Mishmar Dan, Ruiz-Pesini Eduardo, Brandon Martin, Wallace Douglas C
The Center of Molecular and Mitochondrial Genetics and Medicine (MAMMAG), University of California, Irvine, California.
Hum Mutat. 2004 Feb;23(2):125-133. doi: 10.1002/humu.10304.
Nuclear mitochondrial DNA sequences (NUMTs) are common in eukaryotes. However, the mechanism by which they integrate into the nuclear genome remains a riddle. We analyzed 247 NUMTs in the human nuclear DNA (nDNA), along with their flanking regions. This analysis revealed that some NUMTs have accumulated many changes, and thus have resided in the nucleus a long time, while others are >94% similar to the reference human mitochondrial DNA (mtDNA), and thus must be recent. Among the latter, two NUMTs, encompassing the COI gene, carry a set of transitions characteristic of the extant African-specific L macrohaplogroup mtDNAs and are more homologous to human mtDNA than to chimp. Screening for one of these NUMTs revealed its presence in all human samples tested, confirming that the African macrohaplogroup L mtDNAs were present in the earliest modern humans and thus were the first human mtDNAs. An analysis of flanking sequences of the NUMTs revealed that 59% were within 150 bp of repetitive elements, with 26% being within 15 bp of and 33% being within 15-150 bp of repetitive elements. Only 14% were integrated into a repetitive element. This association of NUMTs with repetitive elements is highly nonrandom (p<0.001). These data suggest that the vicinity of transposable elements influences the ongoing integration of mtDNA sequences and their subsequent duplication within the nDNA. Finally, NUMTs appear to preferentially integrate into DNA with different GC content than the surrounding chromosomal band. Our results suggest that chromosomal structure might influence integration of NUMTs.
核线粒体DNA序列（NUMTs）在真核生物中很常见。然而，它们整合到核基因组中的机制仍是一个谜。我们分析了人类核DNA（nDNA）中的247个NUMTs及其侧翼区域。该分析表明，一些NUMTs积累了许多变化，因此已在细胞核中存在很长时间，而另一些与参考人类线粒体DNA（mtDNA）的相似度>94%，因此必定是近期出现的。在后者中，两个包含COI基因的NUMTs携带了一组现存非洲特异性L大支系mtDNA特有的转换，并且与人类mtDNA的同源性高于与黑猩猩mtDNA的同源性。对其中一个NUMTs的筛选显示，它存在于所有测试的人类样本中，证实非洲大支系L mtDNA存在于最早的现代人类中，因此是最早的人类mtDNA。对NUMTs侧翼序列的分析表明，59%位于重复元件的150 bp范围内，其中26%位于重复元件的15 bp内，33%位于重复元件的15 - 150 bp内。只有14%整合到重复元件中。NUMTs与重复元件的这种关联是高度非随机的（p<0.001）。这些数据表明，转座元件的附近区域会影响mtDNA序列的持续整合及其在nDNA中的后续复制。最后，NUMTs似乎优先整合到与周围染色体带GC含量不同的DNA中。我们的结果表明，染色体结构可能会影响NUMTs的整合。
