Data Sheet 1_Characterization of novel human endogenous retrovirus structures on chromosomes 6 and 7.pdf

Human endogenous retroviruses (HERV) represent nearly 8% of the human genome. Of these, HERV-K subtype HML-2 is a transposable element that plays a critical role in embryonic development and in the pathogenesis of several diseases. Quantification and characterization of these multiple HML-2 insertions in the human chromosome has been challenging due to their size, sequence homology with each other, and their repetitive nature. We examined a cohort of 222 individuals for HML-2 proviruses 6q14.1 and 7p22.1a, two loci that are capable of producing full-length viral proteins and have been previously implicated in several cancers, autoimmune disorders and neurodegenerative diseases, using long-read DNA sequencing. While the reference genome for both regions suggests these two loci are structurally dissimilar, we found that for both loci about 5% of individuals have a unique tandem repeat-like sequence (three long terminal repeat sequences sandwiching two internal, potentially protein coding sequences), while most individuals have a standard proviral structure (one internal region sandwiched by two long terminal repeats). Moreover, both proviruses can make full-length, or nearly full-length, HERV-K proteins in multiple transcription orientations. The amino acid sequences from different loci in the same transcriptional orientation share sequence homology with each other. These results demonstrate a clear, previously unreported, relationship between HML-2 loci 6q14.1 and 7p22.1a and highlight the utility of long-read sequencing to study repetitive elements. Future studies need to determine if these polymorphisms determine genetic susceptibility to diseases that are associated with them.

人类内源性逆转录病毒（human endogenous retroviruses, HERV）约占人类基因组的8%。其中，HERV-K亚型HML-2属于转座因子，在胚胎发育及多种疾病的致病机制中发挥关键作用。由于此类插入序列的长度、彼此间的序列同源性以及自身的重复特性，对人类染色体中多个HML-2插入位点进行定量与特征分析一直颇具挑战。本研究采用长读长DNA测序技术，对222名受试者的两个HML-2原病毒位点6q14.1与7p22.1a进行了分析。这两个位点可编码全长病毒蛋白，既往研究已证实其与多种癌症、自身免疫性疾病及神经退行性疾病存在关联。尽管两个区域的参考基因组显示这两个位点的结构存在差异，但本研究发现，在两个位点中均有约5%的受试者携带独特的类串联重复序列——即由三个长末端重复序列夹合两个内部潜在蛋白编码序列，而多数受试者的位点则呈现标准原病毒结构：由两个长末端重复序列夹合一个内部区域。此外，这两种原病毒均可通过多种转录方向合成全长或近全长的HERV-K蛋白。处于相同转录方向的不同位点所编码的氨基酸序列彼此间存在序列同源性。本研究结果明确揭示了HML-2位点6q14.1与7p22.1a之间此前未被报道的关联，同时凸显了长读长测序技术在重复元件研究中的应用价值。未来研究需明确此类多态性是否会影响与之相关疾病的遗传易感性。