The contribution of evolutionarily volatile promoters to molecular phenotypes and human trait variation.
The contribution of evolutionarily volatile promoters to molecular phenotypes and human trait variation.
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DOI：
10.1186/s13059-022-02634-w
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发表时间：
2022-04-04
期刊：
影响因子：
12.3
通讯作者：
Taylor MS
中科院分区：
文献类型：
--
作者：
Young RS;Talmane L;Marion de Procé S;Taylor MS
启动子是具有高度表型相关遗传变异的转录起始点。物种间启动子的进化获得和丢失(统称为更替)普遍存在于哺乳动物基因组中，并可能在推动人类表型多样性方面发挥重要作用。我们根据人类启动子的进化历史对人类启动子进行分类，这些启动子是在小鼠和人类从共同祖先进化而来的过程中产生的。这定义了保守的、人类插入的和鼠标删除的启动子，以及一类功能更新的启动子，这些启动子在物种之间排列一致，但只在人类中有效。我们发现，所有进化类别的启动子都是替换和插入突变的热点。有插入和缺失历史的基因座在当代人类中延续着这种进化模式。基因中进化的挥发性启动子的存在与个体间表达差异的增加有关，但只有在人类插入和鼠标缺失的启动子的情况下，这才对应于启动子-近端遗传效应的丰富。尽管这些分子数量性状基因座(QTL)在进化上易挥发的启动子上有所丰富，但这并不意味着与这些基因座相对应的表型性状的丰富。启动子的更替在人类基因组中普遍存在，这些启动子在基因表达中存在丰富的分子可量化但表现为无关紧要的变异。然而，由于进化上易挥发的启动子表现出选择的证据，再加上高突变率和QTL的丰富，这意味着它们是进化创新和表型变异的来源，尽管它们具有选择性中性表达变异的高背景。网上版载有补充材料，可在10.1186/s13059-022-02634-w查阅。
Promoters are sites of transcription initiation that harbour a high concentration of phenotype-associated genetic variation. The evolutionary gain and loss of promoters between species (collectively, termed turnover) is pervasive across mammalian genomes and may play a prominent role in driving human phenotypic diversity. We classified human promoters by their evolutionary history during the divergence of mouse and human lineages from a common ancestor. This defined conserved, human-inserted and mouse-deleted promoters, and a class of functional-turnover promoters that align between species but are only active in humans. We show that promoters of all evolutionary categories are hotspots for substitution and often, insertion mutations. Loci with a history of insertion and deletion continue that mode of evolution within contemporary humans. The presence of an evolutionary volatile promoter within a gene is associated with increased expression variance between individuals, but only in the case of human-inserted and mouse-deleted promoters does that correspond to an enrichment of promoter-proximal genetic effects. Despite the enrichment of these molecular quantitative trait loci (QTL) at evolutionarily volatile promoters, this does not translate into a corresponding enrichment of phenotypic traits mapping to these loci. Promoter turnover is pervasive in the human genome, and these promoters are rich in molecularly quantifiable but phenotypically inconsequential variation in gene expression. However, since evolutionarily volatile promoters show evidence of selection, coupled with high mutation rates and enrichment of QTLs, this implicates them as a source of evolutionary innovation and phenotypic variation, albeit with a high background of selectively neutral expression variation. The online version contains supplementary material available at 10.1186/s13059-022-02634-w.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
14.9
作者：
Flicek P;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt S;Johnson N;Juettemann T;Kähäri AK;Keenan S;Kulesha E;Martin FJ;Maurel T;McLaren WM;Murphy DN;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ruffier M;Sheppard D;Taylor K;Thormann A;Trevanion SJ;Vullo A;Wilder SP;Wilson M;Zadissa A;Aken BL;Birney E;Cunningham F;Harrow J;Herrero J;Hubbard TJ;Kinsella R;Muffato M;Parker A;Spudich G;Yates A;Zerbino DR;Searle SM
通讯作者：
Searle SM
影响因子：
4.4
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Kindt AS;Navarro P;Semple CA;Haley CS
通讯作者：
Haley CS
影响因子：
64.8
作者：
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通讯作者：
Skol, Andrew
影响因子：
4.3
作者：
Baillie JK;Bretherick A;Haley CS;Clohisey S;Gray A;Neyton LPA;Barrett J;Stahl EA;Tenesa A;Andersson R;Brown JB;Faulkner GJ;Lizio M;Schaefer U;Daub C;Itoh M;Kondo N;Lassmann T;Kawai J;IIBDGC Consortium;Mole D;Bajic VB;Heutink P;Rehli M;Kawaji H;Sandelin A;Suzuki H;Satsangi J;Wells CA;Hacohen N;Freeman TC;Hayashizaki Y;Carninci P;Forrest ARR;Hume DA
通讯作者：
Hume DA