近日,，國際著名學(xué)術(shù)期刊Genome Research在線刊登了上海生科院計算生物學(xué)所金力教授等的最新研究成果“Genome-Wide Detection of Natural Selection in African Americans Pre-and Post-Admixture”。該研究充分利用混合人群的群體基因組結(jié)構(gòu)特征,，建立了檢測現(xiàn)代人群經(jīng)歷大規(guī)?；蚪涣髑昂笫艿江h(huán)境壓力下的自然選擇信號的分析方法,，研究結(jié)果對于認(rèn)識現(xiàn)代人類與環(huán)境因素相互作用、適應(yīng)生存環(huán)境以及基因組進(jìn)化機(jī)制具有重要意義,。
生物的進(jìn)化不是完美的,，朝任何一個方向的發(fā)展都會付出代價。從某種程度上講,，發(fā)生在今天人們身上的各種疾病就是進(jìn)化過程中人類適應(yīng)生存環(huán)境的一些副產(chǎn)物或者必然產(chǎn)物,。研究現(xiàn)代人類的環(huán)境適應(yīng)（或者自然對人類的選擇），有助于了解基因?qū)π誀畹挠绊?，建立遺傳變異與表型變異之間的相互關(guān)系,，闡明復(fù)雜性狀（疾病）的分子與遺傳基礎(chǔ),，從而對深入了解疾病發(fā)生的生物學(xué)機(jī)制和制定有效治療方案和開發(fā)藥物具有指導(dǎo)意義和應(yīng)用價值,。
自然選擇不僅發(fā)生在幾萬或幾十萬年前現(xiàn)代人類的祖先向地球的每一個角落探索和遷移的過程中，在近期的人群遷移和基因交流過程中也會發(fā)生,?；旌先巳阂话闶怯杀舜烁綦x分化的祖先人群在近期大規(guī)模基因交流產(chǎn)生,。隔離分化幾萬年的人群,，從原世居地遷移到數(shù)千里之隔的新地域，在近期彼此接觸,、交流形成新人群,。新建立的人群在遺傳結(jié)構(gòu)上顯著不同于其祖先人群，并且在新居住地新的環(huán)境中經(jīng)歷了上十個世代的適應(yīng)性演變,，成為研究現(xiàn)代人類適應(yīng)新環(huán)境可遇而不可求的天然素材,。
該項工作利用全基因組數(shù)據(jù)對典型的近期混合人群——美國黑人進(jìn)行了研究，發(fā)現(xiàn)其在混合前后受到了明顯的自然選擇,。該研究建立了一種檢測自然選擇的新方法,，不但檢測到的信號更為可靠，并能很好的解釋美國黑人經(jīng)歷的歷史和自然環(huán)境的變遷,。該研究發(fā)現(xiàn),，很多受自然選擇的基因與美國黑人的高發(fā)疾病相關(guān),，推測這些高發(fā)性疾病可能和美國黑人的非洲祖先最近經(jīng)歷的巨大環(huán)境變化有關(guān)。另外,，該研究還發(fā)現(xiàn),，很多抵抗瘧疾的等位基因頻率在美國黑人中明顯降低，反映了北美和非洲的不同病原體在人類基因組中留下了顯著的但不同的烙印,。同時也提示人類生存環(huán)境中的微生物群落和體內(nèi)的病原體可能是自然選擇發(fā)生的重要推動力之一,。
該研究工作由計算生物學(xué)所博士生靳文菲在導(dǎo)師金力教授和徐書華研究員的共同指導(dǎo)下，與國家人類基因組南方研究中心及哈佛兒科醫(yī)院的研究人員合作完成,。該研究工作得到了國家自然科學(xué)基金委、上海市科委,、中國科學(xué)院,、德國馬普學(xué)會、香港王寬誠教育基金會等多項基金的資助,。（生物谷Bioon.com）
doi:10.1101/gr.124784.111
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Genome-Wide Detection of Natural Selection in African Americans Pre-and Post-Admixture
Wenfei Jin1, Shuhua Xu1, Haifeng Wang2, Yongguo Yu3, Yiping Shen4, Bailin Wu4 and Li Jin4,5
It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal SNPs genotyped in 5,210 individuals and conducted a genome-wide search for selection signals in 1,890 AfA. Several genomic regions showing excess of African or European ancestry, which were thought as the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre-and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF). Interestingly, many selection-candidate genes identified by the new approach were associated with AfA specific high-risk diseases such as prostate cancer and hypertension, suggesting an important role these disease-related genes might have played in adapting to new environment. CD36 and HBB, whose mutations confer a degree of protection against malaria, were also located in the highly differentiated regions between AAF and IAF. Further analysis showed that the frequencies of alleles protecting against malaria in AAF were lower than that in IAF, which consists with the relaxed selection pressure of malaria in the New World. There is no overlap between the top candidate genes detected by the two approaches, indicating the different environmental pressures AfA experienced pre-and post-population-admixture. We suggest that the new approach is reasonably powerful and can also be applied to other admixed populations such as Latinos and Uyghurs.
