Johansson Martin M, Van Geystelen Anneleen, Larmuseau Maarten H D, Djurovic Srdjan, Andreassen Ole A, Agartz Ingrid, Jazin Elena
Department of Organismal Biology, EBC, Uppsala University, Uppsala, Sweden.
Laboratory of Socioecology and Social Evolution, Department of Biology, KU Leuven, Leuven, Belgium.
PLoS One. 2015 Aug 31;10(8):e0137223. doi: 10.1371/journal.pone.0137223. eCollection 2015.
The human Y chromosome is almost always excluded from genome-wide investigations of copy number variants (CNVs) due to its highly repetitive structure. This chromosome should not be forgotten, not only for its well-known relevance in male fertility, but also for its involvement in clinical phenotypes such as cancers, heart failure and sex specific effects on brain and behaviour.
We analysed Y chromosome data from Affymetrix 6.0 SNP arrays and found that the signal intensities for most of 8179 SNP/CN probes in the male specific region (MSY) discriminated between a male, background signals in a female and an isodicentric male containing a large deletion of the q-arm and a duplication of the p-arm of the Y chromosome. Therefore, this SNP/CN platform is suitable for identification of gain and loss of Y chromosome sequences. In a set of 1718 males, we found 25 different CNV patterns, many of which are novel. We confirmed some of these variants by PCR or qPCR. The total frequency of individuals with CNVs was 14.7%, including 9.5% with duplications, 4.5% with deletions and 0.7% exhibiting both. Hence, a novel observation is that the frequency of duplications was more than twice the frequency of deletions. Another striking result was that 10 of the 25 detected variants were significantly overrepresented in one or more haplogroups, demonstrating the importance to control for haplogroups in genome-wide investigations to avoid stratification. NO-M214(xM175) individuals presented the highest percentage (95%) of CNVs. If they were not counted, 12.4% of the rest included CNVs, and the difference between duplications (8.9%) and deletions (2.8%) was even larger.
Our results demonstrate that currently available genome-wide SNP platforms can be used to identify duplications and deletions in the human Y chromosome. Future association studies of the full spectrum of Y chromosome variants will demonstrate the potential involvement of gain or loss of Y chromosome sequence in different human phenotypes.
由于人类Y染色体高度重复的结构，在全基因组拷贝数变异（CNV）研究中几乎总是被排除在外。这条染色体不应被忽视，不仅因其在男性生育方面的众所周知的相关性，还因其与癌症、心力衰竭等临床表型以及对大脑和行为的性别特异性影响有关。
我们分析了Affymetrix 6.0 SNP阵列的Y染色体数据，发现男性特异性区域（MSY）中8179个SNP/CN探针中的大多数信号强度能够区分男性、女性背景信号以及含有Y染色体q臂大缺失和p臂重复的等臂双着丝粒男性。因此，这个SNP/CN平台适用于识别Y染色体序列的增减。在一组1718名男性中，我们发现了25种不同的CNV模式，其中许多是新的。我们通过PCR或qPCR证实了其中一些变异。具有CNV的个体的总频率为14.7%，包括9.5%的重复、4.5%的缺失和0.7%的同时存在重复和缺失。因此，一个新的发现是重复的频率是缺失频率的两倍多。另一个显著结果是，在检测到的25个变异中，有10个在一个或多个单倍群中显著富集，这表明在全基因组研究中控制单倍群以避免分层的重要性。非M214（xM175）个体的CNV比例最高（95%）。如果不计算他们，其余个体中有12.4%存在CNV，重复（8.9%）和缺失（2.8%）之间的差异甚至更大。
我们的结果表明，目前可用的全基因组SNP平台可用于识别人类Y染色体中的重复和缺失。未来对Y染色体变异全谱的关联研究将证明Y染色体序列的增减在不同人类表型中的潜在作用。
