,中国农业科学院北京畜牧兽医研究所,北京 100193Progress on genetic mapping and genetic mechanism of cattle and sheep horns
Xiaohong He, Lin Jiang, Yabin Pu, Qianjun Zhao, Yuehui Ma,Institute of Animal Science, Chinese Academy of Agricultural Science, Beijing 100193, China通讯作者: 马月辉，博士，研究员，研究方向：畜禽遗传资源研究。E-mail:yuehui.ma@263.net
编委: 姜雨
收稿日期:2020-07-21修回日期:2020-11-19网络出版日期:2021-01-20
| 基金资助: |
Received:2020-07-21Revised:2020-11-19Online:2021-01-20
| Fund supported: |
作者简介 About authors
何晓红,博士,副研究员,研究方向：畜禽遗传资源研究。E-mail:
摘要
角属于动物颅骨附属物,为反刍动物所特有。牛(Bos taurus)、绵羊(Ovis aries)角的表型包括野生型两角表型、人工驯化的无角表型、畸形角等多种。牛和绵羊是阐明角的质量性状和数量性状之间的关系以及质量性状的多基因调控机制等方面的理想动物模型。近年来,对角性状研究不断深入,在阐明新器官起源进化、自然选择、性别选择和人工选择对角表型的影响等方面取得了一系列进展。本文详细介绍了角的研究概况、多角表型遗传定位、无角位点基因遗传定位和畸形角等,并对目前牛和绵羊角的遗传机制及存在的问题进行了分析,以期为反刍动物角性状和其他特异性性状遗传机制研究提供参考。
关键词：
Abstract
Horns are cranial appendages, which are unique in ruminants. Cattle (Bos taurus) and sheep (Ovis aries) cranial appendages exhibit various forms of morphology, including wild-type two-horn phenotype, polled phenotype and scur phenotype. These animals provide an ideal model for studies on the underlying relationship between quality and quantitative traits of cattle and sheep horn and the molecular mechanisms of horn phenotype as a polygenic regulation for quality traits. In recent years, some research progresses of cattle and sheep horns are successively reported, which helps us better understand the evolutionary origin of new organ, the effects of natural selection, sex selection and artificial selection on horn phenotypes. In this review, we introduce in details the recent advances on the research of horn traits in cattle and sheep, and summarize the genetic mapping of multi-horned phenotypes, the genetic mapping of polled locus, and studies on scur phenotype. Moreover, we discuss potential problems in such research, thereby providing a reference for investigation on the genetic mechanisms of horn traits in ruminants.
Keywords：
PDF (629KB)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
何晓红, 蒋琳, 浦亚斌, 赵倩君, 马月辉. 牛、绵羊角的遗传定位及遗传机制研究进展. 遗传[J], 2021, 43(1): 40-51 doi:10.16288/j.yczz.20-229
Xiaohong He.
动物角属于颅骨附属物(cranial appendages),又称骨质角(headgear),主要出现在反刍动物中。颅骨附属物主要包括4类,分别为牛科(Bovidae)动物的洞角[1,2]、长颈鹿科(Giraffidae)的瘤角、叉角羚科(Antilocapridae)的叉角和鹿科(Cervidae)的实角。洞角是牛科动物特有的附属物,包括牛(Bos taurus)、绵羊(Ovis aries)、山羊(Capra hircus)等,洞角主要由骨质角心和外部包裹的坚硬角质鞘组成,终生不脱落[1,3]。牛和绵羊能够在包括高原、沙漠在内的广泛生态环境下生存并适应多种环境[4,5],据FAOSTAT (Food and Agriculture Organization of the United Nations)数据库统计,截至到2018年,全世界牛和绵羊存栏分别为14.90和12.09亿只。牛和绵羊角表型具有丰富的多态性,包括野生型的两角表型、人工选择形成的无角表型以及在古老品种中存在的多角表型(绵羊特有),还包括发育不完全的畸形角表型,这些表型为角性状提供了丰富的研究素材。基于牛和绵羊角多样化的表型特征,多年来一直是重要的研究热点之一,也是动物表型遗传进化研究的重要模型。
1 多角表型研究进展
1.1 多角绵羊品种及分布
绵羊是唯一具有多角表型的家养反刍动物。绵羊角性状具有丰富的多样性,按照角的有无和个数分为无角、两角、多角表型,其中多角是家养绵羊品种中存在的古老而珍稀的表型[6,7],至少在两百多年以前就已经存在[6]。多角绵羊(multi-horned sheep)即头上存在2只以上角的绵羊,一般有3~6只角,据报道最多角可以达到9只,一般以4只角表型最多,所以又称为四角羊(图1A)。多角绵羊现分布于亚洲[8]、欧洲、非洲和美洲大陆[9,10,11],是开展绵羊角遗传调控的理想动物模型。图1
新窗口打开|下载原图ZIP|生成PPT图1绵羊角的表型
A：多角表型;B：两角表型;C：畸形角;D：无角表型。
Fig. 1The phenotype of sheep
多角绵羊历史上曾经在亚洲、欧洲广泛分布[12],经过强烈的人工选择,该表型目前仅有十几个品种留存下来,且群体数量都较小。现存的多角绵羊品种主要包括Jacob[13]、Manx Loaghtan、Hebridean、Navajo-Churro[10]、Icelandic[9]、Damara[14]、阿勒泰绵羊、蒙古羊[15]、巴什拜羊[16,17]和泗水裘皮羊[18]等。这些品种无一例外都是当地的古老绵羊品种。最近,在我国青藏高原海拔5200米的地区调查时,新发现了藏绵羊品种中的多角群体——多角藏绵羊,也是目前唯一在高海拔地区发现的多角绵羊群体[19]。此外,由于自然界并不存在多角绵羊的野生祖先,由此推测多角绵羊可能是在较早时期完成的驯化[20]。
1.2 多角表型遗传定位
早在1913年,Nature杂志发表了关于多角绵羊的研究[7];Alderson[21]推测绵羊角性状由2个基因座调控,当两个基因座都为隐性纯合基因型时,绵羊表现为多角表型;Dyrmundsson[9]认为多角表型对两角表型而言为显性遗传,对无角表型为隐性遗传。He等[22]以阿勒泰多角羊、蒙古多角羊、泗水裘皮羊为研究对象,对34只两角和32只多角羊进行全基因组关联分析(genome wide association study, GWAS),成功将多角基因位点定位于绵羊2号染色体的132.6~132.7 Mb 区间,并发现畸形角表型并不影响多角表型的遗传。Ren等[23]利用700K Illumina高密度芯片对24只两角和22只四角泗水裘皮羊进行GWAS分析,在绵羊2号染色体132.0~133.1 Mb区间筛选出4个显著性SNP (single nucleotide polymorphisms)位点。Kijas等[24]利用芯片对多角Jacobs和Navajo-Churro羊进行GWAS分析,在绵羊2号染色体131.9~132.6 Mb区域筛选出10个显著性SNP位点,最显著的位点在132.568 Mb处,且发现Navajo-Churro绵羊的无角位点定位于10号染色体29.3~29.5 Mb间。Greyvenstein等[25]对26只多角和16只两角的Damara绵羊进行GWAS分析,多角位点定位在绵羊2号染色体128~135 Mb区间,没有发现多角表型的CNV(copy number variations),且发现显著性SNP在多角个体上都是杂合基因型。综上所述,对分布于中国、非洲、美洲和欧洲的6个多角绵羊群体进行多角位点遗传定位研究(表1),表明多角位点定位在绵羊2号染色体,首次成功在绵羊上定位到多角基因控制位点。2020年Li等[26]发表最新研究进展,利用高通量重测序数据对泗水裘皮羊(多角表型)和小尾寒羊(两角表型)进行角性状SNP关联分析和品种间的选择性清扫分析,在2号染色体HOXD基因簇(homeobox D cluster)的HOXD1、HOXD3、HOXD8、HOXD9和HOXD10等基因上筛选到显著性信号,基本明确了绵羊多角基因的遗传定位。He等[19]对多角藏绵羊的深入调查发现,多角绵羊群体中存在角数量3~6个不等的遗传表型,其中4个角表型个体比例最高,并将多角分为典型多角表型(4个角)和非典型多角表型(3、5或者6个角)两类,两种表型定位于染色体的相同位置,均位于绵羊2号染色体132.8 Mb处,该结果表明多角表型的两类亚型(典型和非典型多角)可能具有相同的遗传位点(表1)。
Table 1
表1
表1绵羊角性状相关遗传区间、SNPs和候选基因
Table 1
| 表型或功能 | 遗传区间、候选基因或SNPs | 数据类型 | 分析方法 | 物种或品种 | 野生或家养 | 参考文献 |
|---|---|---|---|---|---|---|
| 无角 | Chr.10: OarHH41、AGLA226 | 微卫星标记 | 连锁分析 | (美利奴羊×罗姆尼羊)×美利奴羊 | 家养 | [40] |
| Chr.10: 7.4 cM区间 | 微卫星和 等位酶标记 | 关联分析 | 索艾羊 | 野生 | [44,48] | |
| Chr.10: 200 kb区间 | SNPs | 连锁分析 | 美利奴羊×罗姆尼羊 | 家养 | [41] | |
| Chr.10:OAR10_29546872,RXFP2 | DNA芯片、 重测序数据 | 选择信号分析、关联分析和选择性清扫分析 | 陶赛特羊、美利奴羊;小尾寒羊、湖羊 | 家养 | [26,37] | |
| Chr.10:29.3~29.5 Mb,RXFP2、EEF1DP3 | DNA芯片、 测序 | 连锁不平衡分析、芯片GWAS分析、多态性检测 | 澳洲美利奴羊、Navajo-Churro绵羊、滩羊、萨福克羊 | 家养 | [24,42,52] | |
| RXFP2 3′UTR 1.8 kb片段插入 | 测序、分型 | 序列分析 | 7个瑞士绵羊品种 | 家养 | [51] | |
| 角的多态性 | Chr.10:RXFP2 | DNA芯片;RXFP2基因型 | GWAS分析、选择系数和平衡频率分析、基因型之间的适应度差异分析 | 索艾羊 | 野生 | [49,50] |
| 角的长度、 角的方向 | Chr.10:CSRD87、OarSEJ09 Chr.10:RXFP2 | 微卫星标记 DNA芯片、 重测序 | 连锁图谱QTL定位、GWAS分析、选择性清扫分析 | 索艾羊、大角羊、 藏绵羊 | 野生、家养 | [45,46,48~50,55] |
| 角早期发育 | (1) SOX9和HOXD; (2) SOX10、SNAI1、SNAI2、TFAP2A、NGFR和COL11A2 | 基因组测序、 转录组数据 | 基因组、转录组分析 | 有角反刍动物 | 野生和家养 | [7] |
| 畸形角 | COL6A2、COL6A1、PARVA、TNN、TNC | 蛋白质组学 数据 | 差异分析 | 阿勒泰羊 | 家养 | [62] |
| Chr.10：RXFP2 | DNA芯片 | GWAS分析 | 索艾羊 | 野生 | [49] | |
| 多角表型 | Chr.2: 128~135 Mb、HOXD基因簇、MTX2、EVX2、KIAA1715 | DNA芯片、 重测序数据 | GWAS分析、关联分析和品种间的选择性清扫分析 | 阿勒泰羊、蒙古羊、泗水裘皮羊、Jacobs羊、Navajo-Churro羊和Damara绵羊 | 家养 | [9,22~24,26] |
| 多角亚型 | Chr.2:132.8 Mb,MTX2、HOXD基因簇 | DNA芯片 | 芯片GWAS分析 | 多角藏绵羊 | 家养 | [19] |
新窗口打开|下载CSV
2 无角表型研究进展
2.1 牛无角表型
2.1.1 牛无角位点(POLLED)的遗传定位1993年,Georges等[27]将牛的无角位点定位在1号染色体上,并进一步将范围缩小到1号染色体的着丝粒区域[28]。研究人员陆续在该区间发现4个无角突变(表2)。Medugorac等[29]首先在欧洲凯尔特地区牛品种中发现Celtic POLLED (PC)突变,该突变位于IFNAR2和OLIG1基因之间,是一个202 bp的插入-缺失复合体,研究人员通过基因编辑技术制成含该突变的荷斯坦牛成纤维细胞,通过克隆得到了无角表型的犊牛[30]。Medugorac等[29]和Rothammer等[31]通过对荷斯坦牛分析,发现了第二无角突变,研究表明在260 kb的单体型上存在5个与荷斯坦牛无角表型相关的候选突变,该突变与PC突变彼此不重组也不相互影响,称为Friesian POLLED(PF)突变(表2),该突变位于PC位点下游200 kb处,是一段80 kb的重复序列,且无角荷斯坦牛并不携带PC突变[32]。Utsunomiya等[33]在内洛尔瘤牛中发现了第3个突变——Guarani POLLED(PG)突变,该突变是一段110 kb的重复片段,分析发现该无角基因型来自普通牛。最后一个是Mongolian POLLED(PM)突变[34],存在于蒙古牦牛和蒙古Turano牛,蒙古牦牛的无角突变定位在POLLED位点800 kb长的区域,存在2个基因型：一个是在原序列下游61 bp处插入219 bp重复-插入片段;第二个突变是在原序列上游621 bp处6 bp缺失和7 bp的插入。PM突变的219 bp重复片段内有一个11 bp的基序,其在牛科动物中完全保守,PM突变同时也位于PF和PG变异内。单倍型分析表明,PM变异是由Turano牛渗入到蒙古牦牛中[34]。
Table 2
表2
表2牛角性状相关遗传突变和候选基因
Table 2
| 表型 | 突变位点、候选基因 | 数据类型 | 分析方法 | 品种 | 参考文献 |
|---|---|---|---|---|---|
| 无角 | PC突变,IFNAR2、OLIG1 | DNA芯片,转录组 | 基因组纯合子分析、 差异表达分析 | 多个欧洲牛品种 | [29,30] |
| PF突变 | DNA芯片,全基因组测序 | 单体型分析 | 荷斯坦牛 | [29,31,32] | |
| PG突变 | 全基因组测序 | 基因型分析 | 内洛尔瘤牛 | [33] | |
| PM突变 | DNA芯片,全基因组测序 | 基因渗入分析 | 蒙古牦牛和蒙古Turano牛 | [34] | |
| RXPF2、FOXL2 | 转录组测序, | 差异表达分析 | 荷斯坦牛 | [32] | |
| OTOP3和OLIG1 | 基因组测序 | 正选择分析 | 牛科动物 | [70] | |
| 畸形 | TWIST1 | DNA芯片 | 全基因组关联分析 | 夏洛莱牛 | [59,61] |
新窗口打开|下载CSV
2.1.2 牛无角表型转录组研究
科研人员通过对角芽和角进行转录组及蛋白质组分析,进一步开展了角发育和无角表型的信号通路研究。Allais-Bonnet等[35]对胎儿期90天PC变异区域的基因表达和lincRNA (long intergenic non- coding RNA)进行分析,发现有角和无角表型的角芽组织中RXFP2基因和LincRNA#1存在显著差异。无角表型牛胎儿角芽部位RXFP2表达量显著低于有角表型(P < 0.05),LincRNA#1的表达低于有角表型(P = 0.052)。Wiedemar等[32]对牛胎儿150天的角组织和无角表型角芽部位RNA测序,发现OLIG1、OLIG2、C1H21/f62、RXFP2和FOXL2表达差异显著,同时LincRNA#2表达量也差异显著;对胎儿期70~175天角芽和额部皮肤分析,发现有角表型的RXFP2、FOXL2和 LincRNA#2表达量都高于无角表型,但未达到显著差异。从以上研究发现,RXFP2是两个研究的共同差异表达的基因,其他基因仅在某一时期内存在表达差异。Li等[36]对PM突变无角牦牛80~90天胎儿角芽组织部位进行蛋白组学分析,确定了29个表达上调蛋白和71个表达下调蛋白,表达上调蛋白涉及代谢活动,表达下调蛋白涉及细胞链接、细胞骨架形成和细胞成分组织。有角表型和无角表型在角芽组织结构上的区别可能导致了筛选到差异蛋白多与细胞结构相关。
2.2 绵羊无角表型
2.2.1 绵羊无角(Ho)位点遗传定位人类在驯化绵羊时,同时对毛色、羊毛类型、角型等性状进行了选择[37]。角也是人类最早开始研究的性状之一。Lundrigan[38]发现野生绵羊和地方绵羊品种公羊一般有角,育种学家从16世纪开始选育无角绵羊,家养绵羊的公羊开始出现无角表型,研究人员对“两角-无角”这对表型也开展了大量研究。
在家养绵羊研究及育种中,早期研究认为位于常染色体Ho基因座上的3个等位基因调控绵羊有角对无角表型,分别为HoP、Ho+和Hoh1[39]。Montgomery[40]在美利奴羊和罗姆尼羊的杂交群体中,将绵羊的“无角位点”定位在10号染色体上。Pickering[41]利用美利奴羊和罗姆尼羊的杂交群体,将无角位点定位区间缩小到50 kb的区域内,17个标记构成的单倍型能够使绵羊角表型预测的正确率达97%。Kijas等[37]利用全基因组信号选择分析了陶赛特和美利奴羊,在绵羊10号染色体上发现无角表型的显著性SNP位点(OAR10_29546872),该位点临近RXFP2基因。对Navajo-Churro绵羊的高密度芯片全基因组关联分析发现,无角位点定位在绵羊10号染色体29.3~29.5 Mb区间[24](表1)。Dominik等[42]也在澳洲美利奴绵羊群体发现可以鉴定角表型的单碱基多态性。在美利奴羊品种中,利用OAR10_ 29546872.1和OAR10_29458450两个SNP位点,对母羊无角预测准确率达到32.3%~71.3%,公羊无角预测准确率达到62%~72.5% [43],由于这两个SNPs不是致因突变,所以不能100%的预测角表型。同时,野生绵羊上也发现无角位点,利用251个微卫星和等位酶标记,Dario等[44]将索艾羊(Soay)的无角表型定位到10号染色体。
2.2.2 绵羊角与性别选择相关性研究
角在公羊搏斗和获得交配权的优势互作中发挥了重要作用,角的尺寸越大,公羊的繁殖成功率就越高。性别选择是野生动物强大、持续定向选择的源动力。对大角羊家系研究发现,决定角尺寸的QTL位于10号染色体[45],研究人员对大角羊进行基于重测序的信号选择分析,发现公羊巨大的角是RXFP2受到强烈的正选择而形成的(表1)[46],同时雄性竞争者越多,大角羊的性别选择强度就越大[47]。而在野生索艾羊群体中,虽然具有大角的公羊在同性竞争中具有优势,但公羊群体仍保持了角表型的多态性,群体内存在正常大角和畸形角两种表型,而母羊群体中存在正常角、畸形角和无角3种表型[48,49]。这种多态性是通过RXFP2基因在自然选择和性别选择上相互妥协而形成的[50],既索艾羊在RXFP2有两个等位基因,大角等位基因Ho+与高繁殖率相关,小角等位基因HoP与存活率相关,两者形成杂合子优势,群体中存在Ho+Ho+、Ho+HoP和HoPHoP三种基因型公羊,Ho+Ho+和Ho+HoP基因型公羊的表型是正常角,HoPHoP基因型有大约50%公羊为畸形角表型。
2.2.3 绵羊无角表型遗传的复杂性
Wiedemar等[51]通过对5个欧洲绵羊品种进一步分析,发现RXFP2基因3′UTR区域一段1.8 kb插入片段与无角表型相关,且无角对两角表型为显性。Wang等[52]在中国滩羊中也发现RXFP2基因上一个同义突变与无角表型显著相关,但对国外34个绵羊品种489个个体的大样本检测发现,位于RXFP2基因3′UTR区域的插入片段只在部分绵羊品种的角表型中出现分离[53],而对我国地方绵羊品种阿勒泰羊的无角GWAS分析并未发现显著性位点,同时,检测阿勒泰羊RXFP2基因3′UTR区域1.8 kb插入片段,结果发现该插入片段与无角表型不存在相关性[22]。2020年,Li等[26]对我国小尾寒羊和湖羊进行基于重测序的角性状关联分析和品种间选择性清扫分析,结果表明CNV和SNP关联分析以及选择性清扫分析都检测到了位于10号染色体RXFP2基因附近的信号(表1)。综上所述,无角绵羊在表型上只有无角一种类型,虽然已经在基因组上成功定位了无角的遗传区间,但不同无角绵羊群体中出现截然不同的结果,有些品种角型与RXFP2基因区域变异关联,另一些品种则不存在关联,同时无角表型在不同品种中得到复杂多变的结果表明无角表型基因遗传具有复杂性。
3 正常两角表型的数量性状
最初,角性状被认为是典型的质量性状,既正常两角(图1B)和无角(图1D)。但对索艾羊的研究有了新的发现。野生索艾羊因其角性状在群体中具有丰富的表型,成为研究角遗传调控的理想模型。Dario等[44]通过连锁图谱将野生索艾羊的角性状定位在10号染色体上,Johnston等[48]不仅将这一区域缩小到7.4 cM范围内,而且将确定角长度和角基部位周长的调控基因也定位在这一区域。Johnston等[49]进一步利用芯片分析确定了索艾羊角关键候选基因RXFP2,该基因能解释具备正常角公羊的角长76%的数量QTL,表明RXFP2基因既是无角表型候选基因(质量性状),也是角长度和粗细等数量性状的主效基因。但在其他野生羊群体上并未得到相似的结果,Miller等[54]对76个大角羊(野生绵羊)基于高密度芯片的GWAS分析,并没有发现影响角长度和角基部位周长的QTL。此外,Pan等[55]对89个中国绵羊的重测序分析发现RXFP基因与绵羊的半野化相关,且与角长和角生长方向(螺旋和水平延伸)相关(表1)。总之,绵羊无角表型(质量性状,既有角或者无角)与正常角长度和粗细的数量性状QTL都定位于同一遗传区间和同一候选基因——RXFP2基因。4 畸形角研究进展
角性状除了数量不同外,其发育程度也有很大差异,按照后者可分为正常角、畸形角[56]和无角[12]。畸形角是小的、不规则的,且不能牢固附着于颅骨的角(图1C)。畸形角至少在公元前3800~3500年就已经在家畜中存在[57]。在很多绵羊、山羊、牛的品种中都存在畸形角现象[52],这种角的表型降低了家畜的价值[58]。解剖学上畸形角与正常角有2个主要的区别：一是畸形角不与颅骨相连,额窦并不深入角突;二是畸形角的骨质角心更加致密[59]。4.1 牛畸形角
牛上存在2种类型的畸形角遗传,White等[60]认为牛上存在调控牛角畸形表型的SCURS位点(Sc位点),并将其定位在19号染色体[58],II型畸形角表型是由法国夏洛莱牛TWIST1基因的突变导致(表2)[59,61],这与有角对无角遗传位点定位并不相同。4.2 绵羊畸形角
近期研究发现,索艾羊和野生大角羊的畸形角表型定位到绵羊10号染色体RXFP2基因,这与绵羊的有角对无角位点定位相同。对畸形角的iTRAQ分析发现了PARVA、TNN、TNC、COL6A1、COL6A2等一系列显著性差异蛋白(表1),并发现(ECM)- receptor interactions、focal adhesion和PI3K-Akt是影响绵羊角发育(畸形)的重要信号通路[62]。另有研究表明,前两个信号通路参与细胞粘附功能[63,64],并可能参与细胞存活和细胞交流[65]。有趣的是,Mariasegaram等[66]在牛的研究中发现(ECM)-receptor interactions信号通路也是畸形角对无角的显著性信号通路。PI3K-Akt信号通路能调节上皮细胞中细胞外基质的表达[67],focal adhesion信号通路在体内还调节修复性骨形成[68]。5 角的遗传调控
5.1 牛角遗传机制
牛的有角表型为野生型,对无角位点(POLLED)是隐形遗传,I型畸形角对无角是上位遗传,同时受性别影响[32,60];II型畸形对正常角表型是显性的,但都是杂合子,目前没有发现纯合的TWIST1突变,推测该突变是胚胎致死;而瘤牛公牛的有角表型对无角表型为上位遗传[69],在非洲瘤牛和安格斯牛的杂交群体中,后代母牛全部是无角表型,而后代公牛为3种表型,分别为有角、畸形角和无角,推测可能存在另外一个Ha基因参与角的遗传。目前已经发现4个牛的无角表型遗传位点,它们位于牛1号染色体一段比较集中的区域,分别为PC、PF、PM和PG突变(表2),这4个变异没有定位于任何已知基因、lncRNA(long non-coding RNA)或者miRNAs上,推测是通过影响DNA调控因子,如增强子来调控基因的表达。这一区域包含23个编码基因和非编码基因的拓扑结构域,包括OLIG1、OLIG2、IFNAR2、PAXBP1等。Wang等[70]研究发现OLIG1是有角反刍类动物的特异性正选择基因,其与神经脊分化通路相关[71],在OLIG1基因侧翼65 kb区域的212 bp的重复片段是牛无角表型的致因突变[29,30]。OLIG1基因可能在骨质角的发育上发挥重要作用[70]。同时,Tetens等[72]发现OLIG2、FOXL2和 RXFP2等基因为角芽分化相关基因。
骨组织是由致密的间充质细胞形成[73,74],神经脊的上皮细胞变成迁移间充质细胞被称为上皮-间质转型(epithelial-to-mesenchymal transition, EMT),该过程导致细胞类型多元化和形成器官的组织发育[75]。Betancur等[71]发现TWIST1、SNAI2、SOX9和HOXD基因簇等参与神经脊细胞迁徙。同时,研究发现TWIST基因调控成骨过程,其突变可以造成颅缝早闭[76,77],而TWIST是牛II型畸形角的突变基因。同时Wang等[70]研究还发现SOX10、SNAI1、SNAI2、TFAP2A、NGFR和COL11A2等6个神经脊细胞迁移相关基因在角组织中特异性表达,该家族的COL1A1、COL1A2、COL5A1、COL5A2和COL6A6等基因是影响牛畸形角的差异基因[66]。研究表明TWIST1、TWIST2、ZEB2和FOXC2等转录因子可以直接抑制E-钙粘蛋白的表达[78],而E-钙粘蛋白是EMT的标记蛋白,可能通过影响神经脊细胞迁徙影响牛角的发育。以上研究表明这些候选基因可能通过影响神经脊细胞迁移影响角的形成和发育,从而影响牛角的表型。
5.2 绵羊角的遗传机制
绵羊角性状至少由2个位点调控,一个是位于10号染色体的“无角位点”,另一个是位于2号染色体的“多角位点”,多角表型对两角表型为显性遗传。目前绵羊角的遗传机制并不清楚,仅定位到无角表型和多角表型的遗传区间和候选基因。其中无角表型的候选基因为RXFP2 (松弛素/类胰岛素样家族肽受体2,relaxin/insulin like family peptide receptor 2),位于绵羊10号染色体。Wang等[70]研究表明RXFP2基因为角组织高表达基因,RXFP2为G蛋白偶联受体蛋白,其突变可以导致骨质疏松[79]。RXFP2的配基RLN可以通过激活骨膜内化调控因子,包括ALP、RUNX2和BMP2诱导成骨分化[80],表明RXFP2对角发育起到重要作用,如果RXFP2减少,可能通过减少与配基松弛素的结合,抑制成骨分化,从而抑制骨质角心的形成。多角位点的遗传区域位于2号染色体128~135 Mb,该区域包括MTX2、HNRNPA3、NFE2L2和HOXD基因簇等,其中HOXD属于HOX转录因子家族成员,是一类十分重要并在进化上保守的转录因子,其主要作用是协调肢体对称发育,从而影响肢体的形态。研究发现HOXD基因簇长度约100 kb,包括13个基因,其中HOXD 4下游2.7 kb的缺失可以导致马(Equus caballus)的脊椎发育缺陷[81],HOXD基因家族部分成员的突变可以导致人的多趾畸形[82],如HOXD10、HOXD11、HOXD12和HOXD13与手指和脚趾的发育相关,其突变会影响手指和脚趾的数量[83],HOXD13基因在肢体末端表达,是切断其临近基因调控和开启末端发育调控的转换开关[84],通过这一基因的调控从而实现肢体从中央区域到末端区域发育调控的转换[85]。Jerkovi?等[86]进一步的研究还发现,HOXD9~HOXD13蛋白是通过辅因子与DNA相结合,而非HOXD转录因子直接与DNA相结合。绵羊角主要由外部坚硬的角质化外鞘和内部骨质化角心两部分构成[87],两部分中间还包含骨膜、皮下结缔组织、真皮和表皮[3]。骨质角心主要是由骨组织构成,来源于中胚层(轴旁中胚层和侧中胚层)和神经脊。轴旁中胚层形成中轴骨骼,如肋骨、椎骨和颅骨的顶骨。侧中胚层形成附属骨骼,如四肢[73,88]。神经脊细胞迁移形成额骨和面骨[74],这些影响中胚层形成和神经脊细胞迁移的基因可能是角形成的候选基因。Betancur等[71]发现HOXD基因簇以及SNAI2、TWIST1和SOX9 等基因参与神经脊细胞迁徙,Wang等[70]在HOXD基因簇下游发现一个3.6 kb有角反刍动物特有转座因子插入,进一步分析发现该插入存在一个25 bp的特异性保守元件;同时发现COL11A2等神经脊细胞迁移相关基因在角中特异性表达,而COL11A2基因与绵羊畸形角显著差异蛋白COL6A2、COL6A3、COL6A1和COL1A2同属于胶原蛋白家族成员,这些元件和基因可能对角发育起重要作用。
6 结语与展望
角是反刍动物的标志性特征(少数野生反刍动物如麝科无角),是演化最为成功的器官之一,角的发生、进化和遗传机制一直是遗传学研究的热点之一,也是其他特异性遗传性状研究的参考模型之一。2019年,西北农林科技大学姜雨团队和西北工业大学王文团队[70,89]在Science上连续发表了两篇反刍动物角的相关研究文章,发现反刍动物的角具有共同的基因、细胞和组织起源;驯鹿CCND1基因上游的突变赋予雄激素受体额外的功能性结合基序,可能导致雌性鹿茸生长。前人对牛和绵羊角的遗传调控开展了多年的研究,在多角表型、无角表型和畸形角的遗传位点定位、遗传机制等方面取得了重要进展,目前的研究表明,牛无角表型有4个突变,都位于1号染色体,畸形角有2个突变位点;绵羊角性状至少由2个位点调控,分别是位于10号染色体的“无角位点”和位于2号染色体的“多角位点”。但是对牛和绵羊角性状形成的分子机制仍有待进行深入研究,包括确定角形成的因果突变基因、及其早期发育关键基因,解析角不同表型的遗传调控机制。牛、绵羊不仅为人类提供肉、奶、毛(皮)等生产生活资料,在人类农业发展中扮演着重要角色,同时也是人类农耕文明传播的重要组成部分。牛和绵羊角性状具有丰富的表型,开展角形成和遗传机制的研究将有助于推进动物特异性性状的多基因调控机制机理解析和新器官起源进化等基础研究的进展,为阐明基因在性状调控和遗传分化中的作用提供参考。
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
DOI:10.1002/(ISSN)1097-010XURL [本文引用: 2]
[本文引用: 1]
[本文引用: 1]
DOI:10.1098/rspb.2011.0938URLPMID:21733893 [本文引用: 2]
The horns, ossicones and antlers of ruminants are familiar and diverse examples of cranial appendages. We collectively term ruminant cranial appendages 'headgear'; this includes four extant forms: antlers (in cervids), horns (in bovids), pronghorns (in pronghorn antelope) and ossicones (in giraffids). Headgear evolution remains an open and intriguing question because phylogenies (molecular and morphological), adult headgear structure and headgear development (where data are available) all suggest different pictures of ruminant evolution. We discuss what is known about the evolution of headgear, including the evidence motivating previous hypotheses of single versus multiple origins, and the implications of recent phylogenetic revisions for these hypotheses. Inclusion of developmental data is critical for progress on the question of headgear evolution, and we synthesize the scattered literature on this front. The areas most in need of attention are early development in general; pronghorn and ossicone development in particular; and histological study of fossil forms of headgear. An integrative study of headgear development and evolution may have ramifications beyond the fields of systematics and evolution. Researchers in organismal biology, as well as those in biomedical fields investigating skin, bone and regenerative medicine, may all benefit from insights produced by this line of research.
DOI:10.1093/molbev/msu264URL [本文引用: 1]
Following domestication, sheep (Ovis aries) have become essential farmed animals across the world through adaptation to a diverse range of environments and varied production systems. Climate-mediated selective pressure has shaped phenotypic variation and has left genetic "footprints" in the genome of breeds raised in different agroecological zones. Unlike numerous studies that have searched for evidence of selection using only population genetics data, here, we conducted an integrated coanalysis of environmental data with single nucleotide polymorphism (SNP) variation. By examining 49,034 SNPs from 32 old, autochthonous sheep breeds that are adapted to a spectrum of different regional climates, we identified 230 SNPs with evidence for selection that is likely due to climate-mediated pressure. Among them, 189 (82%) showed significant correlation (P a parts per thousand currency sign 0.05) between allele frequency and climatic variables in a larger set of native populations from a worldwide range of geographic areas and climates. Gene ontology analysis of genes colocated with significant SNPs identified 17 candidates related to GTPase regulator and peptide receptor activities in the biological processes of energy metabolism and endocrine and autoimmune regulation. We also observed high linkage disequilibrium and significant extended haplotype homozygosity for the core haplotype TBC1D12-CH1 of TBC1D12. The global frequency distribution of the core haplotype and allele OAR22_18929579-A showed an apparent geographic pattern and significant (P a parts per thousand currency sign 0.05) correlations with climatic variation. Our results imply that adaptations to local climates have shaped the spatial distribution of some variants that are candidates to underpin adaptive variation in sheep.
DOI:10.1038/s41467-018-04737-0URLPMID:29904051 [本文引用: 1]
Cattle domestication and the complex histories of East Asian cattle breeds warrant further investigation. Through analysing the genomes of 49 modern breeds and eight East Asian ancient samples, worldwide cattle are consistently classified into five continental groups based on Y-chromosome haplotypes and autosomal variants. We find that East Asian cattle populations are mainly composed of three distinct ancestries, including an earlier East Asian taurine ancestry that reached China at least ~3.9 kya, a later introduced Eurasian taurine ancestry, and a novel Chinese indicine ancestry that diverged from Indian indicine approximately 36.6-49.6 kya. We also report historic introgression events that helped domestic cattle from southern China and the Tibetan Plateau achieve rapid adaptation by acquiring ~2.93% and ~1.22% of their genomes from banteng and yak, respectively. Our findings provide new insights into the evolutionary history of cattle and the importance of introgression in adaptation of cattle to new environmental challenges in East Asia.
[本文引用: 2]
[本文引用: 2]
[本文引用: 1]
[本文引用: 1]
[本文引用: 4]
DOI:10.2527/2004.82102900xURLPMID:15484940 [本文引用: 2]
The objectives of this study were to 1) evaluate the genetic diversity of Navajo-Churro sheep using pedigree information; 2) examine the distribution of the Navajo-Churro population; and 3) evaluate the effect of breeder dynamics on genetic conservation of the breed. Pedigree data and breeder information (city and state) were obtained from the Navajo-Churro Sheep Breed Association. Inbreeding coefficients were calculated for each individual animal using pedigree information. A geographic information system program was used to divide the United States into four regions and overlay breeder locations, flock size, and flock inbreeding level. The small correlation between level of inbreeding and flock size (r = -0.07, P = 0.07) indicated that inbreeding levels are not different across flock sizes. The mean flock inbreeding levels ranged from 0 to 11% across regions. The level of inbreeding did not differ among regions (P = 0.15), except for Region 4 (Kansas and Missouri; P = 0.001). The number of breeders registering sheep averaged 34 per year. Most of the breeders were transient, with only eight breeders maintaining ownership for more than 7 yr. Average inbreeding level for 2000 was found to be 1.2%, with a linear increase in inbreeding of 0.1%/yr over the period studied, suggesting a minimal loss of genetic diversity for the Navajo-Churro. However, given the relatively small effective population size (92) and the transient nature of the breeders, development of an ex situ cryo-preserved germplasm bank may be the best long-term strategy for maintaining this breed's genetic diversity.
[本文引用: 1]
[本文引用: 2]
[本文引用: 1]
[本文引用: 1]
[本文引用: 1]
[本文引用: 1]
[本文引用: 1]
[本文引用: 1]
[本文引用: 1]
URL [本文引用: 1]
泗水裘皮羊原产于山东省泗水县的泗河两岸。公羊头长2~6只角，形状怪异，是目前我国仅存唯一的多角绵羊品种。泗水裘皮羊成年体重：公羊56.12±5.63 kg,母羊40.67±4.85 kg；母羊繁殖率121.05%。由泗水裘皮羊所产二毛羔皮花穗美观，皮板轻柔，是制作高档皮衣的上等原料。开展对泗水裘皮羊的研究和利用意义重大，目前社会存养量不足2000只，实施必要的品种保护措施势在必行。
DOI:10.1111/age.12644URLPMID:29441598 [本文引用: 3]
[本文引用: 1]
[本文引用: 1]
DOI:10.1111/age.12464URLPMID:27427781 [本文引用: 3]
Four-horned sheep are an ideal animal model for illuminating the genetic basis of horn development. The objective of this study was to locate the genetic region responsible for the four-horned phenotype and to verify a previously reported polled locus in three Chinese breeds. A genome-wide association study (GWAS) was performed using 34 two-horned and 32 four-horned sheep from three Chinese indigenous breeds: Altay, Mongolian and Sishui Fur sheep. The top two significant single nucleotide polymorphisms (SNPs) associated with the four-horned phenotype were both located in a region spanning positions 132.6 to 132.7 Mb on sheep chromosome 2. Similar locations for the four-horned trait were previously identified in Jacob, Navajo-Churro, Damara and Sishui Fur sheep, suggesting a common genetic component underlying the four-horned phenotype. The two identified SNPs were both downstream of the metaxin 2 (MTX2) gene and the HOXD gene cluster. For the top SNP-OAR2:g.132619300G>A-the strong associations of the AA and AG genotypes with the four-horned phenotype and the GG genotype with the two-horned phenotype indicated the dominant inheritance of the four-horned trait. No significant SNPs for the polled phenotype were identified in the GWAS analysis, and a PCR analysis for the detection of the 1.8-kb insertion associated with polled sheep in other breeds failed to verify the association with polledness in the three Chinese breeds. This study supports the hypothesis that two different loci are responsible for horn existence and number. This study contributes to the understanding of the molecular regulation of horn development and enriches the knowledge of qualitative traits in domestic animals.
DOI:10.1038/srep21111URLPMID:26883901 [本文引用: 1]
Horns are a cranial appendage found exclusively in Bovidae, and play important roles in accessing resources and mates. In sheep (Ovies aries), horns vary from polled to six-horned, and human have been selecting polled animals in farming and breeding. Here, we conducted a genome-wide association study on 24 two-horned versus 22 four-horned phenotypes in a native Chinese breed of Sishui Fur sheep. Together with linkage disequilibrium (LD) analyses and haplotype-based association tests, we identified a genomic region comprising 132.0-133.1 Mb on chromosome 2 that contained the top 10 SNPs (including 4 significant SNPs) and 5 most significant haplotypes associated with the polycerate phenotype. In humans and mice, this genomic region contains the HOXD gene cluster and adjacent functional genes EVX2 and KIAA1715, which have a close association with the formation of limbs and genital buds. Our results provide new insights into the genetic basis underlying variable numbers of horns and represent a new resource for use in sheep genetics and breeding.
DOI:10.1111/age.12409URLPMID:26767438 [本文引用: 4]
Phenotypic variability in horn characteristics, such as their size, number and shape, offers the opportunity to elucidate the molecular basis of horn development. The objective of this study was to map the genetic determinant controlling the production of four horns in two breeds, Jacob sheep and Navajo-Churro, and examine whether an eyelid abnormality occurring in the same populations is related. Genome-wide association mapping was performed using 125 animals from the two breeds that contain two- and four-horned individuals. A case-control design analysis of 570 712 SNPs genotyped with the ovine HD SNP Beadchip revealed a strong association signal on sheep chromosome 2. The 10 most strongly associated SNPs were all located in a region spanning Mb positions 131.9-132.6, indicating the genetic architecture underpinning the production of four horns is likely to involve a single gene. The closest genes to the most strongly associated marker (OAR2_132568092) were MTX2 and the HOXD cluster, located approximately 93 Kb and 251 Kb upstream respectively. The occurrence of an eyelid malformation across both breeds was restricted to polled animals and those carrying more than two horns. This suggests the eyelid abnormality may be associated with departures from the normal developmental production of two-horned animals and that the two conditions are developmentally linked. This study demonstrated the presence of separate loci responsible for the polled and four-horned phenotypes in sheep and advanced our understanding of the complexity that underpins horn morphology in ruminants.
DOI:10.1111/age.12411URLPMID:26767563 [本文引用: 1]
Polyceraty (presence of multiple horns) is rare in modern day ungulates. Although not found in wild sheep, polyceraty does occur in a small number of domestic sheep breeds covering a wide geographical region. Damara are fat-tailed hair sheep, from the south-western region of Africa, which display polyceraty, with horn number ranging from zero to four. We conducted a genome-wide association study for horn number with 43 Damara genotyped with 606 006 SNP markers. The analysis revealed a region with multiple significant SNPs on ovine chromosome 2, in a location different from the mutation for polled in sheep on chromosome 10. The causal mutation for polyceraty was not identified; however, the region associated with polyceraty spans nine HOXD genes, which are critical in embryonic development of appendages. Mutations in HOXD genes are implicated in polydactly phenotypes in mice and humans. There was no evidence for epistatic interactions contributing to polyceraty. This is the first report on the genetic mechanisms underlying polyceraty in the under-studied Damara.
DOI:10.1038/s41467-020-16485-1URLPMID:32499537 [本文引用: 4]
Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.
DOI:10.1038/ng0693-206URLPMID:8348158 [本文引用: 1]
The presence or absence of horns in Bos taurus is thought to be under the genetic control of the autosomal polled locus, characterized by two alleles: P dominant over p, and causing the polled or hornless phenotype. We have demonstrated genetic linkage between the polled locus and two microsatellite markers, GMPOLL-1 and GMPOLL-2, and have assigned the corresponding linkage group to bovine chromosome 1. This confirms the existence of the postulated polled locus and the hypothesized inheritance pattern. It will allow marker assisted selection for the polledness trait in breeding programs and is a first step towards positional cloning and molecular study of a gene that has been subjected to both natural and artificial selection.
DOI:10.1007/BF00354293URLPMID:8563169 [本文引用: 1]
Five Charolais families known to segregate for both horned and polled were selected and tested for linkage analysis by use of microsatellites and karyotyping for Robertsonian translocation 1;29. No recombinants were found between any of these markers and the polled phenotype or each other. When statistical analysis was performed, the logarithm of the odds (LOD) indicated that there was 100% linkage occurring between the markers and the phenotype (p < 0.001). These microsatellite markers, TGLA49 and BM6438, can be assumed to be very close to the actual gene that determines the polled phenotype. Another linked marker, SOD1, was physically mapped, which places all of these markers within 1q12-14, very near the centromere of Chromosome (Chr) 1. A homozygous polled cow was identified in this study by following the alleles at both markers and the phenotypes in her family.
DOI:10.1371/journal.pone.0039477URLPMID:22737241 [本文引用: 5]
The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a approximately 381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations.
DOI:10.1038/nbt.3560URL [本文引用: 3]
DOI:10.1186/1297-9686-46-44URL [本文引用: 2]
URLPMID:24671182 [本文引用: 5]
The molecular regulation of horn growth in ruminants is still poorly understood. To investigate this process, we collected 1019 hornless (polled) animals from different cattle breeds. High-density SNP genotyping confirmed the presence of two different polled associated haplotypes in Simmental and Holstein cattle co-localized on BTA 1. We refined the critical region of the Simmental polled mutation to 212 kb and identified an overlapping region of 932 kb containing the Holstein polled mutation. Subsequently, whole genome sequencing of polled Simmental and Holstein cows was used to determine polled associated genomic variants. By genotyping larger cohorts of animals with known horn status we found a single perfectly associated insertion/deletion variant in Simmental and other beef cattle confirming the recently published possible Celtic polled mutation. We identified a total of 182 sequence variants as candidate mutations for polledness in Holstein cattle, including an 80 kb genomic duplication and three SNPs reported before. For the first time we showed that hornless cattle with scurs are obligate heterozygous for one of the polled mutations. This is in contrast to published complex inheritance models for the bovine scurs phenotype. Studying differential expression of the annotated genes and loci within the mapped region on BTA 1 revealed a locus (LOC100848215), known in cow and buffalo only, which is higher expressed in fetal tissue of wildtype horn buds compared to tissue of polled fetuses. This implicates that the presence of this long noncoding RNA is a prerequisite for horn bud formation. In addition, both transcripts associated with polledness in goat and sheep (FOXL2 and RXFP2), show an overexpression in horn buds confirming their importance during horn development in cattle.
DOI:10.1111/age.12764URLPMID:30644114 [本文引用: 2]
DOI:10.1038/ng.3775URLPMID:28135247 [本文引用: 3]
The yak is remarkable for its adaptation to high altitude and occupies a central place in the economies of the mountainous regions of Asia. At lower elevations, it is common to hybridize yaks with cattle to combine the yak's hardiness with the productivity of cattle. Hybrid males are sterile, however, preventing the establishment of stable hybrid populations, but not a limited introgression after backcrossing several generations of female hybrids to male yaks. Here we inferred bovine haplotypes in the genomes of 76 Mongolian yaks using high-density SNP genotyping and whole-genome sequencing. These yaks inherited approximately 1.3% of their genome from bovine ancestors after nearly continuous admixture over at least the last 1,500 years. The introgressed regions are enriched in genes involved in nervous system development and function, and particularly in glutamate metabolism and neurotransmission. We also identified a novel mutation associated with a polled (hornless) phenotype originating from Mongolian Turano cattle. Our results suggest that introgressive hybridization contributed to the improvement of yak management and breeding.
DOI:10.1371/journal.pone.0063512URLPMID:23717440 [本文引用: 1]
Despite massive research efforts, the molecular etiology of bovine polledness and the developmental pathways involved in horn ontogenesis are still poorly understood. In a recent article, we provided evidence for the existence of at least two different alleles at the Polled locus and identified candidate mutations for each of them. None of these mutations was located in known coding or regulatory regions, thus adding to the complexity of understanding the molecular basis of polledness. We confirm previous results here and exhaustively identify the causative mutation for the Celtic allele (PC) and four candidate mutations for the Friesian allele (PF). We describe a previously unreported eyelash-and-eyelid phenotype associated with regular polledness, and present unique histological and gene expression data on bovine horn bud differentiation in fetuses affected by three different horn defect syndromes, as well as in wild-type controls. We propose the ectopic expression of a lincRNA in PC/p horn buds as a probable cause of horn bud agenesis. In addition, we provide evidence for an involvement of OLIG2, FOXL2 and RXFP2 in horn bud differentiation, and draw a first link between bovine, ovine and caprine Polled loci. Our results represent a first and important step in understanding the genetic pathways and key process involved in horn bud differentiation in Bovidae.
DOI:10.1186/s12953-018-0141-9URL [本文引用: 1]
DOI:10.1371/journal.pbio.1001258URLPMID:22346734 [本文引用: 3]
Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep populations contain high SNP diversity and have retained an effective population size much higher than most cattle or dog breeds, suggesting domestication occurred from a broad genetic base. Extensive haplotype sharing and generally low divergence time between breeds reveal frequent genetic exchange has occurred during the development of modern breeds. A scan of the genome for selection signals revealed 31 regions containing genes for coat pigmentation, skeletal morphology, body size, growth, and reproduction. We demonstrate the strongest selection signal has occurred in response to breeding for the absence of horns. The high density map of genetic variability provides an in-depth view of the genetic history for this important livestock species.
DOI:10.2307/1382822URL [本文引用: 1]
[本文引用: 1]
DOI:10.1093/oxfordjournals.jhered.a023014URLPMID:8904835 [本文引用: 2]
The presence or absence of horns in Merino sheep is under the genetic control of the autosomal Horns (Ho) locus. Sheep chromosome OOV1 is a candidate region for the Ho locus because it shows conserved synteny with cattle chromosome BBO1 where the cattle polled locus has been located. We demonstrate that the Ho locus in sheep is excluded from sheep chromosome OOV1 and we identified linkage between the Ho locus and markers from sheep chromosome OOV10. These data suggest that there are at least two loci affecting the presence or absence of horns in sheep and cattle. The orthologous regions to OOV10 are likely to be on cattle, human, and mouse chromosomes BBO12, HSA13, and MMU14.
[本文引用: 2]
DOI:10.1111/j.1365-2052.2011.02271.xURL [本文引用: 2]
The aim of this study was to fine map the genomic location of the Horns locus in the Australian Merino sheep population and to identify markers that can be used to predict the horn phenotype. A linkage disequilibrium analysis of horn data from Australian Merino sheep mapped the Horns locus to a small region on chromosome 10. A single nucleotide polymorphism in the region was found to be highly predictive for the polled phenotype in an experimental population of Merino sheep. This was owing to a dominance effect of one of the alleles when inherited maternally. It was suggested that a genetic test would provide a good predictor of the polled phenotype. Finally, an evaluation of industry data showed that the SNP is at very different frequencies in Poll Merino sheep that have been bred for polledness (based on phenotype alone) compared with the Merino sheep breed.
DOI:10.1186/s12711-018-0398-6URLPMID:29788905 [本文引用: 1]
BACKGROUND: In horned sheep breeds, breeding for polledness has been of interest for decades. The objective of this study was to improve prediction of the horned and polled phenotypes using horn scores classified as polled, scurs, knobs or horns. Derived phenotypes polled/non-polled (P/NP) and horned/non-horned (H/NH) were used to test four different strategies for prediction in 4001 purebred Merino sheep. These strategies include the use of single 'single nucleotide polymorphism' (SNP) genotypes, multiple-SNP haplotypes, genome-wide and chromosome-wide genomic best linear unbiased prediction and information from imputed sequence variants from the region including the RXFP2 gene. Low-density genotypes of these animals were imputed to the Illumina Ovine high-density (600k) chip and the 1.78-kb insertion polymorphism in RXFP2 was included in the imputation process to whole-genome sequence. We evaluated the mode of inheritance and validated models by a fivefold cross-validation and across- and between-family prediction. RESULTS: The most significant SNPs for prediction of P/NP and H/NH were OAR10_29546872.1 and OAR10_29458450, respectively, located on chromosome 10 close to the 1.78-kb insertion at 29.5 Mb. The mode of inheritance included an additive effect and a sex-dependent effect for dominance for P/NP and a sex-dependent additive and dominance effect for H/NH. Models with the highest prediction accuracies for H/NH used either single SNPs or 3-SNP haplotypes and included a polygenic effect estimated based on traditional pedigree relationships. Prediction accuracies for H/NH were 0.323 for females and 0.725 for males. For predicting P/NP, the best models were the same as for H/NH but included a genomic relationship matrix with accuracies of 0.713 for females and 0.620 for males. CONCLUSIONS: Our results show that prediction accuracy is high using a single SNP, but does not reach 1 since the causative mutation is not genotyped. Incomplete penetrance or allelic heterogeneity, which can influence expression of the phenotype, may explain why prediction accuracy did not approach 1 with any of the genetic models tested here. Nevertheless, a breeding program to eradicate horns from Merino sheep can be effective by selecting genotypes GG of SNP OAR10_29458450 or TT of SNP OAR10_29546872.1 since all sheep with these genotypes will be non-horned.
DOI:10.1534/genetics.106.057141URLPMID:16868121 [本文引用: 3]
An understanding of the determinants of trait variation and the selective forces acting on it in natural populations would give insights into the process of evolution. The combination of long-term studies of individuals living in the wild and better genomic resources for nonmodel organisms makes achieving this goal feasible. This article reports the development of a complete linkage map in a pedigree of free-living Soay sheep on St. Kilda and its application to mapping the loci responsible for three morphological polymorphisms for which the maintenance of variation demands explanation. The map was derived from 251 microsatellite and four allozyme markers and covers 3350 cM (approximately 90% of the sheep genome) at approximately 15-cM intervals. Marker order was consistent with the published sheep map with the exception of one region on chromosome 1 and one on chromosome 12. Coat color maps to chromosome 2 where a strong candidate gene, tyrosinase-related protein 1 (TYRP1), has also been mapped. Coat pattern maps to chromosome 13, close to the candidate locus Agouti. Horn type maps to chromosome 10, a location similar to that previously identified in domestic sheep. These findings represent an advance in the dissection of the genetic diversity in the wild and provide the foundation for QTL analyses in the study population.
DOI:10.1038/hdy.2011.69URLPMID:21847139 [本文引用: 2]
Dissecting the genetic architecture of fitness-related traits in wild populations is key to understanding evolution and the mechanisms maintaining adaptive genetic variation. We took advantage of a recently developed genetic linkage map and phenotypic information from wild pedigreed individuals from Ram Mountain, Alberta, Canada, to study the genetic architecture of ecologically important traits (horn volume, length, base circumference and body mass) in bighorn sheep. In addition to estimating sex-specific and cross-sex quantitative genetic parameters, we tested for the presence of quantitative trait loci (QTLs), colocalization of QTLs between bighorn sheep and domestic sheep, and sex x QTL interactions. All traits showed significant additive genetic variance and genetic correlations tended to be positive. Linkage analysis based on 241 microsatellite loci typed in 310 pedigreed animals resulted in no significant and five suggestive QTLs (four for horn dimension on chromosomes 1, 18 and 23, and one for body mass on chromosome 26) using genome-wide significance thresholds (Logarithm of odds (LOD) >3.31 and >1.88, respectively). We also confirmed the presence of a horn dimension QTL in bighorn sheep at the only position known to contain a similar QTL in domestic sheep (on chromosome 10 near the horns locus; nominal P<0.01) and highlighted a number of regions potentially containing weight-related QTLs in both species. As expected for sexually dimorphic traits involved in male-male combat, loci with sex-specific effects were detected. This study lays the foundation for future work on adaptive genetic variation and the evolutionary dynamics of sexually dimorphic traits in bighorn sheep.
DOI:10.1111/mec.13415URLPMID:26454263 [本文引用: 2]
The identification of genes influencing fitness is central to our understanding of the genetic basis of adaptation and how it shapes phenotypic variation in wild populations. Here, we used whole-genome resequencing of wild Rocky Mountain bighorn sheep (Ovis canadensis) to >50-fold coverage to identify 2.8 million single nucleotide polymorphisms (SNPs) and genomic regions bearing signatures of directional selection (i.e. selective sweeps). A comparison of SNP diversity between the X chromosome and the autosomes indicated that bighorn males had a dramatically reduced long-term effective population size compared to females. This probably reflects a long history of intense sexual selection mediated by male-male competition for mates. Selective sweep scans based on heterozygosity and nucleotide diversity revealed evidence for a selective sweep shared across multiple populations at RXFP2, a gene that strongly affects horn size in domestic ungulates. The massive horns carried by bighorn rams appear to have evolved in part via strong positive selection at RXFP2. We identified evidence for selection within individual populations at genes affecting early body growth and cellular response to hypoxia; however, these must be interpreted more cautiously as genetic drift is strong within local populations and may have caused false positives. These results represent a rare example of strong genomic signatures of selection identified at genes with known function in wild populations of a nonmodel species. Our results also showcase the value of reference genome assemblies from agricultural or model species for studies of the genomic basis of adaptation in closely related wild taxa.
DOI:10.1111/jeb.12883URLPMID:27090379 [本文引用: 1]
Sexual selection has a critical role in evolution, and it is fundamental to identify what ecological factors drive its variation. Disentangling the ecological correlates of sexual selection over the long term, however, is challenging and has rarely been done in nature. We sought to assess how demographic changes influenced the intensity, direction and form of sexual selection and whether selective pressures varied with age. We tested whether breeder sex ratio, number of competitors and age structure influenced selection differentials on horn length of wild bighorn rams (Ovis canadensis) of different age classes on Ram Mountain, Alberta. We used 21 years of data including a detailed pedigree, demographic parameters and repeated morphological measurements. Sexual selection on horn length of males of all ages was directional and positive. Selection intensity increased with the number of competitors, reflecting male-male encounter rate during the rut, but was independent of breeder sex ratio or age structure. This result can also be linked to changes in population size because the number of competitors was highly correlated to total number of sheep. This demographic effect likely arises from age-dependent mating tactics. Males aged 2-4 years are weakly competitive and experienced stronger sexual selection as they accounted for a greater proportion of all males. Selection experienced by mature males appeared independent of demography. Our study provides a rare description of the demographic determinants of sexual selection in nature.
DOI:10.1038/hdy.2009.109URLPMID:19690581 [本文引用: 4]
The evolution of male weaponry in animals is driven by sexual selection, which is predicted to reduce the genetic variability underlying such traits. Soay sheep have an inherited polymorphism for horn type in both sexes, with males presenting with either large, normal horns or small, deformed horns (scurs). In addition, there is additive genetic variation in horn length among males with normal horns. Given that scurred males cannot win conflicts with normal-horned males, it is unusual that genes conferring scurs should persist in the population. Identifying the genetic basis of these traits should help us in understanding their evolution. We developed microsatellite markers in a targeted region of the Soay sheep genome and refined the location of the Horns locus (Ho) to a approximately 7.4 cM interval on chromosome 10 (LOD=8.78). We then located quantitative trait loci spanning a 34 cM interval with a peak centred close to Ho, which explained the majority of the genetic variation for horn length and base circumference in normal-horned males (LOD=2.51 and LOD=1.04, respectively). Therefore, the genetic variation in both horn type and horn length is attributable to the same chromosomal region. Understanding the maintenance of horn type and length variation will require an investigation of selection on genotypes that (co)determine both traits.
DOI:10.1111/j.1365-294X.2011.05076.xURL [本文引用: 4]
Understanding the genetic architecture of phenotypic variation in natural populations is a fundamental goal of evolutionary genetics. Wild Soay sheep (Ovis aries) have an inherited polymorphism for horn morphology in both sexes, controlled by a single autosomal locus, Horns. The majority of males have large normal horns, but a small number have vestigial, deformed horns, known as scurs; females have either normal horns, scurs or no horns (polled). Given that scurred males and polled females have reduced fitness within each sex, it is counterintuitive that the polymorphism persists within the population. Therefore, identifying the genetic basis of horn type will provide a vital foundation for understanding why the different morphs are maintained in the face of natural selection. We conducted a genome-wide association study using similar to 36 000 single nucleotide polymorphisms (SNPs) and determined the main candidate for Horns as RXFP2, an autosomal gene with a known involvement in determining primary sex characters in humans and mice. Evidence from additional SNPs in and around RXFP2 supports a new model of horn-type inheritance in Soay sheep, and for the first time, sheep with the same horn phenotype but different underlying genotypes can be identified. In addition, RXFP2 was shown to be an additive quantitative trait locus (QTL) for horn size in normal-horned males, accounting for up to 76% of additive genetic variation in this trait. This finding contrasts markedly from genome-wide association studies of quantitative traits in humans and some model species, where it is often observed that mapped loci only explain a modest proportion of the overall genetic variation.
DOI:10.1038/nature12489URL [本文引用: 3]
Sexual selection, through intra-male competition or female choice, is assumed to be a source of strong and sustained directional selection in the wild(1,2). In the presence of such strong directional selection, alleles enhancing a particular trait are predicted to become fixed within a population, leading to a decrease in the underlying genetic variation(3). However, there is often considerable genetic variation underlying sexually selected traits in wild populations, and consequently, this phenomenon has become a long-discussed issue in the field of evolutionary biology(1,4,5). In wild Soay sheep, large horns confer an advantage in strong intra-sexual competition, yet males show an inherited polymorphism for horn type and have substantial genetic variation in their horn size(6). Here we show that most genetic variation in this trait is maintained by a trade-off between natural and sexual selection at a single gene, relaxin-like receptor 2 (RXFP2). We found that an allele conferring larger horns, Ho+, is associated with higher reproductive success, whereas a smaller horn allele, Ho-P, confers increased survival, resulting in a net effect of overdominance (that is, heterozygote advantage) for fitness at RXFP2. The nature of this trade-off is simple relative to commonly proposed explanations for the maintenance of sexually selected traits, such as genic capture(7,8) ('good genes') and sexually antagonistic selection(5,9). Our results demonstrate that by identifying the genetic architecture of trait variation, we can determine the principal mechanisms maintaining genetic variation in traits under strong selection and explain apparently counter-evolutionary observations.
DOI:10.1111/age.12309URLPMID:26103004 [本文引用: 2]
Sheep breeds show a broad spectrum of different horn phenotypes. In most modern production breeds, sheep are polled (absence of horns), whereas horns occur mainly in indigenous breeds. Previous studies mapped the responsible locus to the region of the RXFP2 gene on ovine chromosome 10. A 4-kb region of the 3'-end of RXFP2 was amplified in horned and polled animals from seven Swiss sheep breeds. Sequence analysis identified a 1833-bp genomic insertion located in the 3'-UTR region of RXFP2 present in polled animals only. An efficient PCR-based genotyping method to determine the polled genotype of individual sheep is presented. Comparative sequence analyses revealed evidence that the polled-associated insertion adds a potential antisense RNA sequence of EEF1A1 to the 3'-end of RXFP2 transcripts.
DOI:10.1016/j.smallrumres.2013.10.022URL [本文引用: 3]
DOI:10.1186/s12711-016-0256-3URLPMID:27760516 [本文引用: 1]
BACKGROUND: The mode of inheritance of horn status in sheep is far more complex than a superficial analysis might suggest. Observations, which were mostly based on crossbreeding experiments, indicated that the allele that results in horns is dominant in males and recessive in females, and some authors even speculated about the involvement of more than two alleles. However, all recent genome-wide association analyses point towards a very strong effect of a single autosomal locus on ovine chromosome 10, which was narrowed down to a putatively causal insertion polymorphism in the 3'-untranslated region of the relaxin/insulin-like family peptide receptor 2 gene (RXFP2). The main objective of this study was to test this insertion polymorphism as the causal mutation in diverse sheep breeds, including breeds with a variable and/or sex-dependent horn status. RESULTS: After re-sequencing a region of about 246 kb that covered the RFXP2 gene and its flanking regions for 24 sheep from six completely horned and six completely polled breeds, we identified the same insertion polymorphism that was previously published as segregating with horn status in these breeds. Multiplex PCR genotyping of 489 sheep from 34 breeds and some crosses between sheep breeds showed a nearly perfect segregation of the insertion polymorphism with horn status in sheep breeds of Central and Western European origin. In these breeds and their crossings, heterozygous males were horned and heterozygous females were polled. However, this segregation pattern was not, or at least not completely, reproducible in breeds with sex-dependent and/or variable horn status, especially in sheep that originated from even more southern European regions and from Africa. In such breeds, we observed almost all possible combinations of genotype, sex and horn status phenotype. CONCLUSIONS: The 1.78-kb insertion polymorphism in the 3'-untranslated region of RXFP2 and SNPs in the 3'-UTR, exon 14 and intron 11 of this gene that we analyzed in this study cannot be considered as the only cause of polledness in sheep and are not useful as a universal marker to define the genetic horn status in sheep.
DOI:10.7717/peerj.4364URL [本文引用: 1]
DOI:10.1093/gigascience/gix134URLPMID:29300887 [本文引用: 2]
Background: Characterization of genetic variations in maize has been challenging, mainly due to deterioration of collinearity between individual genomes in the species. An international consortium of maize research groups combined resources to develop the maize haplotype version 3 (HapMap 3), built from whole-genome sequencing data from 1218 maize lines, covering predomestication and domesticated Zea mays varieties across the world. Results: A new computational pipeline was set up to process more than 12 trillion bp of sequencing data, and a set of population genetics filters was applied to identify more than 83 million variant sites. Conclusions: We identified polymorphisms in regions where collinearity is largely preserved in the maize species. However, the fact that the B73 genome used as the reference only represents a fraction of all haplotypes is still an important limiting factor.
DOI:10.1086/281224URL [本文引用: 1]
DOI:10.1016/j.jas.2009.12.024URL [本文引用: 1]
Abstract
Archaeological finds of a ritual character from Hostivice–Litovice are classed as Eneolithic cattle burials (depositions). One pit from the Funnel Beaker Period (Baalberge group; ca. 3800–3500 BC) contained a subadult bovine skeleton, whose skull bore loose horns (scurs) while still alive. This type of horn, which is movable or possibly hanging, is known from recent breeds and is caused by a special combination of alleles on two locuses and its phenotypic expression is sexually specific. However, this can also be simply a pathological state (teratology, atrophy, dysplasia or fractures), possibly caused by deliberate deformative manipulation on the horns. Such manipulations are known from recent breeding as well as from the prehistory. Both possible causations of this unique find from Hostivice–Litovice and related finds of hornlessness are discussed.DOI:10.1111/j.1365-2052.2003.01079.xURLPMID:14731227 [本文引用: 2]
Polled, or the absence of horns, is a desirable trait for many cattle breeders. However, the presence of scurs, which are small horn-like structures that are not attached to the skull, can lower the value of an animal. The scurs trait has been reported as sex influenced. Using a genome scan with 162 autosomal microsatellite markers genotyped across three full-sib families, the scurs locus was mapped near BMS2142 on cattle chromosome 19 (LOD = 4.21). To more precisely map scurs, the families from the initial analysis and three additional families were genotyped for 16 microsatellite markers and SNPs in three genes on chromosome 19. In this subsequent analysis, the scurs locus was mapped 4 cM distal of BMS2142 (LOD = 4.46) and 6 cM proximal to IDVGA46 (LOD = 2.56). ALOX12 and MFAP4 were the closest genes proximal and distal, respectively, to the scurs locus. Three microsatellite markers on the X chromosome were genotyped across these six families but were not linked to scurs, further demonstrating that this trait was not sex linked. Because the polled locus has been mapped to the centromeric end of chromosome 1 and scurs has now been mapped to chromosome 19, these two traits are not linked in Bos taurus.
DOI:10.1371/journal.pone.0022242URLPMID:21814570 [本文引用: 3]
The developmental pathways involved in horn development are complex and still poorly understood. Here we report the description of a new dominant inherited syndrome in the bovine Charolais breed that we have named type 2 scurs. Clinical examination revealed that, despite a strong phenotypic variability, all affected individuals show both horn abnormalities similar to classical scurs phenotype and skull interfrontal suture synostosis. Based on a genome-wide linkage analysis using Illumina BovineSNP50 BeadChip genotyping data from 57 half-sib and full-sib progeny, this locus was mapped to a 1.7 Mb interval on bovine chromosome 4. Within this region, the TWIST1 gene encoding a transcription factor was considered as a strong candidate gene since its haploinsufficiency is responsible for the human Saethre-Chotzen syndrome, characterized by skull coronal suture synostosis. Sequencing of the TWIST1 gene identified a c.148_157dup (p.A56RfsX87) frame-shift mutation predicted to completely inactivate this gene. Genotyping 17 scurred and 20 horned founders of our pedigree as well as 48 unrelated horned controls revealed a perfect association between this mutation and the type 2 scurs phenotype. Subsequent genotyping of 32 individuals born from heterozygous parents showed that homozygous mutated progeny are completely absent, which is consistent with the embryonic lethality reported in Drosophila and mouse suffering from TWIST1 complete insufficiency. Finally, data from previous studies on model species and a fine description of type 2 scurs symptoms allowed us to propose different mechanisms to explain the features of this syndrome. In conclusion, this first report on the identification of a potential causal mutation affecting horn development in cattle offers a unique opportunity to better understand horn ontogenesis.
DOI:10.1007/BF02982500URL [本文引用: 2]
DOI:10.1186/1471-2156-10-33URLPMID:19575823 [本文引用: 2]
BACKGROUND: Polled animals are valued in cattle industry because the absence of horns has a significant economic impact. However, some cattle are neither polled nor horned but have so-called scurs on their heads, which are corneous growths loosely attached to the skull. A better understanding of the genetic determinism of the scurs phenotype would help to fine map the polled locus. To date, only one study has attempted to map the scurs locus in cattle. Here, we have investigated the inheritance of the scurs phenotype in the French Charolais breed and examined whether the previously proposed localisation of the scurs locus on bovine chromosome 19 could be confirmed or not. RESULTS: Our results indicate that the inheritance pattern of the scurs phenotype in the French Charolais breed is autosomal recessive with complete penetrance in both sexes, which is different from what is reported for other breeds. The frequency of the scurs allele (Sc) reaches 69.9% in the French Charolais population. Eleven microsatellite markers on bovine chromosome 19 were genotyped in 267 offspring (33 half-sib and full-sib families). Both non-parametric and parametric linkage analyses suggest that in the French Charolais population the scurs locus may not map to the previously identified region. A new analysis of an Angus-Hereford and Hereford-Hereford pedigree published in 1978 enabled us to calculate the frequency of the Sc allele in the Hereford breed (89.4%) and to study the penetrance of this allele in males heterozygous for both polled and scurs loci (40%). This led us to revise the inheritance pattern of the scurs phenotype proposed for the Hereford breed and to suggest that allele Sc is not fully but partially dominant in double heterozygous males while it is always recessive in females. Crossbreeding involving the Charolais breed and other breeds gave results similar to those reported in the Hereford breed. CONCLUSION: Our results suggest the existence of unknown genetics factors modifying the expression of the scurs locus in double heterozygous Hereford and Angus males. The specific inheritance pattern of the scurs locus in the French Charolais breed represents an opportunity to map this gene and to identify the molecular mechanisms regulating the growth of horns in cattle.
DOI:10.1016/S2095-3119(17)61894-XURL [本文引用: 2]
URLPMID:2199285 [本文引用: 1]
Cell-cell and cell-substratum interactions are mediated through several different families of receptors. In addition to targeting cell adhesion to specific extracellular matrix proteins and ligands on adjacent cells, these receptors influence many diverse processes including cellular growth, differentiation, junction formation, and polarity. Several families of adhesion receptors have been identified. These include: 1) the integrins, heterodimeric molecules that function both as cell-substratum and cell-cell adhesion receptors; 2) the adhesion molecules of the immunoglobulin superfamily, which are involved in cell-cell adhesion and especially important during embryo-genesis, wound healing, and the inflammatory response; 3) the cadherins, developmentally regulated, calcium-dependent homophilic cell-cell adhesion proteins; 4) the LEC-CAMs, cell adhesion molecules with lectin-like domains that mediate white blood cell/endothelial cell adhesion; and 5) homing receptors that target lymphocytes to specific lymphoid tissue. In this review we summarize recent data describing the structure and function of some of these cell adhesion molecules (with special emphasis on the integrin family) and discuss the possible role of these molecules in development, inflammation, wound healing, coagulation, and tumor metastasis.
DOI:10.1186/1471-2350-12-174URLPMID:22208904 [本文引用: 1]
BACKGROUND: Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs. METHODS: The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery. RESULTS: The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways. CONCLUSION: This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.
DOI:10.4137/BMI.S25132URLPMID:25922570 [本文引用: 1]
BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia with no curative therapy currently available. Establishment of sensitive and non-invasive biomarkers that promote an early diagnosis of AD is crucial for the effective administration of disease-modifying drugs. MicroRNAs (miRNAs) mediate posttranscriptional repression of numerous target genes. Aberrant regulation of miRNA expression is implicated in AD pathogenesis, and circulating miRNAs serve as potential biomarkers for AD. However, data analysis of numerous AD-specific miRNAs derived from small RNA-sequencing (RNA-Seq) is most often laborious. METHODS: To identify circulating miRNA biomarkers for AD, we reanalyzed a publicly available small RNA-Seq dataset, composed of blood samples derived from 48 AD patients and 22 normal control (NC) subjects, by a simple web-based miRNA data analysis pipeline that combines omiRas and DIANA miRPath. RESULTS: By using omiRas, we identified 27 miRNAs expressed differentially between both groups, including upregulation in AD of miR-26b-3p, miR-28-3p, miR-30c-5p, miR-30d-5p, miR-148b-5p, miR-151a-3p, miR-186-5p, miR-425-5p, miR-550a-5p, miR-1468, miR-4781-3p, miR-5001-3p, and miR-6513-3p and downregulation in AD of let-7a-5p, let-7e-5p, let-7f-5p, let-7g-5p, miR-15a-5p, miR-17-3p, miR-29b-3p, miR-98-5p, miR-144-5p, miR-148a-3p, miR-502-3p, miR-660-5p, miR-1294, and miR-3200-3p. DIANA miRPath indicated that miRNA-regulated pathways potentially downregulated in AD are linked with neuronal synaptic functions, while those upregulated in AD are implicated in cell survival and cellular communication. CONCLUSIONS: The simple web-based miRNA data analysis pipeline helps us to effortlessly identify candidates for miRNA biomarkers and pathways of AD from the complex small RNA-Seq data.
DOI:10.1186/1471-2164-11-370URL [本文引用: 2]
DOI:10.1155/2015/920280URLPMID:25695094 [本文引用: 1]
Prolonged hyperglycemia is an important risk factor of the pathogenesis of diabetic retinopathy (DR). Extracellular matrix molecules, such as fibronectin, collagen IV, and laminin, are associated with fibrotic membranes. In this study, we investigated the expression of fibronectin, collagen IV, and laminin in RPE cells under high glucose conditions. Furthermore, we also detected the phosphorylation of protein kinase B (Akt) under high glucose conditions in RPE cells. Our results showed that high glucose upregulated fibronectin, collagen IV, and laminin expression, and activated Akt in RPE cells. We also found that pretreatment with LY294002 (an inhibitor of phosphatidylinositol 3-kinase) abolished high glucose-induced expression of fibronectin, collagen IV, and laminin in RPE cells. Thus, high glucose induced the expression of fibronectin, collagen IV, and laminin through PI3K/Akt signaling pathway in RPE cells, and the PI3K/Akt signaling pathway may contribute to the formation of fibrotic membrane during the development of DR.
[本文引用: 1]
DOI:10.1007/BF02983113URL [本文引用: 1]
[本文引用: 8]
DOI:10.1146/annurev.cellbio.042308.113245URLPMID:19575671 [本文引用: 3]
The neural crest is a multipotent stem cell–like population that gives rise to a wide range of derivatives in the vertebrate embryo including elements of the craniofacial skeleton and peripheral nervous system as well as melanocytes. The neural crest forms in a series of regulatory steps that include induction and specification of the prospective neural crest territory–neural plate border, specification of bona fide neural crest progenitors, and differentiation into diverse derivatives. These individual processes during neural crest ontogeny are controlled by regulatory circuits that can be assembled into a hierarchical gene regulatory network (GRN). Here we present an overview of the GRN that orchestrates the formation of cranial neural crest cells. Formulation of this network relies on information largely inferred from gene perturbation studies performed in several vertebrate model organisms. Our representation of the cranial neural crest GRN also includes information about direct regulatory interactions obtained from the cis-regulatory analyses performed to date, which increases the resolution of the architectural circuitry within the network.
DOI:10.1111/age.12237URLPMID:25645725 [本文引用: 1]
DOI:10.3340/jkns.2016.59.3.192URLPMID:27226848 [本文引用: 2]
Understanding the development of a skull deformity requires an understanding of the normal morphogenesis of the cranium. Craniosynostosis is the premature, pathologic ossification of one or more cranial sutures leading to skull deformities. A review of the English medical literature using textbooks and standard search engines was performed to gather information about the prenatal development and growth of the cranial vault of the neurocranium. A process of morphogenic sequencing begins during prenatal development and growth, continues postnatally, and contributes to the basis for the differential manner of growth of cranial vault bones. This improved knowledge might facilitate comprehension of the pathophysiology of craniosynostosis.
DOI:10.1387/ijdb.170051gcURLPMID:29139535 [本文引用: 2]
The mammalian skull vault is a highly regulated structure that evolutionally protects brain growth during vertebrate development. It consists of several membrane bones with different tissue origins (e.g. neural crest-derived frontal bone and mesoderm-derived parietal bone). Although membrane bones are formed through intramembranous ossification, the neural crest-derived frontal bone has superior capabilities for osteoblast activities and bone regeneration via TGF, BMP, Wnt, and FGF signaling pathways. Neural crest (NC) cells are multipotent, and once induced, will follow specific paths to migrate to different locations of the body where they give rise to a diverse array of cell types and tissues. Recent studies using genetic mouse models have greatly advanced our knowledge of NC cell induction, proliferation, migration and differentiation. Perturbations or disruptions of neural crest patterning lead to severe developmental defects or diseases. This review summarizes recent discoveries including novel functions of genes or signaling molecules that are capable of governing developmental processes of neural crest patterning, which may function as a gene regulatory network in controlling skull development. The proposed regulatory network will be important to understand how the signaling pathways and genes converge to regulate osteoblast activities and bone formation, which will be beneficial for the potential identification of molecular targets to prevent or alleviate human diseases or disorders involving defective neural crest development.
DOI:10.1172/JCI39104URLPMID:19487818 [本文引用: 1]
The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
DOI:10.1371/journal.pone.0099331URLPMID:24971743 [本文引用: 1]
BACKGROUND: Twist1 and Twist2 are highly homologous bHLH transcription factors that exhibit extensive highly overlapping expression profiles during development. While both proteins have been shown to inhibit osteogenesis, only Twist1 haploinsufficiency is associated with the premature synostosis of cranial sutures in mice and humans. On the other hand, biallelic Twist2 deficiency causes only a focal facial dermal dysplasia syndrome or additional cachexia and perinatal lethality in certain mouse strains. It is unclear how these proteins cooperate to synergistically regulate bone formation. METHODS: Twist1 floxed mice (Twist1(f/f)) were bred with Twist2-Cre knock-in mice (Twist2(Cre/+)) to generate Twist1 and Twist2 haploinsufficient mice (Twist1(f/+); Twist2(Cre/+)). X-radiography, micro-CT scans, alcian blue/alizarin red staining, trap staining, BrdU labeling, immunohistochemistry, in situ hybridizations, real-time PCR and dual luciferase assay were employed to investigate the overall skeletal defects and the bone-associated molecular and cellular changes of Twist1(f/+);Twist2(Cre/+) mice. RESULTS: Twist1 and Twist2 haploinsufficient mice did not present with premature ossification and craniosynostosis; instead they displayed reduced bone formation, impaired proliferation and differentiation of osteoprogenitors. These mice exhibited decreased expressions of Fgf2 and Fgfr1-4 in bone, resulting in a down-regulation of FGF signaling. Furthermore, in vitro studies indicated that both Twist1 and Twist2 stimulated 4.9 kb Fgfr2 promoter activity in the presence of E12, a Twist binding partner. CONCLUSION: These data demonstrated that Twist1- and Twist2-haploinsufficiency caused reduced bone formation due to compromised FGF signaling.
DOI:10.1242/jcs.000067URLPMID:17374642 [本文引用: 1]
Basic helix-loop-helix (bHLH) transcription factors are known as key regulators for mesenchymal differentiation. The present study showed that overexpression of Twist-1, a bHLH transcription factor, suppresses bone morphogenetic protein (BMP)-induced osteoblast differentiation, and downregulation of endogenous Twist-1 enhances BMP signaling. Maximal inhibition of BMP signaling was observed when Twist-1 was bound to E47, which markedly enhanced the stability of Twist-1. Co-immunoprecipitation assays revealed that Twist-1 formed a complex with Smad4 and histone deacetylase (HDAC) 1 in MC3T3-E1 cells stably expressing Twist-1. With trichostatin, an HDAC inhibitor, osteogenic factors such as alkaline phosphatase, Runx2 and osteopontin increased. Those results suggested that Twist-1 inhibited BMP signaling by recruiting HDAC1 to Smad4. Furthermore, the inhibitory effects of Twist-1 on BMP signaling were overcome by Id1 through induction of Twist-1 degradation. These findings suggest that Twist-1 can act as an inhibitor of BMP signaling, and Id1 can regulate BMP signaling through a positive feedback loop repressing Twist-1 function. These two molecules may therefore regulate differentiation of mesenchymal cells into progeny such as osteoblasts by controlling BMP signaling.
DOI:10.1002/jcp.25797URLPMID:28079253 [本文引用: 1]
The lineage transition between epithelium and mesenchyme is a process known as epithelial-mesenchymal transition (EMT), by which polarized epithelial cells lose their adhesion property and obtain mesenchymal cell phenotypes. EMT is a biological process that is often involved in embryogenesis and diseases, such as cancer invasion and metastasis. The EMT and the reverse process, mesenchymal-epithelial transition (MET), also play important roles in stem cell differentiation and de-differentiation (or reprogramming). In this review, we will discuss current research progress of EMT in embryonic development, cellular differentiation and reprogramming, and cancer progression, all of which are representative models for researches of stem cell biology in normal and in diseases. Understanding of EMT and MET may help to identify specific markers to distinguish normal stem cells from cancer stem cells in future.
DOI:10.1359/jbmr.080204URLPMID:18433302 [本文引用: 1]
INTRODUCTION: Insulin-like factor 3 (INSL3) is produced primarily by testicular Leydig cells. It acts by binding to its specific G protein-coupled receptor RXFP2 (relaxin family peptide 2) and is involved in testicular descent during fetal development. The physiological role of INSL3 in adults is not known, although substantial INSL3 circulating levels are present. The aim of this study was to verify whether reduced INSL3 activity could cause or contribute to some signs of hypogonadism, such as reduced BMD, currently attributed to testosterone deficiency. MATERIALS AND METHODS: Extensive clinical, biochemical, and hormonal study, including bone densitometry by DXA, was performed on 25 young men (age, 27-41 yr) with the well-characterized T222P mutation in the RXFP2 gene. Expression analysis of INSL3 and RXFP2 on human bone biopsy and human and mouse osteoblast cell cultures was performed by RT-PCR, quantitative RT-PCR, and immunohistochemistry. Real-time cAMP imaging analysis and proliferation assay under the stimulus of INSL3 was performed on these cells. Lumbar spine and femoral bone of Rxfp2-deficient mice were studied by static and dynamic histomorphometry and muCT, respectively. RESULTS: Sixteen of 25 (64%) young men with RXFP2 mutations had significantly reduced BMD. No other apparent cause of osteoporosis was evident in these subjects, whose testosterone levels and gonadal function were normal. Expression analyses showed the presence of RXFP2 in human and mouse osteoblasts. Stimulation of these cells with INSL3 produced a dose- and time-dependent increase in cAMP and cell proliferation, confirming the functionality of the RXFP2/INSL3 receptor-ligand complex. Consistent with the human phenotype, bone histomorphometric and muCT analyses of Rxfp2(-/-) mice showed decreased bone mass, mineralizing surface, bone formation, and osteoclast surface compared with wildtype littermates. CONCLUSIONS: This study suggests for the first time a role for INSL3/RXFP2 signaling in bone metabolism and links RXFP2 gene mutations with human osteoporosis.
[本文引用: 1]
DOI:10.1111/age.12531URLPMID:28111759 [本文引用: 1]
In the horse, the term occipitoatlantoaxial malformation (OAAM) is used to describe a developmental defect in which the first cervical vertebra (atlas) resembles the base of the skull (occiput) and the second cervical vertebra (axis) resembles the atlas. Affected individuals demonstrate an abnormal posture and varying degrees of ataxia. The homeobox (HOX) gene cluster is involved in the development of both the axial and appendicular skeleton. Hoxd3-null mice demonstrate a strikingly similar phenotype to Arabian foals with OAAM. Whole-genome sequencing was performed in an OAAM-affected horse (OAAM1) and seven unaffected Arabian horses. Visual inspection of the raw reads within the region of HOXD3 identified a 2.7-kb deletion located 4.4 kb downstream of the end of HOXD4 and 8.2 kb upstream of the start of HOXD3. A genotyping assay revealed that both parents of OAAM1 were heterozygous for the deletion. Additional genotyping identified two of 162 heterozygote Arabians, and the deletion was not present in 371 horses of other breeds. Comparative genomics studies have revealed that this region is highly conserved across species and that the entire genomic region between Hoxd4 and Hoxd3 is transcribed in mice. Two additional Arabian foals diagnosed with OAAM (OAAM 2 and 3) were genotyped and did not have the 2.7-kb deletion. Closer examination of the phenotype in these cases revealed notable variation. OAAM3 also had facial malformations and a patent ductus arteriosus, and the actual malformation at the craniocervical junction differed. Genetic heterogeneity may exist across the HOXD locus in Arabian foals with OAAM.
DOI:10.1086/302070URLPMID:9758628 [本文引用: 1]
Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation consisting of 3/4 syndactyly in the hands and 4/5 syndactyly in the feet, with digit duplication in the syndactylous web. The condition recently has been found to result from different-sized expansions of an amino-terminal polyalanine tract in HOXD13. We report a novel type of mutation in HOXD13, associated in some cases with features of classic SPD and in all cases with a novel foot phenotype. In two unrelated families, each with a different intragenic deletion in HOXD13, all mutation carriers have a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. This phenotype has not been reported in any mice with genetic modifications of the HoxD gene cluster. The two different deletions affect the first exon and the homeobox, respectively, in each case producing frameshifts followed by a long stretch of novel sequence and a premature stop codon. Although the affected genes may encode proteins that exert a dominant negative or novel effect, they are most likely to act as null alleles. Either possibility has interesting implications for the role of HOXD13 in human autopod development.
DOI:10.1002/dvdy.23756URLPMID:22374744 [本文引用: 1]
BACKGROUND: Four posterior Hoxd genes, from Hoxd13 to Hoxd10, are collectively regulated during the development of tetrapod digits. Besides the well-documented role of Hoxd13, the function of the neighboring genes has been difficult to evaluate due to the close genetic linkage and potential regulatory interferences. We used a combination of five small nested deletions in cis, involving from two to four consecutive genes of the Hoxd13 to Hoxd9 loci, in mice, to evaluate their combined functional importance. RESULTS: We show that deletions leading to a gain of function of Hoxd13, via regulatory re-allocation, generate abnormal phenotypes, in agreement with the dominant negative role of this gene. We also show that Hoxd10, Hoxd11, and Hoxd12 all seem to play a genuine role in digit development, though less compelling than that of Hoxd13. In contrast, the nearby Hoxd9 contributed no measurable function in digits. CONCLUSIONS: We conclude that a slight and transient deregulation of Hoxd13 expression can readily affect the relative lengths of limb segments and that all posterior Hoxd genes likely contribute to the final limb morphology. We discuss the difficulty to clearly assess the functional share of individual genes within such a gene family, where closely located neighbors, coding for homologous proteins, are regulated by a unique circuitry and all contribute to shape the distal parts of our appendages.
DOI:10.1101/gad.281055.116URLPMID:27198226 [本文引用: 1]
During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.
DOI:10.1101/gad.283598.116URLPMID:27222515 [本文引用: 1]
The striking correlation between the genomic arrangement of Hox genes and their temporal and spatial pattern of expression during embryonic development has been a source of fascination since its discovery. This correspondence has been used as a privileged example in the investigation of the connection between genomic architecture and function. In this issue of Genes & Development, Beccari and colleagues (pp. 1172-1186) make a big step forward in understanding Hox gene regulation during limb development by showing the pivotal role of HOXA13 and HOXD13 proteins in the transition from a proximal to a distal type of Hoxd transcriptional regulation.
DOI:10.1371/journal.pgen.1006567URLPMID:28103242 [本文引用: 1]
Homeotic genes code for key transcription factors (HOX-TFs) that pattern the animal body plan. During embryonic development, Hox genes are expressed in overlapping patterns and function in a partially redundant manner. In vitro biochemical screens probing the HOX-TF sequence specificity revealed largely overlapping sequence preferences, indicating that co-factors might modulate the biological function of HOX-TFs. However, due to their overlapping expression pattern, high protein homology, and insufficiently specific antibodies, little is known about their genome-wide binding preferences. In order to overcome this problem, we virally expressed tagged versions of limb-expressed posterior HOX genes (HOXA9-13, and HOXD9-13) in primary chicken mesenchymal limb progenitor cells (micromass). We determined the effect of each HOX-TF on cellular differentiation (chondrogenesis) and gene expression and found that groups of HOX-TFs induce distinct regulatory programs. We used ChIP-seq to determine their individual genome-wide binding profiles and identified between 12,721 and 28,572 binding sites for each of the nine HOX-TFs. Principal Component Analysis (PCA) of binding profiles revealed that the HOX-TFs are clustered in two subgroups (Group 1: HOXA/D9, HOXA/D10, HOXD12, and HOXA13 and Group 2: HOXA/D11 and HOXD13), which are characterized by differences in their sequence specificity and by the presence of cofactor motifs. Specifically, we identified CTCF binding sites in Group 1, indicating that this subgroup of HOX-proteins cooperates with CTCF. We confirmed this interaction by an independent biological assay (Proximity Ligation Assay) and demonstrated that CTCF is a novel HOX cofactor that specifically associates with Group 1 HOX-TFs, pointing towards a possible interplay between HOX-TFs and chromatin architecture.
DOI:10.1002/jemt.22681URLPMID:27184115 [本文引用: 1]
The sheep horn presents outstanding mechanical properties of impact resistance and energy absorption, which suits the need of the vehicle bumper design, but the mechanism behind this phenomenon is less investigated. The microstructure and mechanical properties of the sheep horn of Small Tailed Han Sheep (Ovis aries) living in northeast China were investigated in this article. The effect of sampling position and orientation of the sheep horn sheath on mechanical properties were researched by tensile and compression tests. Meanwhile, the surface morphology and microstructure of the sheep horn were observed using scanning electron microscopy (SEM). The formation mechanism of the mechanical properties of the sheep horn was investigated by biological coupling analysis. The analytical results indicated that the outstanding mechanical properties of the sheep horn are determined by configuration, structure, surface morphology and material coupling elements. These biological coupling elements make the sheep horn possess super characteristics of crashworthiness and energy absorption through the internal coupling mechanism. We suppose that these findings would make a difference in vehicle bumper design. Microsc. Res. Tech. 79:664-674, 2016. (c) 2016 Wiley Periodicals, Inc.
DOI:10.1016/j.semcdb.2016.01.010URLPMID:26805722 [本文引用: 1]
Various ultradian rhythms ensure proper temporal regulations during embryo development. The embryo molecular clock, which was first identified in the presomitic mesoderm (PSM) underlying periodic somite formation, is one among them. Somites are the earliest manifestation of the segmented vertebrate body and they are formed with strict temporal precision. The tetrapod limb is also a segmented structure and the formation of limb bone elements have also been associated with a molecular clock, operating in the distal limb mesenchyme. In both the PSM and the distal limb mesenchyme, the molecular clock (MC) is influenced by FGF, SHH and RA, which are also the key regulators of the development of these tissues. While somitogenesis has been continuously scrutinized to understand the mechanisms of the MC, the limb bud has served as an outstanding paradigm to study how a cohort of undifferentiated cells is organized into functional 3D structures. The fact that both the trunk and limb development are shaped by the MC and by common signaling molecules has prompted the exciting possibility of establishing parallelisms between somitogenesis and limb development. Systematically correlating various parameters during trunk and limb development will help us to appreciate the common principles underlying segmented structure formation and allow the rise of new questions in order to fill the gaps in our present understanding. In this review we have established the parallelisms between somitogenesis and limb development at the level of gene expression patterns and their regulation. Finally, we have also discussed the most evident new avenues this exercise could open to the scientific community.
DOI:10.1126/science.aax8961URLPMID:31221842 [本文引用: 1]
