Park Sung-Sup, Stankiewicz Paweł, Bi Weimin, Shaw Christine, Lehoczky Jessica, Dewar Ken, Birren Bruce, Lupski James R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.
Genome Res. 2002 May;12(5):729-38. doi: 10.1101/gr.82802.
An approximately 4-Mb genomic segment on chromosome 17p11.2, commonly deleted in patients with the Smith-Magenis syndrome (SMS) and duplicated in patients with dup(17)(p11.2p11.2) syndrome, is flanked by large, complex low-copy repeats (LCRs), termed proximal and distal SMS-REP. A third copy, the middle SMS-REP, is located between them. SMS-REPs are believed to mediate nonallelic homologous recombination, resulting in both SMS deletions and reciprocal duplications. To delineate the genomic structure and evolutionary origin of SMS-REPs, we constructed a bacterial artificial chromosome/P1 artificial chromosome contig spanning the entire SMS region, including the SMS-REPs, determined its genomic sequence, and used fluorescence in situ hybridization to study the evolution of SMS-REP in several primate species. Our analysis shows that both the proximal SMS-REP (approximately 256 kb) and the distal copy (approximately 176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (approximately 241 kb) is inverted and appears to have been derived from the proximal copy. The SMS-REP LCRs are highly homologous (>98%) and contain at least 14 genes/pseudogenes each. SMS-REPs are not present in mice and were duplicated after the divergence of New World monkeys from pre-monkeys approximately 40-65 million years ago. Our findings potentially explain why the vast majority of SMS deletions and dup(17)(p11.2p11.2) occur at proximal and distal SMS-REPs and further support previous observations that higher-order genomic architecture involving LCRs arose recently during primate speciation and may predispose the human genome to both meiotic and mitotic rearrangements.
17号染色体短臂11.2区一个约4兆碱基的基因组片段，在史密斯-马吉尼斯综合征（SMS）患者中通常发生缺失，而在dup(17)(p11.2p11.2)综合征患者中则发生重复，其两侧是大型复杂的低拷贝重复序列（LCR），称为近端和远端SMS-REP。第三个拷贝，即中间SMS-REP，位于它们之间。据信SMS-REP介导非等位基因同源重组，导致SMS缺失和相互重复。为了描绘SMS-REP的基因组结构和进化起源，我们构建了一个细菌人工染色体/P1人工染色体重叠群，跨越整个SMS区域，包括SMS-REP，确定了其基因组序列，并使用荧光原位杂交技术研究了几种灵长类物种中SMS-REP的进化。我们的分析表明，近端SMS-REP（约256 kb）和远端拷贝（约176 kb）的方向相同，均源自一个祖先拷贝，而中间SMS-REP（约241 kb）是反向的，似乎源自近端拷贝。SMS-REP LCR高度同源（>98%），每个至少包含14个基因/假基因。SMS-REP在小鼠中不存在，大约在4000万至6500万年前新世界猴与前猴分化后发生了重复。我们的发现可能解释了为什么绝大多数SMS缺失和dup(17)(p11.2p11.2)发生在近端和远端SMS-REP，并进一步支持了先前的观察结果，即涉及LCR的高阶基因组结构在灵长类物种形成过程中最近才出现，可能使人类基因组易发生减数分裂和有丝分裂重排。
