劉剛，孫飛舟，朱芳賢，馮海永，韓旭

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連續(xù)性純合片段在畜禽基因組研究中的應(yīng)用

劉剛，孫飛舟，朱芳賢，馮海永，韓旭

全國(guó)畜牧總站，北京 100193

隨著高通量SNP芯片技術(shù)的快速發(fā)展和測(cè)序成本的大幅降低，SNP基因芯片和基因組重測(cè)序等技術(shù)被廣泛地應(yīng)用于畜禽基因組研究中。在基因組某一段區(qū)域內(nèi)，當(dāng)一定數(shù)量和一定密度的SNPs表現(xiàn)為純合時(shí)，可以判定該區(qū)域存在連續(xù)性純合片段(runs of homozygosity, ROH)。目前，連續(xù)性純合片段已經(jīng)逐漸成為分析畜禽群體近交程度、遺傳結(jié)構(gòu)等方面的重要指標(biāo)之一。但是，ROH計(jì)算應(yīng)用的評(píng)價(jià)標(biāo)準(zhǔn)還相對(duì)匱乏。本文系統(tǒng)介紹了連續(xù)性純合片段的發(fā)展歷史、原理、鑒定方法以及在畜禽群體結(jié)構(gòu)解析、基因組功能分析和種畜禽品質(zhì)檢測(cè)等方面的應(yīng)用情況，以期為畜禽遺傳資源保種區(qū)和保種場(chǎng)在遺傳多樣性等動(dòng)態(tài)監(jiān)測(cè)方面提供參考。

高通量測(cè)序技術(shù)；連續(xù)性純合片段；群體結(jié)構(gòu)；基因組功能；遺傳缺陷

單核苷酸多態(tài)性(single nucleotide ploymorhph-isms, SNPs)是畜禽基因組中最常見的遺傳變異，一般指在畜禽群體中頻率大于1%單個(gè)核苷酸的變異，包括轉(zhuǎn)換、顛換、缺失和插入。在基因組某一段區(qū)域內(nèi)，當(dāng)一定數(shù)量一定密度的SNPs表現(xiàn)為純合時(shí)，可以判定該區(qū)域存在連續(xù)性純合片段(runs of homo-zygosity, ROH)[1]。大量研究表明，ROH信息在畜禽、植物和人類群體近交程度和監(jiān)測(cè)方面發(fā)揮著越來(lái)越重要的作用[2~6]。通過(guò)鑒別和分析ROH分布和頻率等指標(biāo)，可以深入剖析群體在世代間演變的歷程，從而揭示這些群體經(jīng)過(guò)系列變化后基因組中純合片段的模式[7~9]，也可以評(píng)估群體近交水平和群體中個(gè)體間的親緣關(guān)系，進(jìn)一步分析群體選擇壓力和交配模式等[10~12]。利用SNP基因芯片技術(shù)分析基因組中ROH是分析同源遺傳關(guān)系(identical by descent, IBD)的有效方法[1,13]。通過(guò)SNP基因芯片技術(shù)對(duì)畜禽群體進(jìn)行分析，可以獲得同一群體不同世代動(dòng)態(tài)變化的信息，如監(jiān)測(cè)群體有效含量[14,15]和種公畜間近交系數(shù)[16]等。

1999年，Broman和Weber[7]首次發(fā)現(xiàn)并分析了人類染色體上長(zhǎng)純合片段，結(jié)果表明純合片段的長(zhǎng)短與人類健康相關(guān)。Gibson等[1]首次利用高密度SNP基因芯片技術(shù)分析了人類染色體上純合片段的長(zhǎng)度、頻率和分布情況等，解析了人類基因組中存在ROH的機(jī)理[2,15,17]。隨著畜禽SNP基因芯片和重測(cè)序技術(shù)的廣泛應(yīng)用[18~20]，基于畜禽基因組信息的ROH研究也與日俱增。如Marras等[21]對(duì)牛()基因組ROH頻率和分布情況等指標(biāo)進(jìn)行了分析；此外，在牛[4,10,21~24]、豬()[8,9,25~29]、馬([30~33]、綿羊()[34~37]、山羊()[38,39]和雞()[40~42]等畜禽群體結(jié)構(gòu)和群體演變歷史等研究中也利用了ROH特征信息。

本文主要綜述了ROH的原理和方法以及在畜禽群體結(jié)構(gòu)、基因組功能分析和種畜禽品質(zhì)檢測(cè)等方面的應(yīng)用，以期為相關(guān)研究提供參考。

1 連續(xù)性純合片段產(chǎn)生的原理

祖先單倍型相同的兩個(gè)拷貝聚集在一個(gè)個(gè)體時(shí)會(huì)產(chǎn)生純合片段，長(zhǎng)單倍型片段來(lái)源于最近共同祖先，短單倍型片段來(lái)源于親緣關(guān)系較遠(yuǎn)的共同祖先。由于親緣關(guān)系較遠(yuǎn)個(gè)體基因組位點(diǎn)之間的強(qiáng)連鎖不平衡形成了短ROH，不同類型群體可以產(chǎn)生長(zhǎng)短不一的ROH發(fā)散分布。在遠(yuǎn)交群體中ROH產(chǎn)生取決于群體有效含量()，在小的群體中存在更多的ROH，而越大的群體會(huì)產(chǎn)生較少的ROH。由于混合種群血統(tǒng)來(lái)源于兩個(gè)或者更多親緣關(guān)系較遠(yuǎn)的群體，因而比它們祖先群體的ROH少。由于近交群體經(jīng)歷了瓶頸效應(yīng)，尤其在個(gè)體間親緣關(guān)系比較遠(yuǎn)的情況下，會(huì)產(chǎn)生數(shù)量較多的短ROH。但是，隨著世代的交替，群體有效含量會(huì)越來(lái)越小，同時(shí)，由于近期近交事件的發(fā)生，從而在群體基因組片段中出現(xiàn)越來(lái)越多長(zhǎng)短不一的ROH[43]。研究表明，ROH更多地富集在有害突變個(gè)體中，而在非有害突變個(gè)體中聚集較少；即使有害突變頻率低于非有害突變的頻率，ROH區(qū)域可能是有害突變個(gè)體發(fā)生突變的重要載體[16]。

2 檢測(cè)連續(xù)性純合片段的方法

根據(jù)不同類型數(shù)據(jù)的特點(diǎn)，可以制定適合于分析ROH的算法。目前分析方法主要包括觀測(cè)基因型計(jì)數(shù)法和基于模型的分析方法。

2.1 觀測(cè)基因型計(jì)數(shù)法

基因型計(jì)數(shù)法是根據(jù)設(shè)定雜合子最大數(shù)量和允許缺失基因型的數(shù)量，在基因組上鑒定連續(xù)純合基因型的長(zhǎng)片段。常用的軟件有PLINK[44]、GERMLINE[45]和cgaTOH[46]等。Howrigan等[47]通過(guò)計(jì)算機(jī)模擬試驗(yàn)檢測(cè)了已知120 Mb人基因組中純合片段情況，其模擬結(jié)果表明，PLINK軟件檢測(cè)個(gè)體同一性的性能要優(yōu)于GERMLINE軟件。

2.2 基于模型的分析方法

基于模型的分析方法主要利用隱馬爾可夫模型，分辨純合子和雜合子基因組區(qū)域，獲得等位基因頻率和重組率等參數(shù)。常用的軟件有BEAGLE[48]、H3M2[49]、FILTUS[50]、BCFtools/RoH[51]和GARLIC[52]等。全基因組重測(cè)序深度的增加有利于減少基因型判定的錯(cuò)誤率，從而改進(jìn)隱馬爾可夫模型的判定，大大提高檢測(cè)ROH的精度，進(jìn)一步確定較短ROH在近交衰退中的作用。

目前，PLINK軟件廣泛應(yīng)用于ROH分析中。不同畜禽群體中鑒定ROH不同軟件設(shè)置參數(shù)詳見表1。

3 連續(xù)性純合片段信息在畜禽基因組研究中的應(yīng)用

3.1 親緣關(guān)系的鑒定

隨著高通量測(cè)序技術(shù)的迅猛發(fā)展，利用基因組信息分析個(gè)體和群體間的近交程度越來(lái)越被關(guān)注，尤其是檢測(cè)染色體上ROH的長(zhǎng)度和分布情況，從而間接地分析群體中個(gè)體間的近交程度。通過(guò)計(jì)算基因組中特定長(zhǎng)度(如>1 Mb、>2 Mb、>4 Mb、>8 Mb、>16 Mb等)ROH的值反映群體在基因組水平上的近交程度。

近交系數(shù)傳統(tǒng)分析方法是假定群體中祖先沒(méi)有親緣關(guān)系的前提下，通過(guò)通徑原理分析計(jì)算得到的。目前，隨著高密度SNP基因芯片技術(shù)的廣泛應(yīng)用，在不同畜禽群體中利用基因組信息分析真實(shí)的基因組近交程度成為可能。研究表明，基因組信息估測(cè)近交程度比傳統(tǒng)意義上的系譜信息更有效[4,10,79]。利用系譜信息估測(cè)親緣關(guān)系是通過(guò)基因組IBD概率的統(tǒng)計(jì)期望值，而利用基因組信息估測(cè)的是個(gè)體間實(shí)際的親緣關(guān)系[80,81]。不同畜禽群體中鑒定ROH信息以及基于系譜信息和基因組信息近交系數(shù)的相關(guān)系數(shù)見表2。

表1 不同畜禽群體中鑒定ROH設(shè)置參數(shù)比較

Table 1 Comparison of pre-set parameters for identification and characterization of ROH in different animal species

物種軟件/編程語(yǔ)言每個(gè)ROH中連續(xù)SNP數(shù)量①密度②(SNP/kb)最大間隔③最少長(zhǎng)度(kb)④參考文獻(xiàn) 牛 (Bos taurus)Fortran 9015??1000[4] PLINK v 1.07581/50100500[10] PLINK v 1.0730???[53] SNP & VARIATION SUITE v 7.6.8151/100010001000[5] SNP & VARIATION SUITE v 7.6.850,1001/502501000[11] PLINK v 1.07??1000?[54] PLINK v 1.0750??1000[55] SAS 9.215?10001000[20] PLINK v1.0730??1000[56] R Development Core team (2018)?1/50100100[57] SNP & VARIATION SUITE v 7.6.8301/1005004000[58] Perl script50???[59] PLINK v1.07501/1201000500[60] PLINK v1.90501/10018003400[23] PLINK v1.90501/505001000[61] PLINK v1.9020,35,50???[62] vcftools???500[63] PLINK v1.90401/10010004000[24] PLINK v1.9010?1000?[64] cgaTOH581/1201000500[65] SNP & Variation Suite (SVS)151/100010001000[66] PLINK v1.07201/1000?10[8] PLINK v1.07???500[67]

續(xù)表

物種軟件/編程語(yǔ)言每個(gè)ROH中連續(xù)SNP數(shù)量①密度②(SNP/kb)最大間隔③最少長(zhǎng)度(kb)④參考文獻(xiàn) 豬 (Sus scrofa)PLINK v1.07201/1000100010[9] SNP & Variation Suite (SVS)301/1001001000[68] PLINK v1.07101/50010005000[23] Fortran-301/1001000?[24] PLINK v1.09501/50?1000[69] PLINK v1.09???500[25] PLINK v1.0940???[70] PLINK v1.0750??500[71] PLINK v1.07501/1001000[72] PLINK v1.07??250500[73] PLINK v1.07201/50500?[33] 綿羊 (Ovis aries)SNP & Variation Suite program25?1000?[74] PLINK v1.09?1/1002501000[34] PLINK v1.09?1/10010001000[75] PLINK v1.09301/1002501000[22] PLINK v1.950??500[76] PLINK v1.0950???[77] In-house script205002000[37] 山羊 (Capra hircus)PLINK v1.09251/5010001000[78] PLINK v1.07501/501000500[28] PLINK v1.0750??400[29] 馬 (Equus caballus)PLINK v1.71/50100500[30] PLINK v1.071001/50100150[31] PLINK v1.9201/501000?[38] PLINK 1.9?1/100?1000[39] 雞(Gallus gallus)PLINK 1.9?1/50?100[40]

①表示一個(gè)ROH片段中連續(xù)SNP位點(diǎn)數(shù)量；②表示在每個(gè)運(yùn)行單元中SNPs的密度；③表示連續(xù)純合子片段之間的最大間隔；④表示鑒定ROH的最小長(zhǎng)度?！?”表示無(wú)此信息。

表2 畜禽群體中鑒定ROH信息以及基于系譜信息和基因組信息近交系數(shù)的相關(guān)系數(shù)統(tǒng)計(jì)表

Table 2 Studies of ROH and correlations between the inbreeding from pedigree data and from genome data through ROH in livestock and poultry species

物種品種/群體數(shù)量ROH平均數(shù)量ROH平均長(zhǎng)度(Mb)相關(guān)系數(shù)參考文獻(xiàn) FPED①, FROHFPED, FROH>1 MbFPED, FROH>2 MbFPED, FROH>4 MbFPED, FROH>8 MbFPED, FROH>16 Mb 牛 (Bos taurus)Austrian Simmental500???0.640.670.680.680.63[4] Multiple breeds891?0.30~5.09②0.71?????[10] Brown Swiss30498.91.30?0.660.67?0.600.50[5] Fleckvieh50294.50.440.660.690.700.64 Nowegian Red49880.00.510.610.610.620.53 Tyrol Grey11772.31.880.710.720.710.70

續(xù)表

物種品種/群體數(shù)量ROH平均數(shù)量ROH平均長(zhǎng)度(Mb)相關(guān)系數(shù)參考文獻(xiàn) FPED①, FROHFPED, FROH>1 MbFPED, FROH>2 MbFPED, FROH>4 MbFPED, FROH>8 MbFPED, FROH>16 Mb 牛 (Bos taurus)Italian Holstein209381.73.6?0.70?0.690.650.56[20] Italian Brown74994.63.90.660.660.650.58 Italian Simmental47994.32.20.660.740.760.71 Jersey1602??0.70③/0.71④?????[57] Cinisara719.3813.570.45?????[82] Modicana72110.312.310.27 Reggiana16810.4210.160.31 Italian Holstein967.1511.780.44 Holstein210721.28.020.73?????[83] Maasai?10317.460.90?????[84] Tarime5613.120.75 Sukuma3610.650.61 Boran999.480.56 Friesian1559.680.54 Brown Swiss28121.022640.45?????[23] Braunvieh338618.6184.6 Origianl Braunvieh1678.473.7 Holstein256814.2145.2 Red Holstein196011.2112.1 Swiss Fleckvieh5477.175.6 Simmental24810.996.6 Eringer368.566.2 Evolèner2115.5185.7 豬 (Sus scrofa)Iberian64???0.77??0.81?[68] Yorkshire2358??0.69?????[23] Guadyerbas109??0.63-0.24??0.60?[24] Landrace117852.7252.90.24?????[69] Large White120061.4280.10.015 Duroc106616.726.750.31?????[70] Landrace76823.1911.270.32 Yrokshire111125.8811.990.53 Crossbred1128.252.60.00 馬 (Equus caballus)Sorraia2⑤4175⑥0.19??????[29] Dülmen Horse1⑤2804⑥0.14 Arabian1⑤3581⑥0.15 Saxon-Thuringian1⑤3138⑥0.15 Thoroughbred1⑤4595⑥0.20 Hanoverian4⑤311⑥0.14

續(xù)表

物種品種/群體數(shù)量ROH平均數(shù)量ROH平均長(zhǎng)度(Mb)相關(guān)系數(shù)參考文獻(xiàn) FPED①, FROHFPED, FROH>1 MbFPED, FROH>2 MbFPED, FROH>4 MbFPED, FROH>8 MbFPED, FROH>16 Mb 綿羊 (Ovis aries)Belclare30439.94~ 92.61⑦0.83-3.7?0.76?0.75⑧0.71⑨?[34] Suffolk530.540.55⑧0.58⑨ Texel2480.520.47⑧0.41⑨ Vendeen2380.150.15⑧0.12⑨ 山羊 (Capra hircus)Alpine40315.60.450.372?????[77] Boer(Ausralia)6123.60.48 Boer(Canada)6731.50.42 Cashmere488.00.59 LaMancha8119.40.47 Nubian5431.20.43 Rangeland665.20.38 Saanen31816.70.45 Toggenb5324.10.46

①根據(jù)系譜信息計(jì)算的近交系數(shù)；②估計(jì)平均ROH長(zhǎng)度為ROH平均覆蓋基因組長(zhǎng)度與ROH總數(shù)量的平均值；③以連續(xù)100個(gè)純合子SNPs鑒定為一個(gè)ROH；④以連續(xù)30、50、80個(gè)純合子SNPs鑒定為一個(gè)ROH；⑤序列信息從NCBI獲得；⑥使用50 SNPs滑動(dòng)窗口定義的值；⑦品種間變化范圍為39.94~92.61 Mb，每個(gè)品種平均ROH變化范圍為0.83~3.7 Mb(ROH≥20 Mb)；⑧基因組中5 Mb計(jì)算的FROH；⑨基因組中10 Mb計(jì)算的FROH?！?”表示無(wú)此信息。

目前，基于基因組信息估測(cè)近交程度的方法主要有以下3種：(1)基于ROH的近交系數(shù)(FROH)，是指ROH片段長(zhǎng)度之和占整個(gè)基因組總長(zhǎng)度的比例。McQuillan等[2]引入FROH作為檢測(cè)個(gè)體間同一性指標(biāo)，其中計(jì)算公式中整個(gè)基因組是指基因組常染色體上特定區(qū)域的長(zhǎng)度，不同的研究中設(shè)置的具體參數(shù)不同；(2)標(biāo)記基因型中純合子所占的比例(FHOM)，即所檢測(cè)SNP中的純合子比例；(3)基于基因組關(guān)系矩陣的近交系數(shù)(FGRM)，其中G矩陣計(jì)算方法參考文獻(xiàn)[85]。楊湛澄等[83]利用高密度SNP 標(biāo)記通過(guò)兩種基因組近交計(jì)算方法(FROH和FHOM)分析中國(guó)荷斯坦?；蚪M近交程度，其結(jié)果表明，共檢測(cè)到44 676個(gè)ROH片段，ROH在染色體上并非均勻分布，其長(zhǎng)度主要分布在1~10 Mb之間。兩種基因組近交系數(shù)之間的相關(guān)性比較大，而基因組近交系數(shù)與系譜近交之間的相關(guān)性較低。Peripolli等[61]采用4種近交系數(shù)計(jì)算方法(FPED、FHOM、FGRM和FROH)對(duì)瘤牛群體近交程度進(jìn)行了評(píng)估，結(jié)果表明，F(xiàn)ROH和FGRM相關(guān)性為弱到中度相關(guān)；FROH和FHOM相關(guān)性從弱到強(qiáng)相關(guān)；FPED和FHOM與FGRM和FHOM之間的相關(guān)程度為中等；FROH和FPED相關(guān)系數(shù)隨著ROH長(zhǎng)度的增加而增大。因此，在群體系譜信息缺失的情況下，F(xiàn)ROH可以作為替代方法評(píng)價(jià)畜禽群體的近交程度。

Keller等[6]研究表明，F(xiàn)ROH指標(biāo)與FPED指標(biāo)相比，具有以下幾方面優(yōu)點(diǎn)：(1) FROH可以更準(zhǔn)確估計(jì)共同祖先甚至50代前后代個(gè)體基因組中純合性狀態(tài)；(2)在系譜信息不完整或者缺失的情況下，F(xiàn)ROH指標(biāo)可以檢測(cè)基因組中純合片段分布，同時(shí)可以發(fā)現(xiàn)與純合性高的特異性位點(diǎn)；(3) FPED指標(biāo)是相對(duì)于基礎(chǔ)群而言的，在基礎(chǔ)群假定祖先個(gè)體的基因組沒(méi)有選擇和重組事件的發(fā)生。此外，減數(shù)分裂是一個(gè)隨機(jī)過(guò)程，子代獲得父母雙方遺傳物質(zhì)的過(guò)程存在著隨機(jī)變異，且這樣的變異隨著減數(shù)分裂的增加而增加，而FPED僅是IBD概率的期望值。從表2統(tǒng)計(jì)結(jié)果看出，在牛和豬品種鑒定ROH研究中，F(xiàn)ROH和FPED之間的相關(guān)程度為中度或者高度，因此可以僅采用FROH監(jiān)測(cè)牛和豬群體的近交程度。也有研究表明，鑒定ROH的長(zhǎng)度與FROH和FPED之間相關(guān)程度為正相關(guān)(表2)，ROH反映了群體過(guò)去和現(xiàn)在的親緣關(guān)系，而FPED僅根據(jù)現(xiàn)有的系譜記錄數(shù)據(jù)估測(cè)近交程度。隨著群體系譜信息的不斷積累，基于系譜近交系數(shù)與基于基因組近交系數(shù)的相關(guān)性也隨之增加[20]。根據(jù)Saura等[26]報(bào)道，當(dāng)ROH長(zhǎng)度大于5 Mb時(shí)，計(jì)算的FROH值和FPED值接近，而當(dāng)ROH長(zhǎng)度小于5 Mb時(shí)，計(jì)算的FROH值比FPED值小4倍多。利用FROH和FPED兩種方法估測(cè)了和牛群體中個(gè)體親緣關(guān)系，其結(jié)果表明采用系譜信息數(shù)據(jù)低估了和牛群體的近交程度，基因組近交系數(shù)可以反映真實(shí)的近交程度，該結(jié)果與已有的研究結(jié)果一致[20,24,57]。Metzger等[31]估測(cè)了馬基因組近交系數(shù)，在一個(gè)窗口滑動(dòng)50個(gè)SNP條件設(shè)置下，F(xiàn)ROH值變化范圍為0.18~ 0.43。Guangul等[38]估測(cè)了5個(gè)山羊群體的基因組近交程度，ROH長(zhǎng)度從1~16 Mb，其FROH的值從0.0500~0.0048。Brito等[77]采用50K基因芯片通過(guò)4種不同的近交系數(shù)對(duì)9個(gè)山羊群體近交程度進(jìn)行了評(píng)估，其中基于系譜和ROH近交系數(shù)的相關(guān)系數(shù)為0.372；基于基因型計(jì)數(shù)方法和ROH近交系數(shù)的相關(guān)性高達(dá)0.901；而基于ROH和基于VanRaden與基于Leuenegger方法的近交系數(shù)均為負(fù)相關(guān)(相關(guān)系數(shù)分別為-0.133和-0.264)。Grossi等[70]分析了杜洛克、長(zhǎng)白和大約克夏純種豬以及長(zhǎng)白大約克夏豬雜交F1代4個(gè)群體共計(jì)3057個(gè)個(gè)體ROH分布情況，其結(jié)果表明每個(gè)個(gè)體ROH平均長(zhǎng)度在4個(gè)群體中依次為16.72、23.19、25.88和8.25；平均數(shù)量分別為6.75 Mb、11.28 Mb、11.99 Mb和2.65 Mb。FPED和FROH相關(guān)系數(shù)在4個(gè)群體中依次為0.31、0.32、0.53和0.00；FEH和FROH相關(guān)系數(shù)依次為0.41、0.72、0.69和0.64 (表2)。Kim等[63]采用重測(cè)序技術(shù)對(duì)經(jīng)過(guò)選育的126頭Hanwoo牛個(gè)體進(jìn)行了檢測(cè)，通過(guò)遺傳改良提高了其群體的體重，但是群體的近交程度有所增加，其FROH值比未改良的群體升高了約0.02。通過(guò)4種類型近交系數(shù)評(píng)估瘤牛群體的近交程度，其研究結(jié)果表明FPED的值變化范圍為0.00~0.327；FROH值變化范圍為0.001~0.201。FPED與FROH相關(guān)系數(shù)和FGRM與FROH相關(guān)系數(shù)從弱相關(guān)變?yōu)橹械认嚓P(guān)，其變化范圍從-0.11~0.51；FROH和FROM相關(guān)系數(shù)從弱相關(guān)到強(qiáng)相關(guān)；不同長(zhǎng)度估測(cè)的FROH和FPED相關(guān)系數(shù)隨著ROH長(zhǎng)度的增加而增加[61]。通過(guò)ROH方法對(duì)中國(guó)白耳黃雞、北京油雞和狼山雞3個(gè)群體的保種效果進(jìn)行評(píng)估，檢測(cè)到基于系譜的近交系數(shù)為0.0789 (白耳黃雞)~0.2010 (北京油雞)；通過(guò)幾個(gè)世代的保種效果監(jiān)測(cè)，表明其基于系譜的近交系數(shù)在其群體中變動(dòng)幅度比較小，而檢測(cè)到基于ROH近交系數(shù)的值要比基于系譜的值要偏低，其值為0.0511 (白耳黃雞)~0.0745 (北京油雞)，基于系譜和基于ROH近交系數(shù)的相關(guān)系數(shù)為0.76[25]。綜上所述，評(píng)估畜禽群體的近交程度，F(xiàn)ROH是比較有效的評(píng)價(jià)指標(biāo)，可以很好地補(bǔ)充由于系譜信息預(yù)測(cè)群體近交程度的不足，也可以通過(guò)鑒定ROH片段提高IBD片段定位的精度。

3.2 近交衰退的評(píng)估

Garrod等[86]發(fā)現(xiàn)一些人類疾病，如白血病、尿黑酸尿等，這些遺傳疾病在近親婚姻后代個(gè)體中發(fā)病率比較高，尤其在近交個(gè)體的隱性攜帶者，通過(guò)長(zhǎng)純合子片段可以檢測(cè)到致病的隱性有害變異。Zhang等[25]發(fā)現(xiàn)有害純合變異體和基因組中ROH片段之間呈現(xiàn)線性相關(guān)，致病座位有害基因純合子出現(xiàn)在ROH上的頻率要高于正?；虻念l率。Szpiech等[87]研究結(jié)果表明，鑒定的ROH高覆蓋度片段中包含有較長(zhǎng)有害變異區(qū)段，這也與引起近交衰退有害基因變異位點(diǎn)一般以純合子狀態(tài)存在假設(shè)是一致的。Muchadeyi等[35]在南非洲波斯羊3、4和25號(hào)染色體上檢測(cè)到ROH片段上與神經(jīng)系統(tǒng)、骨骼和大腦發(fā)育相關(guān)的基因，如基因、基因和基因。Huson等[88]利用基因組關(guān)聯(lián)分析，結(jié)合單倍型分析、選擇信號(hào)分析和ROH分析共同鑒定了牛20號(hào)染色體上位點(diǎn)。Mészáros等[56]采用ROH和基因組關(guān)聯(lián)分析發(fā)現(xiàn)了弗萊維赫牛眼臉內(nèi)翻遺傳缺陷基因組區(qū)段。Pryce等[89]基于系譜信息的近交系數(shù)估測(cè)了奶牛產(chǎn)量和個(gè)體健康性狀，其研究結(jié)果表明群體中近交程度增加1%，一個(gè)哺乳期內(nèi)荷斯坦牛和澤西奶牛奶產(chǎn)量分別減少21 L和12 L。Kim等[63]分析了近50年來(lái)美國(guó)澤西牛基因組中增加的60多個(gè)ROH區(qū)域與系譜信息估測(cè)的近交增量呈正相關(guān)，在3號(hào)、7號(hào)、8號(hào)和12號(hào)染色體上鑒定的ROH與后代女兒繁殖率呈負(fù)相關(guān)，體細(xì)胞評(píng)分的結(jié)果與繁殖性狀的結(jié)果相似。由于近交衰退引起1號(hào)、3號(hào)、4號(hào)、5號(hào)和13號(hào)染色體上增加的ROH影響了體細(xì)胞評(píng)分的結(jié)果，染色體上高度純合性導(dǎo)致繁殖率的下降和乳房炎易感性的增加。Silió等[68]研究了近交衰退對(duì)斷奶后仔豬生產(chǎn)性能的影響，結(jié)果表明由于群體近交系數(shù)增加，導(dǎo)致其斷奶仔豬生產(chǎn)性能下降，具體表現(xiàn)為近交系數(shù)每增加0.1，其日增重減少4.4%，90日齡體重減少1.52%。Saura等[26]分析了伊比利亞豬兩個(gè)高度近交系中的繁殖性狀，近交系數(shù)每增加0.1，其仔豬初生后存活率和仔豬出生后總數(shù)量有下降的趨勢(shì)。Feren?akovi?等[5]研究牛群體中ROH分布情況，解析了在群體近交增量增加情況下牛精液品質(zhì)下降的機(jī)理，發(fā)現(xiàn)與精子數(shù)量相關(guān)ROH區(qū)域有4個(gè)，與精子活力相關(guān)ROH區(qū)域有5個(gè)，但是同時(shí)與精子數(shù)量和精子活力相關(guān)ROH區(qū)域僅為1個(gè)。

3.3 遺傳多樣性分析

獲得大量畜禽基因組信息使得人們更好地分析畜禽群體遺傳多樣性等指標(biāo)。維持群體遺傳多樣性是畜禽保種的重要任務(wù)之一，以便利用更豐富的育種素材獲得動(dòng)物產(chǎn)品。采用基因組信息分析共祖先策略已經(jīng)應(yīng)用于保護(hù)群體遺傳多樣性和近交增量的分析中[90]。當(dāng)保種群體中出現(xiàn)中高近交繁殖的跡象時(shí)，基于IBD方法分析共同祖先可以作為一個(gè)策略維持遺傳多樣性和保種計(jì)劃的適合度[91]。因此，較小的群體有效含量和較高的近交增量會(huì)降低群體遺傳多樣性，通過(guò)畜禽保種方案的有效實(shí)施，監(jiān)測(cè)群體的遺傳變異，防止群體中發(fā)生不可逆轉(zhuǎn)遺傳多樣性的減少，最大限度地增加保種群體適應(yīng)外部環(huán)境變化的能力。Fleming等[40]采用600K基因芯片分析了非洲3個(gè)雞群體的遺傳多樣性，結(jié)果表明，群體中所有染色體僅有16號(hào)染色體上沒(méi)有檢測(cè)到ROH，每個(gè)個(gè)體ROH在基因組的覆蓋程度為2%~40%。Mastrangelo等[24]為了更好地制定和實(shí)施保種計(jì)劃，分析了30個(gè)意大利牛群體遺傳多樣性，結(jié)果表明觀測(cè)雜合度的值變化范圍為0.297~0.358，期望雜合度的值變化范圍為0.267~0.353。在祖先群體中群體有效含量較高，但是Pontremolese和Mucca Pisana2個(gè)群體有效含量比較低。通過(guò)分析個(gè)體ROH分布和長(zhǎng)度等參數(shù)有助于畜禽保種項(xiàng)目的制定和實(shí)施，在Pontremolese、Varzese-Ottonese和Mucca Pisana群體中檢測(cè)到高水平的ROH，如尤其針對(duì)這些群體，在實(shí)施配種計(jì)劃中盡量增加種公畜血統(tǒng)，減少其遺傳多樣性的損失，維持或者增加其群體有效含量。Zhang等[42]采用ROH方法對(duì)中國(guó)白耳黃雞、北京油雞和狼山雞3個(gè)保種群體的遺傳多樣性、基因組近交系數(shù)和純合性進(jìn)行分析，經(jīng)過(guò)實(shí)施近10年的保種策略，白耳黃雞和北京油雞群體的遺傳多樣性有所下降，狼山雞群體的遺傳多樣性有上升的趨勢(shì)。

3.4 人工選擇的追蹤

基因組中鑒定的選擇信號(hào)揭示了馴化群體中雙向選擇的痕跡。與沒(méi)有受到人工選擇的群體比較，對(duì)于優(yōu)秀種畜禽個(gè)體的選育，降低了其群體表型的多樣性和重塑了基因組，其中包括基因組中ROH存在的模式[12]。有研究表明，對(duì)于選育的優(yōu)秀種畜禽個(gè)體使其基因組中單倍型多樣性下降，同時(shí)也增加了選擇位點(diǎn)相鄰位點(diǎn)的純合性，導(dǎo)致其受到選擇區(qū)域中的ROH頻率增加[11]。ROH并不是隨機(jī)分布在基因組中，大部分ROH出現(xiàn)在受選擇區(qū)域。基因組中受選擇的區(qū)域傾向于產(chǎn)生“ROH島”，相對(duì)于基因組其他區(qū)域，這些區(qū)域遺傳多樣性低，純合性比較高。Purfield等[10]研究了?；蚪M中出現(xiàn)ROH頻率較高的4條染色體，其中在ROH區(qū)域中包含了影響牛免疫力、胴體和難產(chǎn)等重要性狀的主效基因。在不同的阿拉伯馬群體中也開展了ROH的研究，分析了受到正向選擇區(qū)域的ROH。Metzger等[31]研究了馬基因組中受到選擇和未受到選擇區(qū)域中ROH的功能分布，發(fā)現(xiàn)了與細(xì)胞代謝、生長(zhǎng)發(fā)育和免疫系統(tǒng)相關(guān)的候選基因。Fleming等[41]采用FST、綜合單倍型評(píng)分(integrated haplotype score)和ROH等信息檢測(cè)了在非洲和北非不同生態(tài)環(huán)境中生長(zhǎng)雞品種的選擇信號(hào)，分析表明非洲生長(zhǎng)的雞群體選擇傾向于熱應(yīng)激和血管生成，而北非群體更傾向于能量平衡，其中雞品種基因組中2號(hào)和3號(hào)染色體在不同群體中差異最大。通過(guò)長(zhǎng)期優(yōu)秀種畜的選育，群體選擇強(qiáng)度增加和有效群體含量減少有可能會(huì)導(dǎo)致群體生存力和多樣性受到威脅。在畜禽選育和保種過(guò)程中，盡量避免群體遺傳變異性減少，避免基因組中有害基因的表達(dá)。人工選擇會(huì)導(dǎo)致群體近交系數(shù)的增加，因此要采取有效的措施控制近交程度的增加。另外，隨著人工授精技術(shù)的應(yīng)用，用于采精的優(yōu)秀種公牛近交程度也影響著整個(gè)配種群體的近交程度[63]。

3.5 功能基因的篩選

Bosse等[8]利用重測(cè)序技術(shù)和SNP基因芯片技術(shù)檢測(cè)了豬基因組上純合區(qū)域，在歐洲豬品種中發(fā)現(xiàn)兩個(gè)重疊ROH區(qū)域，該區(qū)域上有與神經(jīng)系統(tǒng)發(fā)育細(xì)胞分化相關(guān)的11個(gè)基因，這些基因在大白豬和利比里亞豬中被驗(yàn)證表達(dá)存在差異。在亞洲品種中存在4個(gè)共享區(qū)域，其中有一個(gè)重疊區(qū)域僅存在亞洲野豬中，該區(qū)域中包括91個(gè)基因，并且已經(jīng)有相關(guān)報(bào)道表明該區(qū)域在亞洲豬品種中經(jīng)過(guò)了正向選擇；其中在5號(hào)染色體上另一個(gè)共享區(qū)域包括與氧化還原反應(yīng)相關(guān)的和基因，與脂肪細(xì)胞分化正向調(diào)控的基因。在非洲3個(gè)雞品種中一致的ROH區(qū)域內(nèi)比對(duì)發(fā)現(xiàn)與脂肪代謝、免疫功能和熱激介導(dǎo)相關(guān)的基因(FDR<0.15)，選擇區(qū)域內(nèi)也發(fā)現(xiàn)與健康和氧化應(yīng)激反應(yīng)相關(guān)的基因[38]。通過(guò)瘤牛群體中ROH分析，發(fā)現(xiàn)群體基因組中有7.01% (175.28 Mb)為純合區(qū)域，在整個(gè)群體中鑒定的ROH 14個(gè)區(qū)域的頻率高于50%，發(fā)現(xiàn)與泌乳()、產(chǎn)奶量和乳成分(和)、熱適應(yīng)(、和)等相關(guān)候選基因[61]。Metzger等[31]采用全基因組測(cè)序方法分析了英國(guó)設(shè)得蘭群島上2個(gè)微型矮馬群體和1個(gè)正常體高矮馬群體，發(fā)現(xiàn)在這2個(gè)微型矮馬群體和1個(gè)正常體高矮馬群體中ROH區(qū)域內(nèi)存在4個(gè)變異，這4個(gè)變異解釋了設(shè)得蘭群島上矮馬群體和其他正常體高馬群體中72%體高變異效應(yīng)。

3.6 種畜禽品質(zhì)檢測(cè)

在瑞士Appenzeller Barthuhn雞群體中存在一種十字雞喙的遺傳缺陷，Joller等[92]在該群體和正常群體中通過(guò)檢測(cè)基因組ROH對(duì)存在十字雞喙個(gè)體的遺傳機(jī)理進(jìn)行研究，初步假定角蛋白家族基因?yàn)槭蛛u喙遺傳缺陷的候選基因，在編碼區(qū)內(nèi)發(fā)現(xiàn)有兩個(gè)顯著的同義突變，但是十字雞喙遺傳缺陷的遺傳機(jī)理還有待于進(jìn)一步研究確認(rèn)。目前，利用ROH檢測(cè)種畜禽品質(zhì)的報(bào)道還比較少。通過(guò)基因組中ROH信息剖析畜禽遺傳缺陷的機(jī)制，明確致病基因，采用快速有效的方法進(jìn)行檢測(cè)，進(jìn)一步規(guī)范種畜禽市場(chǎng)。我國(guó)是畜禽資源大國(guó)，據(jù)不完全統(tǒng)計(jì)，截止2018年12月，我國(guó)地方畜禽遺傳資源數(shù)量為556個(gè)，國(guó)家級(jí)保護(hù)區(qū)數(shù)量為24個(gè)，國(guó)家級(jí)保種場(chǎng)數(shù)量為165個(gè)。如何利用應(yīng)用成熟的現(xiàn)代生物技術(shù)手段對(duì)我國(guó)畜禽遺傳資源群體進(jìn)行動(dòng)態(tài)監(jiān)測(cè)，尤其是國(guó)家級(jí)保種場(chǎng)畜禽群體的動(dòng)態(tài)變化情況，已經(jīng)成為當(dāng)前畜禽遺傳資源保護(hù)領(lǐng)域亟待解決的問(wèn)題。目前，ROH在不同畜禽基因組中的廣泛應(yīng)用為解決這一難題提供了一定的措施。對(duì)于群體動(dòng)態(tài)監(jiān)測(cè)而言，主要監(jiān)測(cè)群體近交程度、遺傳多樣性、群體結(jié)構(gòu)以及種群特性生產(chǎn)性狀等變化情況等。近交系數(shù)最初由Wright S. (1921年)提出，在假定群體中祖先沒(méi)有親緣關(guān)系的前提下，通過(guò)通徑原理分析計(jì)算得到的。利用系譜信息估測(cè)親緣關(guān)系是通過(guò)基因組IBD概率的統(tǒng)計(jì)期望值，而利用基因組信息可以估測(cè)個(gè)體間實(shí)際的親緣關(guān)系。在系譜信息缺少的情況下，可以采用FROH估計(jì)其群體近交系數(shù)。如果ROH>5 Mb時(shí)，其基于系譜估測(cè)的平均值與FROH值相關(guān)系數(shù)為0.87，而當(dāng)ROH<5 Mb時(shí)，其基于系譜估測(cè)平均值與FROH值相關(guān)性較小[16,24]，在實(shí)際應(yīng)用中，可以結(jié)合系譜信息，采用較大的ROH估測(cè)群體基因組近交系數(shù)。近交群體會(huì)產(chǎn)生近交衰退現(xiàn)象，近交衰退是由于基因組純合片段增多引起的現(xiàn)象，在生產(chǎn)實(shí)踐中，由于近交衰退導(dǎo)致群體整體生產(chǎn)性能會(huì)逐漸下降，對(duì)于畜禽保種和育種管理者而言，研究近交衰退以及由此引起群體生產(chǎn)性能下降是一個(gè)比較重要的課題。采用ROH信息已經(jīng)成功定位人類許多罕見隱性疾病的致病基因[41]，這對(duì)于研究群體種公畜遺傳缺陷的致病機(jī)理具有很高的借鑒作用，也為規(guī)范種畜禽市場(chǎng)提供檢測(cè)依據(jù)。另外，充分利用ROH信息挖掘畜禽群體適應(yīng)性、繁殖力、耐粗飼等性狀的特有基因更有利于畜禽保種場(chǎng)保護(hù)與利用工作的有序開展。在生物大數(shù)據(jù)時(shí)代下，畜禽遺傳資源保護(hù)與利用工作也需要不斷調(diào)整研究思路和策略來(lái)迎合和充分利用高通量測(cè)序技術(shù)進(jìn)步帶來(lái)的福祉。

4 結(jié)語(yǔ)與展望

本文全面總結(jié)了畜禽基因組中ROH發(fā)展歷史、鑒定方法以及在群體結(jié)構(gòu)、基因組功能分析和種畜禽品質(zhì)檢測(cè)等方面的應(yīng)用。綜上所述，ROH在畜禽基因組中是普遍存在的，通過(guò)分析基因組中分布的ROH，人們可以了解群體近交程度、群體多樣性以及種公畜(禽)遺傳缺陷等。但是，目前研究的物種主要集中在奶牛和豬中，在肉牛和其他家畜以及家禽中研究的較少，今后需要加大對(duì)馬、驢、綿羊、山羊和家禽等畜禽基因組中ROH的研究，從而更好地了解ROH在染色體上分布情況以及其作用機(jī)理。

目前，鑒定畜禽基因組中ROH沒(méi)有統(tǒng)一的標(biāo)準(zhǔn)，在不同畜種的研究中采用不同算法和方法。迄今為止，已有的研究很少關(guān)注優(yōu)化鑒定ROH的參數(shù)組合，如果使用最優(yōu)參數(shù)組合會(huì)更好地理解基因組中純合性形成的機(jī)制[81]。此外，畜禽基因組中鑒定ROH頻率和分布受到許多因素的影響，ROH在染色體內(nèi)和染色體之間分布頻率差異大，因此在染色體上會(huì)出現(xiàn)ROH集中區(qū)域(也稱ROH島)，也會(huì)出現(xiàn)ROH分布少的區(qū)域(也稱ROH荒漠)，但相關(guān)機(jī)理還有待于進(jìn)一步研究。

2015年，動(dòng)物基因組功能注解(Functional Anno-tation of Animal Genomes, FAANG)計(jì)劃啟動(dòng)，充分說(shuō)明農(nóng)業(yè)動(dòng)物領(lǐng)域相關(guān)研究的重要性[93]。隨著畜禽基因組研究時(shí)代的到來(lái)，海量數(shù)據(jù)的獲得便于更加系統(tǒng)地研究ROH特征序列、進(jìn)一步剖析群體近交增量、群體演變歷史、選擇信號(hào)以及遺傳疾病等機(jī)理，從而開啟畜禽基因組研究運(yùn)用于畜禽遺傳資源保護(hù)與利用的新時(shí)代[94]。

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Runs of homozygosity and its application on livestock genome study

Gang Liu, Feizhou Sun, Fangxian Zhu, Haiyong Feng, Xu Han

With the rapid development of high-throughput SNP array and significant reduction of sequencing cost, the techniques of genome-resequencing and SNP chip arrays are widely applied in livestock genomic studies. Long runs of homozygosity (ROH) arose when identical haplotypes were inherited from each parent and thus a long tract of genotypes is homozygous. Nowadays, cumulative studies reported that ROH has progressively served as one of the important indexes to estimate the degree of inbreeding and genetic structure of livestock populations. However, the evaluating criteria of ROH in livestock is still inadequate. In this review, we introduce the history, theory and identification methods of ROH analysis. Meanwhile, we also systematically overview the applications and perspectives of ROH in population genetic structure analysis, genome functional assay, quality investigation and dynamic monitoring of livestock genetic resources.

high-throughput sequencing; runs of homozygosity; population structure; genomic function; genetic defect

2018-10-13;

2019-02-02

畜禽種質(zhì)資源保護(hù)項(xiàng)目(編號(hào)：[2018]45)和家養(yǎng)動(dòng)物平臺(tái)種質(zhì)資源項(xiàng)目(編號(hào)：2018)資助[Supported by the Protection Project of Animal Germplasm Resources (No. [2018]45) and the National Infrastructure of Domestic Animal Resources (No. 2018)]

劉剛，博士，畜牧師，研究方向：畜禽遺傳資源保護(hù)與應(yīng)用。E-mail: lgang-2004@126.com

孫飛舟，博士，研究員，研究方向：畜禽遺傳資源保護(hù)與應(yīng)用。E-mail: fzhsun1968@qq.com朱芳賢，高級(jí)畜牧師，研究方向：畜禽遺傳資源保護(hù)與應(yīng)用。E-mail: 1171277193@qq.com

10.16288/j.yczz.18-287

2019/3/29 9:06:29

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20190329.0906.001.html

(責(zé)任編委: 任軍)