Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome
Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome
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DOI：
10.1101/gr.102970.109
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发表时间：
2010-05-01
期刊：
影响因子：
7
通讯作者：
Hall, Ira M.
中科院分区：
文献类型：
--
作者：
Quinlan, Aaron R.;Clark, Royden A.;Hall, Ira M.
结构变异（SV）是哺乳动物遗传多样性的丰富来源，但由于与复杂基因组中SV的定位相关的挑战，有关其基因组分布和机制起源的基本问题仍然没有答案。我们已经开发了一种算法（HYDROGEN），以本地化SV断点的配对末端映射，和一个通用的方法，全基因组的装配和解释的断点序列。我们将这些方法应用于两个近交系小鼠：C57 BL/6 J和DBA/2 J。我们证明，HYDROGEN准确地映射不同类别的SV，包括那些涉及重复元件，如转座子和片段重复;然而，我们的C57 BL/6 J参考菌株的分析表明，不完整的参考基因组组装是噪声的主要来源。我们报告7196 SV之间的两个菌株，其中超过三分之二是由于转座子插入。其余的59%是缺失（相对于参考），26%是未连接DNA的插入，9%是串联重复，6%是倒位。为了研究SV的起源，我们以单核苷酸分辨率表征了3316个断点序列。我们发现，类似于16%的非转座子SV具有与DNA复制或修复过程中的模板转换一致的复杂断点模式，并且该过程似乎优先产生某些类别的复杂变体。此外，我们发现，SV显着丰富的区域的节段性重复，但这种效果在很大程度上是独立的DNA序列同源性，因此不能单独解释非等位基因同源重组（NAHR）。这一结果表明，这些区域的遗传不稳定性往往是重复的基因组结构的原因，而不是结果。
Structural variation (SV) is a rich source of genetic diversity in mammals, but due to the challenges associated with mapping SV in complex genomes, basic questions regarding their genomic distribution and mechanistic origins remain unanswered. We have developed an algorithm (HYDRA) to localize SV breakpoints by paired-end mapping, and a general approach for the genome-wide assembly and interpretation of breakpoint sequences. We applied these methods to two inbred mouse strains: C57BL/6J and DBA/2J. We demonstrate that HYDRA accurately maps diverse classes of SV, including those involving repetitive elements such as transposons and segmental duplications; however, our analysis of the C57BL/6J reference strain shows that incomplete reference genome assemblies are a major source of noise. We report 7196 SVs between the two strains, more than two-thirds of which are due to transposon insertions. Of the remainder, 59% are deletions (relative to the reference), 26% are insertions of unlinked DNA, 9% are tandem duplications, and 6% are inversions. To investigate the origins of SV, we characterized 3316 breakpoint sequences at single-nucleotide resolution. We find that similar to 16% of non-transposon SVs have complex breakpoint patterns consistent with template switching during DNA replication or repair, and that this process appears to preferentially generate certain classes of complex variants. Moreover, we find that SVs are significantly enriched in regions of segmental duplication, but that this effect is largely independent of DNA sequence homology and thus cannot be explained by non-allelic homologous recombination (NAHR) alone. This result suggests that the genetic instability of such regions is often the cause rather than the consequence of duplicated genomic architecture.