Can 3D diploid genome reconstruction from unphased Hi-C data be salvaged?
Can 3D diploid genome reconstruction from unphased Hi-C data be salvaged?
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DOI：
10.1093/nargab/lqac038
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发表时间：
2022-06
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
染色质的三维（3D）结构影响许多细胞过程。然而，在高分辨率下直接观察染色质结构是具有挑战性的。因此，利用染色质构象捕获分析（特别是Hi-C）推断三维结构已经受到了相当大的关注，并提出了许多重建算法。虽然这些方法增强了对染色质组织的认识，但当面对二倍体基因组时，大多数都有一个严重的缺点：无法消除同源染色体上相应位点之间的接触歧义，使得随之而来的重建可能毫无意义。最近的三个建议以牺牲强假设为代价，提供了一种计算方法。在这里，我们表明，对同源染色体接触的成分作出合理的假设，为挽救传统的基于共识的无阶段重建提供了基础。这将是相应的，因为不仅需要二倍体重建相当大的假设，而且选择非阶段算法的复杂性在分辨率和折叠复杂性方面提供了实质性的优势。而不是假设必要的打捞假设得到满足，我们利用最新的成像技术，原位基因组测序（IGS），全面评估其合理性。我们类似地使用IGS来评估支持二倍体重建算法的假设。结果令人信服地表明，在所有情况下，假设都不满足，这使得进一步的算法开发（可能由IGS数据提供信息）至关重要。
The three-dimensional (3D) configuration of chromatin impacts numerous cellular processes. However, directly observing chromatin architecture at high resolution is challenging. Accordingly, inferring 3D structure utilizing chromatin conformation capture assays, notably Hi-C, has received considerable attention, with a multitude of reconstruction algorithms advanced. While these have enhanced appreciation of chromatin organization, most suffer from a serious shortcoming when faced with diploid genomes: inability to disambiguate contacts between corresponding loci on homologous chromosomes, making attendant reconstructions potentially meaningless. Three recent proposals offer a computational way forward at the expense of strong assumptions. Here, we show that making plausible assumptions about the components of homologous chromosome contacts provides a basis for rescuing conventional consensus-based, unphased reconstruction. This would be consequential since not only are assumptions needed for diploid reconstruction considerable, but the sophistication of select unphased algorithms affords substantive advantages with regard resolution and folding complexity. Rather than presuming that the requisite salvaging assumptions are met, we exploit a recent imaging technology, in situ genome sequencing (IGS), to comprehensively evaluate their reasonableness. We analogously use IGS to assess assumptions underpinning diploid reconstruction algorithms. Results convincingly demonstrate that, in all instances, assumptions are not met, making further algorithm development, potentially informed by IGS data, essential.
影响因子：
4.4
作者：
Capurso D;Segal MR
通讯作者：
Segal MR