Evolutionarily diverse determinants of meiotic DNA break and recombination landscapes across the genome.
Evolutionarily diverse determinants of meiotic DNA break and recombination landscapes across the genome.
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DOI：
10.1101/gr.172122.114
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发表时间：
2014-10
期刊：
影响因子：
7
通讯作者：
Smith GR
中科院分区：
文献类型：
--
作者：
Fowler KR;Sasaki M;Milman N;Keeney S;Smith GR
分裂酵母Rec12 （Spo11同源物）通过形成发育程序性DNA双链断裂（DSBs）启动减数分裂重组。DSB分布影响遗传模式和基因组进化，但对Rec12切割位点高度非随机选择的基础了解甚少，主要是因为现有图谱的分辨率和灵敏度相对较低。在这里，我们通过测序DNA切割后附着在Rec12上的寡核苷酸，以接近核苷酸的分辨率确定了DSBs的全基因组。单一寡核苷酸大小类允许我们对所有断裂事件进行深度采样。我们在整个基因组中发现了强有力的证据，表明DSB的差异修复可以解释交叉不变性（尽管存在DSB热点，但cM/kb不变）。令人惊讶的是，大约一半的交叉发生在dsb以低频发生的区域，并且在细胞到细胞的位置上广泛分散。因此，这些以前未被发现的低水平dsb在减数分裂中起着巨大而关键的作用。我们进一步发现，潜在的核苷酸序列和染色体结构的影响在多个方面不同于出芽酵母。dsb并不强烈局限于核小体耗尽区域，因为它们在出芽酵母中，但仍然受到染色质结构的空间影响。我们的分析表明，进化上的流体因素有助于交叉的起始和调节。
Fission yeast Rec12 (Spo11 homolog) initiates meiotic recombination by forming developmentally programmed DNA double-strand breaks (DSBs). DSB distributions influence patterns of heredity and genome evolution, but the basis of the highly nonrandom choice of Rec12 cleavage sites is poorly understood, largely because available maps are of relatively low resolution and sensitivity. Here, we determined DSBs genome-wide at near-nucleotide resolution by sequencing the oligonucleotides attached to Rec12 following DNA cleavage. The single oligonucleotide size class allowed us to deeply sample all break events. We find strong evidence across the genome for differential DSB repair accounting for crossover invariance (constant cM/kb in spite of DSB hotspots). Surprisingly, about half of all crossovers occur in regions where DSBs occur at low frequency and are widely dispersed in location from cell to cell. These previously undetected, low-level DSBs thus play an outsized and crucial role in meiosis. We further find that the influence of underlying nucleotide sequence and chromosomal architecture differs in multiple ways from that in budding yeast. DSBs are not strongly restricted to nucleosome-depleted regions, as they are in budding yeast, but are nevertheless spatially influenced by chromatin structure. Our analyses demonstrate that evolutionarily fluid factors contribute to crossover initiation and regulation.
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