中较为显著(附表1)。滑动窗口分析未发现EDARV370A在不同年龄区段对表型的效应有明显变化趋势(附图2)。
附表1
附表1 EDARV370A对新疆维吾尔族男性和女性面部形态及耳朵形态表型的相关性
| 表型 | 男性样本 | 女性样本 | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 特征点1 | 特征点2 | 有效样本数 | BETA值 | 标准误 | P值 | 有效样本数 | BETA值 | 标准误 | P值 | |
| 定量表型 | ||||||||||
| 左眼外角点到左耳根下点 | ExL | ObiL | 589 | 0.21 | 0.05 | 2.27E-05 | 22 | 0.14 | 0.25 | 5.87E-01 |
| 右眼外角点到右耳根下点 | ExR | ObiR | 589 | 0.21 | 0.05 | 1.60E-05 | 21 | -0.14 | 0.18 | 4.48E-01 |
| 左眼内角点到左耳根下点 | EnL | ObiL | 588 | 0.19 | 0.05 | 6.92E-05 | 22 | 0.21 | 0.22 | 3.51E-01 |
| 右鼻翼点到口裂点 | AlR | Sto | 588 | 0.19 | 0.05 | 4.62E-04 | 21 | 0.60 | 0.24 | 2.38E-02 |
| 右眼内角点到右耳根下点 | EnR | ObiR | 589 | 0.17 | 0.05 | 2.42E-04 | 21 | 0.06 | 0.17 | 7.11E-01 |
| 左鼻翼点到口裂点 | AlL | Sto | 586 | 0.18 | 0.06 | 1.19E-03 | 22 | 0.61 | 0.22 | 1.45E-02 |
| 鼻根点到右耳根下点 | N | ObiR | 590 | 0.16 | 0.05 | 6.63E-04 | 21 | -0.06 | 0.17 | 7.28E-01 |
| 右鼻翼点到下唇点 | AlR | Li | 590 | 0.18 | 0.06 | 3.56E-03 | 22 | 0.76 | 0.31 | 2.62E-02 |
| 定序表型 | ||||||||||
| 耳垂附着 | / | / | 680 | 0.16 | 0.03 | 1.40E-06 | 25 | 0.06 | 0.17 | 7.40E-01 |
| 耳廓外展程度 | / | / | 681 | 0.11 | 0.03 | 1.01E-04 | 26 | 0.01 | 0.11 | 9.10E-01 |
| 下巴类型 | / | / | 660 | -0.15 | 0.03 | 2.86E-06 | 26 | -0.17 | 0.17 | 3.38E-01 |
| 耳垂类型 | / | / | 679 | 0.14 | 0.05 | 5.69E-03 | 26 | 0.37 | 0.24 | 1.38E-01 |
| 耳垂大小 | / | / | 683 | 0.05 | 0.02 | 1.10E-02 | 26 | 0.02 | 0.09 | 8.36E-01 |
| 对耳屏大小 | / | / | 671 | 0.06 | 0.03 | 6.33E-02 | 26 | -0.03 | 0.12 | 8.14E-01 |
| 耳轮脚延伸程度 | / | / | 682 | 0.00 | 0.02 | 9.79E-01 | 25 | 0.30 | 0.11 | 1.05E-02 |
新窗口打开|下载CSV
附图2
新窗口打开|下载原图ZIP|生成PPT附图2滑动窗口分析EDARV370A在不同年龄区段对表型的效应值趋势图(窗口大小：10岁;步宽：1岁)
2.3 EDARV370A与1个下巴定序分类表型和6个耳朵定序分类表型的关联分析
7个定序分类表型包括1个下巴形态表型和6个耳朵定序分类表型。共有709例维吾尔族样本的二维维照片通过质控。包括683例男性,26例女性,平均年龄为35.6岁(标准差：10.17;附图1B),平均体重指数(BMI)为24.09 (标准差：3.91;附图1B)。性别、年龄和体重指数(BMI)显示与7个面部和耳朵形态定序分类表型有不同程度的相关性(附表2)。对于7个定序分类表型,由matSpD方法评估有7个有效的独立变量,Bonferroni校正后阈值为(0.05/7 = 0.007)。线性回归分析显示,EDARV370A和下巴类型以及3个耳朵分类表型显著相关。其中,等位基因370A对耳垂附着有最显著的效应(P = 3.72×10-7),可以解释经性别、年龄、体重指数(BMI)以及基因组前3个主成分校正后的耳垂附着表型差异的3.59% (表3)。另外,等位基因370A也会导致下巴后缩(P = 1.29×10-6),增加耳廓紧贴的程度(P = 7.43×10-5)以及三角形的耳垂(P = 2.26×10-3)。附表2
附表2 年龄、性别及BMI在新疆维吾尔族人群中(n=709)对耳朵形态定序分类表型的影响
| 耳垂附着 | 下巴类型 | 耳廓外展程度 | 耳垂类型 | 耳垂大小 | 对耳屏大小 | 耳轮脚延伸程度 | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BETA | SE | P | BETA | SE | P | BETA | SE | P | BETA | SE | P | BETA | SE | P | BETA | SE | P | BETA | SE | P | |
| 性别 | -0.02 | 0.12 | 8.84E-01 | -0.08 | 0.11 | 4.92E-01 | 0.33 | 0.10 | 6.25E-04 | -0.39 | 0.17 | 2.54E-02 | 0.16 | 0.07 | 2.66E-02 | -0.11 | 0.10 | 3.07E-01 | 0.07 | 0.08 | 3.72E-01 |
| 年龄 | -0.01 | 0.00 | 2.54E-02 | 0.00 | 0.00 | 4.81E-02 | -0.01 | 0.00 | 8.23E-10 | -0.01 | 0.00 | 4.47E-02 | 0.01 | 0.00 | 1.08E-06 | -0.01 | 0.00 | 9.83E-03 | 0.00 | 0.00 | 2.15E-02 |
| 体重指数 (BMI) | 0.03 | 0.01 | 4.51E-06 | 0.02 | 0.01 | 1.35E-03 | 0.05 | 0.00 | 3.39E-24 | 0.01 | 0.01 | 2.78E-01 | 0.01 | 0.00 | 1.50E-02 | 0.01 | 0.01 | 9.21E-03 | -0.01 | 0.00 | 1.48E-02 |
年龄以1岁为单位。
BETA,SE,P是基于多重线性回归的统计量。
新窗口打开|下载CSV
Table 3
表3
表3 EDARV370A对维吾尔族人群下巴及耳朵定序分类表型的相关性
Table 3
| 表型 | Beta值 | 标准误 | P值 | R2(%) |
|---|---|---|---|---|
| 耳垂附着a | 0.17 | 0.03 | 3.72E-07 | 3.59 |
| 下巴类型a | -0.16 | 0.03 | 1.29E-06 | 3.34 |
| 耳廓外展程度a | 0.11 | 0.03 | 7.43E-05 | 2.19 |
| 耳垂类型a | 0.15 | 0.05 | 2.26E-03 | 1.31 |
| 耳垂大小 | 0.05 | 0.02 | 1.18E-02 | 0.89 |
| 对耳屏大小 | 0.05 | 0.03 | 6.60E-02 | 0.48 |
| 耳轮脚延伸程度 | 0.01 | 0.02 | 6.55E-01 | 0.03 |
新窗口打开|下载CSV
3 讨论
本研究在715例欧亚混合代表人群—新疆维吾尔族群体中,系统性地研究了EDARV370A对面部形态和耳朵形态的影响。结合近期彭倩倩等[17]发表的相关研究,本研究同样使用维吾尔族群体来进行分析。维吾尔族群体作为一个典型的东亚和欧洲混合的群体,混合的时间约为800~2000多年前[20, 21]。有报道估测了维吾尔族个体的东亚和欧洲祖先成分约为50:50混合[20, 21],该特性减少了维吾尔族群体内的亚分层,并导致EDARV370A在群体中的多态性使其可以作为一个理想的进行关联分析研究的群体。另外,彭倩倩等[17]研究发现的370A等位基因对下巴后缩和三角形的显著影响在本研究中得到了验证,且效应值大小也是一致的。在彭倩倩等[17]研究分析的耳垂类型表型之外,本研究对于耳朵形态进行了更详细的表型分类,增加了额外的5个耳朵形态定序表型,其中EDARV370A对耳垂附着[16]、耳廓外展程度[15]和耳垂大小[15]等3个耳朵形态相关表型的显著作用[15]得到证实,且EDARV370A与对耳屏大小表型也存在建议性弱相关。过去的关于EDAR对面部形态影响的小鼠功能性实验,发现EDAR的功能保存的越完整,小鼠下颌骨的长度也越短[14, 22],EDAR突变小鼠相较于野生小鼠有更紧贴的耳朵[15],这与在本研究人群样本中观测到的EDAR对下巴形态以及耳廓外展程度的效应一致。此外,370A在世界范围内的频率分布和不同人群中的下巴形态分布也大体一致,例如,欧洲人高比例的下巴突出与370A的极低频率分布是一致的。与彭倩倩等[17]基于人类学测量标准的获得的12个面部形态分类表型不同,本研究通过面部特征点自动标点的技术系统地获得了一系列共136组直观具体的多维面部形态表型,这显著的提高了检测EDARV370A与面部形态关联的功效。彭倩倩等[17]发现的EDARV370A与3个面部形态表型存在建议性弱相关,其中上嘴唇厚度表型并未在本研究中得到验证,另外两个左眼皮褶皱以及额头形状表型在本研究没有相对应的定量表型。本研究在验证其部分结果的基础上,首次在小样本的维吾尔族群体中发现了EDARV370A对8个面部定量表型的影响,并确定了370A对于这8个面部距离增加的效应。其中,EDARV370A显著影响表型右眼外角到右耳根下点的距离,通过绘制370V纯合等位基因个体以及370A纯合等位基因个体的平均脸,比较可发现纯合370A的个体平均脸的耳根下点低于纯合370V个体平均脸,右眼外角和纯合370V个体位置基本一致,所以纯合370A个体平均脸的右外眼角点到右耳根下点距离要大于纯合370V个体平均脸的距离,证实了EDARV370A对于该表型的显著作用。这揭示了EDARV370A除了对过去发现的其他人类外胚层发育而来的表型有影响外,对人类面部形态也有重要的作用,加深了关于EDARV370A对人类外胚层衍生表型作用多效性的理解。
本研究在验证了EDARV370A对1个下巴定序表型和3个耳朵定序表型影响的基础上,首次系统性检测了EDARV370A对于具体面部形态的影响以及如何改变面部形态,发现EDARV370A和8个面部定量表型增加显著相关,同时确定了EDARV370A对8个面部定量表型的具体效应大小。这使EDARV370A对其作用表型产生的改变可以更加具体直观地展示出来成为了可能,而其作为一个对多组面部表型影响的遗传因子,对于构建从DNA标记推断具体完整的人类面部形态的模型具有重要的意义,为人类外貌的法医分子表型刻画提供了基础,从而推动刑侦工作向更加主动、更加智能的方向发展。
附录：
附图和附表请见文章电子版
参考文献 原文顺序
文献年度倒序
文中引用次数倒序
被引期刊影响因子
URLPMID:21916884 [本文引用: 1]
Br J Dermatol. 2012 Mar;166(3):678-81. doi: 10.1111/j.1365-2133.2011.10620.x. Epub 2011 Dec 5. Letter
URLPMID:23415220 [本文引用: 3]
An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.
URLPMID:20056855 [本文引用: 2]
Abstract The human genome contains hundreds of regions whose patterns of genetic variation indicate recent positive natural selection, yet for most the underlying gene and the advantageous mutation remain unknown. We developed a method, composite of multiple signals (CMS), that combines tests for multiple signals of selection and increases resolution by up to 100-fold. By applying CMS to candidate regions from the International Haplotype Map, we localized population-specific selective signals to 55 kilobases (median), identifying known and novel causal variants. CMS can not just identify individual loci but implicates precise variants selected by evolution.
URL [本文引用: 2]
URLPMID:18493316 [本文引用: 1]
Genome-wide scans for positive selection in humans provide a promising approach to establish links between genetic variants and adaptive phenotypes. From this approach, lists of hundreds of candidate genomic regions for positive selection have been assembled. These candidate regions are expected to contain variants that contribute to adaptive phenotypes, but few of these regions have been associated with phenotypic effects. Here we present evidence that a derived nonsynonymous substitution (370A) in EDAR, a gene involved in ectodermal development, was driven to high frequency in East Asia by positive selection prior to 10,000 years ago. With an in vitro transfection assay, we demonstrate that 370A enhances NF- B activity. Our results suggest that 370A is a positively selected functional genetic variant that underlies an adaptive human phenotype.
URL [本文引用: 1]
URLPMID:23793515 [本文引用: 1]
Hair straightness/curliness is a highly heritable trait amongst human populations. Previous studies have reported European specific genetic variants influencing hair straightness, but those in East Asians remain unknown. One promising candidate is a derived coding variant of the ectodysplasin A receptor (EDAR), EDARV370A (370A), associated with several phenotypic changes of epidermal appendages. One of the strongest signals of natural selection in human genomes, 370A, has risen to high prevalence in East Asian and Native American populations, whilst being almost absent in Europeans and Africans. This striking frequency distribution and the pleiotropic nature of 370A led us to pursue if hair straightness, another epidermal appendage-related phenotype, is affected by this variant. By studying 1,718 individuals from four distinctive East Asian populations (Han, Tibetan, Mongolian, and Li), we found a significant association between 370A and the straight hair type in the Han (p = 2.90 x 10(-6)), Tibetan (p = 3.07 x 10(-2)), and Mongolian (p = 1.03 x 10(-5)) populations. Combining all the samples, the association is even stronger (p = 5.18 x 10(-10)). The effect of 370A on hair straightness is additive, with an odds ratio of 2.05. The results indicate very different biological mechanisms of straight hair in Europe and Asia, and also present a more comprehensive picture of the phenotypic consequences of 370A, providing important clues into the potential adaptive forces shaping the evolution of this extraordinary genetic variant.
URLPMID:18065779 [本文引用: 1]
Hair morphology is one of the most differentiated traits among human populations. However, genetic backgrounds of hair morphological differences among populations have not been clarified yet. In addition, little is known about the evolutionary forces that have acted on hair morphology. To identify hair morphology-determining genes, the levels of local genetic differentiation in 170 genes that are related to hair morphogenesis were evaluated by using data from the International HapMap project. Among highly differentiated genes, ectodysplasin A receptor (EDAR) harboring an Asian-specific non-synonymous single nucleotide polymorphism (1540T/C, 370Val/Ala) was identified as a strong candidate. Association studies between genotypes and hair morphology revealed that the Asian-specific 1540C allele is associated with increase in hair thickness. Reporter gene assays suggested that 1540T/C affects the activity of the downstream transcription factor NF-kappaB. It was inferred from geographic distribution of 1540T/C and the long-range haplotype test that 1540C arose after the divergence of Asians from Europeans and its frequency has rapidly increased in East Asian populations. These findings lead us to conclude that EDAR is a major genetic determinant of Asian hair thickness and the 1540C allele spread through Asian populations due to recent positive selection.
URLPMID:18704500 [本文引用: 1]
Hair morphology is a highly divergent phenotype among human populations. We recently reported that a nonsynonymous SNP in the ectodysplasin A receptor ( EDAR 1540T/C) is associated with head hair fiber thickness in an ethnic group in Thailand (Thai-Mai) and an Indonesian population. However, these Southeast Asian populations are genetically and geographically close, and thus the genetic contribution of EDAR to hair morphological variation in the other Asian populations has remained unclear. In this study, we examined the association of 1540T/C with hair morphology in a Japanese population (Northeast Asian). As observed in our previous study, 1540T/C showed a significant association with hair cross-sectional area ( P 02=022.702×0210 616 ) in Japanese. When all populations (Thai-Mai, Indonesian, and Japanese) were combined, the association of 1540T/C was stronger ( P 02=023.802×0210 6110 ) than those of age, sex, and population. These results indicate that EDAR is the genetic determinant of hair thickness as well as a strong contributor to hair fiber thickness variation among Asian populations.
[本文引用: 1]
[本文引用: 1]
URLPMID:19804850 [本文引用: 1]
Shovel shape of upper incisors is a common characteristic in Asian and Native American populations but is rare or absent in African and European populations. Like other common dental traits, genetic polymorphisms involved in the tooth shoveling have not yet been clarified. In ectodysplasin A receptor ( EDAR), where dysfunctional mutations cause hypohidrotic ectodermal dysplasia, there is a nonsynonymous-derived variant, 1540C (rs3827760), that has a geographic distribution similar to that of the tooth shoveling. This allele has been recently reported to be associated with Asian-specific hair thickness. We aimed to clarify whether EDAR 1540C is also associated with dental morphology. For this purpose, we measured crown diameters and tooth-shoveling grades and analyzed the correlations between the dental traits and EDAR genotypes in two Japanese populations, inhabitants around Tokyo and in Sakishima Islands. The number of EDAR 1540C alleles in an individual was strongly correlated with the tooth-shoveling grade (p = 7.7 × 10 6110). The effect of the allele was additive and explained 18.9% of the total variance in the shoveling grade, which corresponds to about one-fourth of the heritability of the trait reported previously. For data reduction of individual-level metric data, we applied a principal-component analysis, which yielded PC1-4, corresponding to four patterns of tooth size; this result implies that multiple factors are involved in dental morphology. The 1540C allele also significantly affected PC1 (p = 4.9 × 10 613), which denotes overall tooth size, and PC2 (p = 2.6 × 10 613), which denotes the ratio of mesiodistal diameter to buccolingual diameter.
URLPMID:22648185 [本文引用: 1]
Dental morphology is highly diverse among individuals and between human populations. Although it is thought that genetic factors mainly determine common dental variations, only a few such genetic factors have been identified. One study demonstrated that a nonsynonymous single-nucleotide polymorphism (370V/A, rs3827760) in the ectodysplasin A receptor gene (EDAR) is associated with shoveling and double-shoveling grades of upper first incisors and tooth crown size. Here, we examined the association of EDAR 370V/A with several dental characters in Korean and Japanese subjects. A meta-analysis that combined analyses of Korean and Japanese subjects revealed that the Asian-specific 370A allele is associated with an increase in the grades of shoveling and double shoveling, as previously found. We also showed a highly significant association between EDAR 370V/A genotype and crown size, especially mesiodistal diameters of anterior teeth. Moreover, we found that the 370A allele was associated with the presence of hypoconulids of lower second molars. These results indicated that the EDAR polymorphism is responsible, in part, for the Sinodonty and Sundadonty dichotomy in Asian populations, and clearly demonstrated that the EDAR polymorphism has pleiotropic effects on tooth morphology. As the 370A allele is known to be a most likely target of positive selection in Asian populations, some phenotypes associated with the variant may be 'hitchhiking phenotypes', while others may be actual targets of selection.
[本文引用: 1]
[本文引用: 1]
[本文引用: 3]
URLPMID:4491814 [本文引用: 5]
Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10618 to 3 × 106114). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1. The shape of the pinna varies widely in the general human population but the genetic basis of this variation is unknown. Here Adhikari et al. conduct a genome-wide association study in Latin Americans and discover seven gene regions influencing pinna morphology, including EDAR and TBX15.
URLPMID:29198719 [本文引用: 2]
The genetic basis of earlobe attachment has been a matter of debate since the early 20thcentury, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, includingEDAR,SP5,MRPS22,ADGRG6(GPR126),KIAA1217, andPAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 10 8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.
URLPMID:26603699 [本文引用: 7]
An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370Awas found to affect ectodermal-derived...
URLPMID:3724574 [本文引用: 1]
Background Traditional anthropometric studies of human face rely on manual measurements of simple features, which are labor intensive and lack of full comprehensive inference. Dense surface registration of three-dimensional (3D) human facial images holds great potential for high throughput quantitative analyses of complex facial traits. However there is a lack of automatic high density registration method for 3D faical images. Furthermore, current approaches of landmark recognition require further improvement in accuracy to support anthropometric applications. Result Here we describe a novel non-rigid registration method for fully automatic 3D facial image mapping. This method comprises two steps: first, seventeen facial landmarks are automatically annotated, mainly via PCA-based feature recognition following 3D-to-2D data transformation. Second, an efficient thin-plate spline (TPS) protocol is used to establish the dense anatomical correspondence between facial images, under the guidance of the predefined landmarks. We demonstrate that this method is highly accurate in landmark recognition, with an average RMS error of ~1.7 mm. The registration process is highly robust, even for different ethnicities. Conclusion This method supports fully automatic registration of dense 3D facial images, with 17 landmarks annotated at greatly improved accuracy. A stand-alone software has been implemented to assist high-throughput high-content anthropometric analysis.
URLPMID:16077740 [本文引用: 1]
Correlated multiple testing is widely performed in genetic research, particularly in multilocus analyses of complex diseases. Failure to control appropriately for the effect of multiple testing will either result in a flood of false-positive claims or in true hits being overlooked. Cheverud proposed the idea of adjusting correlated tests as if they were independent, according to an 'effective number' (M(eff)) of independent tests. However, our experience has indicated that Cheverud's estimate of the Meff is overly large and will lead to excessively conservative results. We propose a more accurate estimate of the M(eff), and design M(eff)-based procedures to control the experiment-wise significant level and the false discovery rate. In an evaluation, based on both real and simulated data, the M(eff)-based procedures were able to control the error rate accurately and consequently resulted in a power increase, especially in multilocus analyses. The results confirm that the M(eff) is a useful concept in the error-rate control of correlated tests. With its efficiency and accuracy, the M(eff) method provides an alternative to computationally intensive methods such as the permutation test.
URLPMID:18760393 [本文引用: 2]
> 0.25, mean F = 0.43) but small frequency differences (7999 AIMs validated) within both populations (F
URLPMID:18355773 [本文引用: 2]
2
URLPMID:3082932 [本文引用: 1]
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder due to a mutation of the EDA gene and is mainly characterized by an impaired formation of hair, teeth and sweat glands, and craniofacial dysmorphologies. Although tooth abnormalities in Tabby (Ta) mutant mice – the murine model of XLHED – have been extensively studied, characterization of the craniofacial complex, and more specifically the mandibular morphology has received less attention. From 3D micro-CT reconstructions of the left mandible, the mandibular outline observed in lateral view, was quantified using 2D elliptical Fourier analysis. Comparisons between Ta specimens and their wild-type controls were carried out showing significant shape differences between mouse strains enabling a clear distinction between hemizygous Ta specimens and the other mouse groups (WT and heterozygous EdaTa/+ specimens). Morphological differences associated with HED correspond not only to global mandibular features (restrained development of that bone along dorsoventral axis), but also to subtle aspects such as the marked backward projection of the coronoid process or the narrowing of the mandibular condylar neck. These modifications provide for the first time, evidence of a predominant effect of the Ta mutation on the mandibular morphology. These findings parallel the well described abnormalities of jugal tooth row and skeletal defects in Ta mice, and underline the role played by EDA-A in the reciprocal epithelial–mesenchymal interactions that are of critical importance in normal dental and craniofacial development.
