周萌，景軍紅，毛瑞涵，郭靜，王志鵬

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代謝組學在家養(yǎng)動物遺傳育種中的應(yīng)用

周萌1,2,3，景軍紅1,2,3，毛瑞涵1,2,3，郭靜1,2,3，王志鵬1,2,3

1. 農(nóng)業(yè)農(nóng)村部雞遺傳育種重點試驗室，哈爾濱 150030 2. 黑龍江省普通高等學校動物遺傳育種與繁殖重點試驗室，哈爾濱 150030 3. 東北農(nóng)業(yè)大學動物科學技術(shù)學院，哈爾濱 150030

代謝組學是使用分析化學技術(shù)對生物樣品(如乳液、血漿、血清等)中的大量小分子代謝物進行全面鑒定和定量分析，已經(jīng)廣泛應(yīng)用于生物醫(yī)學、營養(yǎng)學、作物學和畜牧學研究中。最初，代謝組學主要應(yīng)用于畜牧生產(chǎn)中的非遺傳學研究。目前，隨著生理基因組學、生理遺傳學研究的增多，越來越多的研究者開始利用代謝組學的技術(shù)和方法開展動物遺傳育種研究。本文綜述了代謝組學檢測技術(shù)與平臺特點及代謝組學在動物遺傳學與基因組中的應(yīng)用，著重總結(jié)了動物代謝分子遺傳參數(shù)估計、品系(品種)間代謝圖譜差異、代謝組全基因組關(guān)聯(lián)分析、篩選影響重要經(jīng)濟性狀的生物標記等領(lǐng)域的研究進展，討論了代謝組學研究還需亟待解決的問題。本文通過綜述代謝組學在動物育種中的研究進展，旨在為進一步利用代謝組學技術(shù)開展動物重要經(jīng)濟性狀的遺傳基礎(chǔ)研究提供參考。

代謝組學；家養(yǎng)動物；遺傳學；動物育種

代謝組學(metabonomics)是對生物體內(nèi)所有代謝分子進行定量分析，尋找代謝分子與生理、病理變化的相對關(guān)系的研究，是繼基因組學和蛋白質(zhì)組學之后新近發(fā)展起來的研究某一時刻細胞內(nèi)所有代謝分子集合的一門學科[1,2]。與其他組學相比，代謝組學具有以下特點：基因和蛋白質(zhì)表達的微小變化在代謝分子上得到的放大使代謝組學檢測更加容易；代謝組學技術(shù)需要相對完整的代謝分子信息庫，但其遠沒有全基因組測序及大量表達序列標簽的數(shù)據(jù)庫復(fù)雜；代謝分子種類遠小于基因和蛋白質(zhì)的數(shù)量，其物質(zhì)的分子結(jié)構(gòu)也更為簡單[3]。

隨著高通量測序技術(shù)和生物信息學的發(fā)展，代謝組學也已成為生物學研究的重要領(lǐng)域，已廣泛應(yīng)用在人類生物醫(yī)學研究中，并取得了豐碩的成果，特別是在疾病的生物標志物研究、疾病機理研究等方面都展現(xiàn)出巨大的應(yīng)用潛力與優(yōu)勢[4~8]。但是，在畜牧生產(chǎn)和研究中代謝組學的應(yīng)用相對較少。根據(jù)已發(fā)表的相關(guān)文獻，其應(yīng)用主要集中在評估胴體品質(zhì)和牛奶質(zhì)量、預(yù)測飼料效率或剩余飼料攝入量(residual feed intake, RFI)、生殖生理學研究、營養(yǎng)生理學研究、疾病檢測的生物標記開發(fā)和藥物使用檢測等非遺傳學研究方面。而利用代謝組學開展動物遺傳學研究長期被忽視，直到最近以精確、高通量為特點的動物表型組學以及生理基因組學、生理遺傳學研究的開展，科研人員在解析動物重要經(jīng)濟性狀遺傳機制的研究中才更多地使用了代謝組學的技術(shù)和方法[9]。

動物基因組上的變異不一定直接對動物表型產(chǎn)生影響，而相關(guān)代謝分子的變化可能是該變異的最 終結(jié)果。換言之，基因組上的變異需通過相關(guān)代謝分子的轉(zhuǎn)化而最終傳遞到表型。這可能是科研人員在將表型和遺傳變異直接進行關(guān)聯(lián)分析時，遺漏一些變異位點的原因之一，利用代謝組學數(shù)據(jù)則可以篩查出這些遺漏的位點[10]。隨著代謝組學的快速發(fā)展，與其他組學數(shù)據(jù)的整合研究將有助于解析動物生命活動許多復(fù)雜的調(diào)控機制。

本文比較了代謝組學檢測技術(shù)的優(yōu)缺點，概述了利用代謝組學技術(shù)在主要家養(yǎng)動物體液中所檢測到的代謝分子的分布情況，綜述了關(guān)鍵代謝標志物在遺傳育種領(lǐng)域中的應(yīng)用，以期為進一步利用代謝組學技術(shù)開展動物重要經(jīng)濟性狀的遺傳基礎(chǔ)研究提供參考。

1 代謝組學的分類及檢測平臺

1.1 代謝組學的分類

代謝組學的研究對象大都是相對分子質(zhì)量1000以內(nèi)的小分子物質(zhì)，到目前為止，有114 100個代謝分子被收錄到人類代謝組學數(shù)據(jù)庫[11]。根據(jù)不同的理化屬性可以將代謝組學所包含的物質(zhì)主要分為氨基酸類(amino acid)、肽類(peptide)、碳水化合物類(carbohydrate)、能量類(energy)、脂類(lipid)、核苷酸(nucleotide)、維生素和輔助因子(cofactors and vitamins)及外源化合物類(xenobiotics)；根據(jù)代謝分子的產(chǎn)生來源則可以分為內(nèi)源性代謝分子和外源性代謝分子。根據(jù)代謝組學研究策略的不同，代謝組學研究可分為非靶標代謝組學和靶標代謝組學[9]，這兩種研究策略相輔相成，從發(fā)現(xiàn)到驗證，從“無假設(shè)”到“假設(shè)驅(qū)動”，共同組成了代謝組學研究[12]。代謝組學包含物質(zhì)及研究策略的分類特點見表1。

1.2 代謝組學檢測平臺

目前用于開展高通量代謝組學研究最常見的儀器平臺主要包括核磁共振儀(nuclear magnetic reson-ance, NMR)、質(zhì)譜儀(mass spectrometer, MS)、色譜-質(zhì)譜聯(lián)用儀(chromatograph-mass spectrometer, C-MS)。Goldansaz等[13]詳細介紹了上述檢測技術(shù)平臺的特性(圖1)及其應(yīng)用。NMR是最早應(yīng)用于代謝組學研究的高通量分析技術(shù)，其優(yōu)勢在于對樣品檢測前的預(yù)處理較為簡單，且對樣品無破壞性；其缺點在于檢測靈敏度較低，只能檢測μmol/L~mmol/L濃度的代謝分子。質(zhì)譜技術(shù)具有高靈敏度和專屬性等優(yōu)勢，能夠檢測nmol/L~pmol/L濃度的代謝分子。近年來，代謝組學研究普遍采用的方法是色譜-質(zhì)譜聯(lián)用技術(shù)，主要包括氣相色譜-質(zhì)譜(gas chromatography- mass spectrometry, GC-MS)和液相色譜-質(zhì)譜(high performance liquid chromatography-mass spectrometry, LC-MS)聯(lián)用技術(shù)。該技術(shù)的優(yōu)勢在于檢測覆蓋率達到前所未有的高度，可以檢測到更多的小分子代謝產(chǎn)物，包括糖、糖醇、氨基酸、有機酸、脂肪酸和芳胺，以及包括大量次級代謝分子在內(nèi)的數(shù)百種化學性質(zhì)不同的化合物[14]。由于GC-MS需要對揮發(fā)性較低的代謝分子進行衍生化預(yù)處理，樣品制備較為繁瑣，甚至會引起樣品的變化，因此與LC-MS相比，GC-MS沒有被普遍使用。

2 代謝組學技術(shù)檢測家養(yǎng)動物體液中關(guān)鍵代謝分子

在家養(yǎng)動物代謝組學研究中，主要是利用核磁技術(shù)和質(zhì)譜技術(shù)測定血漿、血清、乳汁、尿液、糞便、瘤胃、肌肉、脂肪等樣品的代謝分子。其中對血漿、血清、乳汁中的代謝組學研究最多，所檢測到的代謝分子也最多?；谀壳皥蟮赖臋z測結(jié)果，Goldansaz等[13]將在不同物種、不同樣品中通過代謝組學技術(shù)所檢測到的1070個代謝分子收錄在LMDB數(shù)據(jù)庫，該數(shù)據(jù)庫中除了收集每個代謝分子的理化特性以外，重點收錄了特定物種的特定樣品內(nèi)該代謝分子的標準化濃度等注釋信息。通過檢索該數(shù)據(jù)庫，在不同動物的血漿中累計檢測到408個代謝分子，在血清中累計檢測到351個代謝分子，在乳汁中累計檢測到422個代謝分子。上述檢測到的代謝分子約70%來自牛和豬的組織或體液，在不同年份豬和牛各種組織或體液中所檢測到代謝分子的分布情況見圖2。隨著敏感度更高的檢測設(shè)備在動物代謝組學中的應(yīng)用，動物各種組織或體液中的代謝分子將會被陸續(xù)檢測出來。

表1 代謝組學包含物質(zhì)及研究策略的分類特點

圖1 不同代謝組學檢測平臺的敏感度

根據(jù)文獻[13]修改繪制。

3 家養(yǎng)動物關(guān)鍵代謝標志物在遺傳育種中的應(yīng)用

如前所述，在家養(yǎng)動物上利用代謝組學的研究手段開展復(fù)雜性狀遺傳學機制的研究較少。目前所開展的相關(guān)研究主要集中在代謝分子遺傳參數(shù)估計、篩選能夠鑒別不同品種(系)的生物標記、代謝分子全基因組關(guān)聯(lián)分析研究(genome-wide association studies with metaotypes, mGWAS)以及尋找代謝分子與重要經(jīng)濟性狀的關(guān)系等方面。為了系統(tǒng)地解析乳品質(zhì)或肉品質(zhì)等相關(guān)性狀的遺傳學機制，目前對牛和豬的研究較多。相對而言，在其他家養(yǎng)動物上利用代謝組學開展遺傳育種方面的研究較少，其研究多集中于營養(yǎng)生理學研究、疾病檢測的生物標記開發(fā)和藥物或食品添加劑使用效果檢測等非遺傳學研究。

3.1 動物代謝分子遺傳參數(shù)估計

機體內(nèi)的代謝水平會隨時間而發(fā)生變化，更易受到環(huán)境和生活習慣的影響。因此，每個生物樣品的代謝組學圖譜僅僅是刻畫了該個體在特定時間的代謝狀態(tài)。在將代謝分子的表達量作為中間性狀開展遺傳學分析時，需要充分了解遺傳因素解釋這些代謝分子表型變異的份額，即需要對代謝分子表達水平開展遺傳參數(shù)估計工作。如果期望將鑒定的代謝分子應(yīng)用于動物遺傳評估，估計這些代謝分子的遺傳參數(shù)則更是一項必要的研究工作。在牛、豬和雞等家養(yǎng)動物群體中，科研人員已經(jīng)系統(tǒng)地估計了各類代謝分子的遺傳參數(shù)。

對牛的代謝分子估計遺傳參數(shù)的研究較多。Soyeurt等[15]檢測了瑞士褐牛(Brown Swiss)、比利時藍牛(Dual-Purpose Belgian Blue)、荷斯坦-弗里斯牛(Holstein Friesian)、澤西牛(Jersey)、蒙貝利亞牛(Montbeliarde)、諾曼地牛(Normande)等總計7700個牛乳樣品，分析發(fā)現(xiàn)牛乳中不同長鏈脂肪酸代謝分子的遺傳力在0.05~0.38之間，它們之間的遺傳相關(guān)在?0.06~0.84之間。Stoop等[16]估計了1953只荷蘭荷斯坦(Holstein)黑白花母牛尿素氮的遺傳力，分析發(fā)現(xiàn)該代謝分子為低遺傳力性狀(2=0.14)。Oikono-mou等[17]對初次泌乳奶牛的血清代謝分子開展了遺傳參數(shù)估計，研究發(fā)現(xiàn)葡萄糖的遺傳力為0.12~0.39，β-羥基丁酸酯為0.08~0.40，非酯化脂肪酸為0.08~ 0.35。Nogi等[18]對日本黑牛(Japanese Black cattle)進行了研究，單不飽和脂肪酸、飽和脂肪酸和多不飽和脂肪酸遺傳力估計值分別為0.68、0.66和0.47。Buitenhuis等[19]對456只丹麥荷斯坦奶牛和436只丹麥澤西牛的牛乳開展了代謝分子的遺傳力估計，其中乳清酸和β-羥基丁酸的遺傳力均大于0.8。Wittenburg等[20]利用GC-MS測定了1295頭奶牛乳中190種代謝分子的遺傳力，發(fā)現(xiàn)這些代謝分子的廣義遺傳力為0~0.699，中位數(shù)為0.125。Gebreyesus等[21]對650頭丹麥荷斯坦奶牛主要乳蛋白的遺傳力進行估計，發(fā)現(xiàn)不同乳蛋白的遺傳力為0.05~0.78。

圖2 在不同年份牛和豬中檢測到的代謝分子數(shù)

數(shù)據(jù)來自于LMDB數(shù)據(jù)庫。X軸表示年份，Y軸表示每年度在牛和豬不同組織或體液上檢測到的代謝分子總數(shù)；每年度的圈圖表示該年度在牛和豬不同組織或體液中檢測到的代謝分子的分布情況，其中扇面顏色表示所檢測的組織或體液類型，扇面的面積大小代表檢測到的代謝分子數(shù)。

在對豬的研究中，重點估計了與肉質(zhì)性狀相關(guān)的各種長鏈脂肪酸的遺傳力。Ntawubizi等[22]估計豬肉肌內(nèi)脂肪酸的組成和參與多不飽和脂肪酸代謝的去飽和酶和延長酶活性指標的遺傳參數(shù)，發(fā)現(xiàn)長鏈多不飽和脂肪酸的遺傳力值通常在0.50以上。Ibá?ez-Escriche等[23]對伊比利亞豬(Iberian pig)皮下脂肪組織的不同長鏈脂肪酸的遺傳力進行估計，發(fā)現(xiàn)這些脂質(zhì)代謝分子的遺傳力范圍為0.06~0.53。

另外，科研人員對特定幾項雞血液生化指標開展了遺傳參數(shù)估計研究。Dong等[24]以肉雞高、低脂雙向選擇品系為實驗材料，估計了多項血液生化指標的遺傳參數(shù)，研究發(fā)現(xiàn)總膽汁酸、肌酐、低密度脂蛋白膽固醇的遺傳力為0.60~0.85。Zhang等[25]測定了332只廣西黃雞進食和禁食狀況下的血液生化指標以及腹部脂肪性狀，研究發(fā)現(xiàn)，在進食狀態(tài)下，甘油三酯、總膽固醇等血液生化指標的遺傳力較高，從0.26~0.60不等，在禁食狀態(tài)下，這些血液生化指標的遺傳力為0.22~0.59。

3.2 動物代謝分子在品種(系)中的鑒定

在對牛、豬和雞等家養(yǎng)動物的代謝組學研究中，通過檢測動物血清、組織、乳汁等研究材料，篩選出一些代謝分子作為區(qū)分品種(系)的生物標記物。目前，已有多篇文獻報道了牛、豬、雞的不同品種(系)間存在顯著差異表達的代謝分子，這些代謝分子可以作為品種(系)鑒定的生物標記。例如：Karisa等[26]利用NMR技術(shù)檢測了純種安格斯牛(Augus)和雜交牛(58.3%安格斯、30.6%西門塔爾(Simmemal)和11.1%海福特牛(Hareford)等歐系肉牛)的血漿代謝圖譜，發(fā)現(xiàn)肌酸、肉堿、馬尿酸等代謝分子的表達在兩個品種間差異顯著。D'Alessandro等[27]分析發(fā)現(xiàn)可以用甘油-3-磷酸脫氫酶、甘油3-磷酸和甘油代謝分子來區(qū)分高脂的卡斯塔納豬(Casertana)和瘦肉型大白豬(Large White)；He等[28]用代謝組學方法比較肥胖型豬(寧鄉(xiāng)品系)和瘦肉型雜交豬間的血清代謝圖譜，發(fā)現(xiàn)寧鄉(xiāng)品系豬血清的胰島素、胰高血糖素、脂質(zhì)、不飽和脂質(zhì)、糖蛋白、肌肉肌醇、丙酮酸鹽、蘇氨酸、酪氨酸和肌酸均顯著高于瘦肉型豬，而血清中葡萄糖和尿素則低于瘦肉型豬；Straadt等[29]通過NMR技術(shù)，檢測了杜洛克/長白/約克夏(Duroc/ Landrace/Yorkshire)、伊比利亞/杜洛克(Iberian/Duroc)、伊比利亞/杜洛克/長白(Iberian/Duroc/Landrace)、曼加利薩/杜洛克(Mangalitza/Duroc)和曼加利薩/長白/約克夏(Mangalitza/Landrace/Yorkshire)5個雜交組合的豬背最長肌的代謝分子，發(fā)現(xiàn)氨基酸(丙氨酸、肌肽、異亮氨酸、甲硫氨酸、苯丙氨酸和纈氨酸)、乳酸鹽、肌苷酸、肌苷、甘油和含膽堿的化合物等可以區(qū)分這些雜交豬；Bovo等[30]利用質(zhì)譜技術(shù)檢測了大白豬和杜洛克豬的血漿、血清，共檢測到180種代謝分子，其中鞘磷脂在杜洛克豬中表達量較高，乙酰鳥氨酸在大白豬中表達量較高。Ji等[31]利用LC-MS檢測來航雞(Leghorn)、Fayoumi和商業(yè)肉雞的脂肪組織，共檢測到92種代謝分子，與商業(yè)肉雞相比，F(xiàn)ayoumi和來航雞脂肪組織中的肉堿、鳥苷、胞嘧啶、腺苷和磷酸戊糖含量顯著增加，來航雞脂肪組織中的3-磷酸甘油酸和磷酸烯醇丙酮酸含量較高；Baéza等[32]利用H-NMR技術(shù)，通過比較飼喂同樣日糧、同一日齡的腹脂雙向選擇系公雞的血漿，發(fā)現(xiàn)谷氨酰胺、組氨酸、甜菜堿等代謝分子的表達在兩系間差異顯著。

3.3 動物代謝分子的全基因組關(guān)聯(lián)分析

基于基因組學研究技術(shù)，特別是全基因組SNP標記檢測平臺，將血清、血液、尿液等體液所檢測到的代謝分子表達量作為表型值，開展了代謝分子全基因組關(guān)聯(lián)分析，這是將代謝組學與基因組學耦合在一起的關(guān)鍵，也是目前代謝組學領(lǐng)域以遺傳學研究為落腳點，鑒定代謝分子功能與遺傳調(diào)控方面最主要的研究進展之一。從已有的文獻報道可以發(fā)現(xiàn)，人類代謝組學mGWAS研究結(jié)果極為豐富，且已經(jīng)篩選到多個與代謝分子表達顯著相關(guān)的遺傳標記或基因，通過進一步的分析發(fā)現(xiàn)這些代謝分子可以作為人類疾病的生物標記。家養(yǎng)動物mGWAS的報道相對較少，主要集中在牛和豬上，其目的是通過對某一類代謝分子的全基因組關(guān)聯(lián)分析篩選出影響肉質(zhì)或乳質(zhì)的遺傳標記或重要候選基因。例如，已篩選出DGAT1、FASN、SCD、ELOVL家族等重要候選基因與牛乳液和肌肉中各種不同鏈長的脂肪酸含量顯著相關(guān)；篩選出FASD家族、ELOVL家族等重要候選基因與豬最長肌中脂肪酸含量顯著相關(guān)。其他研究結(jié)果詳見表2。在動物群體上開展mGWAS的樣本量規(guī)模都比人類研究群體的規(guī)模小很多，這是由于：一方面，在飼養(yǎng)過程中可以有效的控制飼養(yǎng)環(huán)境，使動物所受到的環(huán)境因素趨于一致；另一方面，試驗群體的遺傳背景相似。

3.4 與動物重要經(jīng)濟性狀相關(guān)的代謝分子鑒定

代謝組學所反映的小分子物質(zhì)的產(chǎn)生和代謝能更直接、準確地反映生物體的生理狀態(tài)和生理表型，是復(fù)雜表型的分子展現(xiàn)。相對于表型數(shù)據(jù)而言，代謝分子更容易進行標準化和批量化的分析檢測，所檢測得到的數(shù)據(jù)更為準確。篩選與重要經(jīng)濟性狀或疾病相關(guān)的代謝分子是代謝組學研究的重要熱點。在人類代謝組學研究方面，通過比較對照與處理組之間的代謝組學差異篩選出表征疾病的生物標記，或通過將代謝組學和其他組學整合分析篩選出影響復(fù)雜疾病發(fā)生、發(fā)展的重要代謝分子。

表2 牛、豬、雞mGWAS研究結(jié)果匯總

續(xù)表

物種動物群體樣品代謝分子(類別)重要候選基因文獻 牛日本黑牛肌間脂肪油酸FMNL1、FASN、HRNBP3和SMURF2[55] 內(nèi)洛爾肉牛肌間脂肪不同鏈長脂肪酸SLITRK6、DHRS7、NUP214、SREBP-SCAP、GNG11、RGS5、WARS2、HMGCS2和PHGDH、HSD3B1、HAO2、GAD1、Sp5、ABCG5、GPC6、GPC4、MGCS2, PHGDH、RAPGEF2、AQP7、RORA、LOXL2、SPAG17和WDR3[56] 韓牛肌間脂肪肉豆蔻酸、油酸CCDC57和FASN[57] 夏洛萊?！涞聡伤固古2群體血清精氨酸NCAPG[58] 豬伊比利亞豬′長白背最長肌中鏈、長鏈脂肪酸DECR1、FABP4、FABP5、APOA2、USF1、FAS、MTTP、CYP2U1、PLA2G12A、PLA2、HADH、AACS和ELOVL7[59] 伊比利亞豬′長白背最長肌中鏈、長鏈脂肪酸LDLR, LIPG、ELOVL6, MGST2 KIT、RDH16和NUDT7[60] 杜洛克′皮特蘭雜交豬背最長肌三羧酸循環(huán)中間代謝產(chǎn)物PIK3C3、TTLL5、PTPRT、VAPB ANK3、RASGEF1A、SAMD4A、LRGUK、AKT3、ENPP3、CREB3L2、NFE2L3、HLCS、NTNG1、GBP4、PKN2、ZNHIT6、DDAH1和WDR63[61] 杜洛克′二花臉?F2、杜洛克′ (長白′約克夏)、蘇太豬、二花臉豬和萊蕪豬背最長肌不同鏈長脂肪酸FADS2、SREBF1和PLA2G7[62] 杜洛克背最長肌中鏈、長鏈脂肪酸NDUFC2、FASN、ACO、RANBP9、PSMD1、WNT8B、APBB2、ROBO2、ADGRL2、LIN7A、ZNF37A和TENM2[63] 八馬香豬背最長肌長鏈脂肪酸FADS2、FADS1、ABCD2、ELOVL7 ACSBG1、ELOVL7和ACOX2[64] 二花臉豬背最長肌長鏈脂肪酸FASN、ELOVL5、ELOVL6、ELOVL7、ABCD3, ABCA4和FADS2 杜洛克背最長肌不同鏈長脂肪酸GBF1、SCD、CUEDC2、NFKB2、HPS6、ELOVL3、FBXW4、BTRC、TMEM180、ACTR1A、SUFU、TRIM8、ABCC2 PAX2、HPSE2、DNMBP和HOGA1[65] 伊比利亞豬′長白背最長肌、背膘棕櫚油酸ELOVL6[66] 杜洛克′二花臉F2和蘇太豬背最長肌、腹脂長鏈脂肪酸ADIPOR2、ABCD2、PPARD、HMGA1、ACSBG1、ELOVL7和SCD[67] 杜洛克皮下脂肪不同鏈長脂肪酸CPN1、PKD2L1 、PAX2、ENTPD7和SEMAG4[68] 長白豬皮下脂肪棕櫚油酸ELOVL6 意大利大白豬背膘組織不同鏈長脂肪酸ELOVL6、ACSBG1、IDH3A、SCD、ELOVL3、APBB1IP、ADIPOR2、PNLIPRP1、PNLIPRP2、PNLIP、NLIPRP3、ME3、MTMR3、INPP5J、PLA2G3和PISD[69] 公豬頸下脂肪雄甾酮SULT2A1、SULT2B1、HSD17B14和CYP2A19[70] 雞Fayoumi雞血漿葡萄糖TPGS2[71] 伊朗Urmia雞× AA雞構(gòu)成F2血漿甘油三酯DOCK10和AP1S3[72]

在動物群體中，目前主要是利用研究代謝分子與重要經(jīng)濟性狀之間的相關(guān)性或差異分析來篩選生物標記物，育種者也期望能夠在育種實踐中利用這些篩選到的代謝分子作為生物標記物，并由此應(yīng)用于標記輔助選擇中，從而提高選擇的準確性。目前，一些代謝分子已被篩選出來作為奶牛產(chǎn)奶性狀或疾病的生物標記；尿碳酸酐酶-Ⅵ等代謝分子可以作為豬腎病診斷的生物標記；甘油磷脂等代謝分子可以作為雞腹水綜合征的生物標記。其他相關(guān)研究結(jié)果詳見表3。

隨著家養(yǎng)動物基因組數(shù)據(jù)的積累，研究者開始整合分析代謝組學與基因組、轉(zhuǎn)錄組、表觀組、表型組的數(shù)據(jù)，嘗試構(gòu)建出“遺傳標記或基因-代謝分子-表型”的關(guān)系網(wǎng)絡(luò)，從而篩選出相關(guān)的生物標記，同時進一步解析相關(guān)性狀的遺傳機制。如Weikard等[75]整合肉牛基因組、代謝分子和生產(chǎn)性能數(shù)據(jù)，發(fā)現(xiàn)“基因、基因-精氨酸、肉堿-牛生長性狀和體脂性狀”的通路，從而推測精氨酸、肉堿可以作為生長性狀和體脂性狀的生物標記物；Tetens等[47]通過整合基因組、代謝組學數(shù)據(jù)，發(fā)現(xiàn)“基因-甘油磷酸膽堿-酮體耐受性”的關(guān)系；Ha等[38]通過比較產(chǎn)犢前3周、產(chǎn)犢后4周、產(chǎn)犢后13周3個時間點的代謝產(chǎn)物，結(jié)合GWAS和基因組富集分析，篩選出參與脂質(zhì)和類固醇代謝的代謝分子與奶牛哺乳早期代謝適應(yīng)性性狀相關(guān)；Widmann等[58]和Weikard等[75]整合表型、代謝組學和基因組學數(shù)據(jù)推斷基因上的突變位點，通過調(diào)控精氨酸代謝而影響NO通路，從而促進血管平滑肌收縮，最終影響牛的生長；Lundén等[74]發(fā)現(xiàn)了“基因-三甲胺-魚腥味性狀”的關(guān)系，Chu等[92]利用此關(guān)系在北京油雞群體中剔除基因有害等位基因，從而培育出沒有魚腥味性狀的北京油雞。

表3 牛、豬、雞代謝分子與重要經(jīng)濟性狀之間的關(guān)系

4 結(jié)語與展望

目前，在人和家養(yǎng)動物群體中，代謝組學已廣泛應(yīng)用于遺傳學、功能基因組學、疾病預(yù)測、藥物設(shè)計等領(lǐng)域[93]。同時，代謝組學的研究也為動物育種技術(shù)開辟了新思路，如利用特定生理狀態(tài)的標記代謝分子對動物進行選育，或利用代謝組學信息理解動物潛在的遺傳差異。隨著代謝組學技術(shù)的日趨臻熟，該技術(shù)將會更為廣泛地應(yīng)用于牛、豬、雞等家養(yǎng)動物重要經(jīng)濟性狀的選育上，而且將會有助于闡明復(fù)雜的生物學機制問題。

當然，代謝組學研究還有很多亟待解決的問題。例如，生物體代謝產(chǎn)物的變化除受生理刺激和遺傳因素影響，與環(huán)境因素也密切相關(guān)，所以在代謝組學樣品收集和實驗設(shè)計時應(yīng)該考慮代謝對環(huán)境條件的敏感性；其次，目前已知的代謝組學技術(shù)平臺在儀器的靈敏度、檢測的覆蓋度上仍存在一定的局限性，檢測到的所有代謝分子可能也只代表了基因變異的一小部分，所以應(yīng)該提高代謝組學檢測技術(shù)的靈敏性、穩(wěn)定性、廣譜性和特異性；另外，代謝組學研究產(chǎn)生的海量高維數(shù)據(jù)，需要利用多元統(tǒng)計、生物信息等多種數(shù)據(jù)挖掘技術(shù)進行分析，代謝組學數(shù)據(jù)的分析是代謝組學研究的重要組成部分之一，但目前相關(guān)的研究方法還不夠成熟，仍需要進一步的完善。

隨著代謝組學數(shù)據(jù)的積累，將基因組、轉(zhuǎn)錄組、表觀組、蛋白組與代謝組學、表型組整合分析將成為今后的研究熱點，代謝組學信息的使用和發(fā)展也將有助于各種組學數(shù)據(jù)的整合分析。例如通過整合分析，篩選出影響重要經(jīng)濟性狀的“基因-蛋白質(zhì)-代謝分子-表型”網(wǎng)絡(luò)或通路；通過將代謝組學和表觀遺傳組整合分析，發(fā)現(xiàn)某些代謝分子與染色質(zhì)活躍區(qū)域的關(guān)系，從而更全面地解析機體內(nèi)的代謝分子遺傳學機制。

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Applications of metabonomics in animal genetics and breeding

Meng Zhou1,2,3, Junhong Jing1,2,3, Ruihan Mao1,2,3, Jing Guo1,2,3, Zhipeng Wang1,2,3

Metabolomics uses advanced analytical chemistry techniques to comprehensively identify, quantify, and characterize a large number of small molecule metabolites in biological samples (e.g., milk, plasma, and serum). It is routinely used in biomedical, nutritional, crop and farm animal research. Metabolomic analyses in farm animals have been initiated in many non-genetic application fields. Recently, it is being increasingly used in animal breeding with the emergence of physiological genomics/genetics and refined phenotypic description. In this review, we describe the features of metabolomics platforms and approaches, and summarize the metabolomics applications in animal genetics and genomics with a focus on some key areas, such as the heritability estimates of metabolomic profiles, identification differences metabolites between lines or breeds, genome-wide association studies with metabotypes, biomarker discovery for economic traits. Moreover, we also discuss the potential applications based on current livestock metabolomics studies. The intent of this review is to provide a critical overview of the trends in the applications of metabolomics in animal breeding, aiming to provide a reference for further studies on the genetic background of the important traits of farm animals combined metabolomics with genomics.

metabonomics; domestic animals; genetics; animal breeding

2018-08-08;

2018-10-17

國家自然科學基金項目(編號：31101709)，國家留學基金委項目(編號：201308230102)，東北農(nóng)業(yè)大學東農(nóng)學者計劃“學術(shù)骨干”項目(編號：15XG14)和農(nóng)業(yè)部雞遺傳育種重點實驗室開放課題(編號：CGB-201706)資助 [Supported by the Natural Science Foundation of China (No. 31101709), China Scholarship Council (No. 201308230102), Academic Backbone Project of Northeast Agricultural University (No. 15XG14) and the Open Projects of Key Laboratory of Chicken Genetics and Breeding Ministry of Agriculture and Rural Affairs (No. CGB-201706)]

周萌，碩士研究生，專業(yè)方向：動物分子數(shù)量遺傳學。E-mail: 1341417113@qq.com

王志鵬，博士，副教授，研究方向：動物分子數(shù)量遺傳學。E-mail: wangzhipeng@neau.edu.cn

10.16288/j.yczz.18-226

2019/1/14 13:15:25

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20190114.1315.006.html

(責任編委: 李明洲)