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Microarray Analysis of Copy Number Variants on the Human Y Chromosome Reveals Novel and Frequent Duplications Overrepresented in Specific Haplogroups.

Johansson MM, Van Geystelen A, Larmuseau MH, Djurovic S, Andreassen OA, Agartz I, Jazin E - PLoS ONE (2015)

Bottom Line: In a set of 1718 males, we found 25 different CNV patterns, many of which are novel.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.Our results demonstrate that currently available genome-wide SNP platforms can be used to identify duplications and deletions in the human Y chromosome.

View Article: PubMed Central - PubMed

Affiliation: Department of Organismal Biology, EBC, Uppsala University, Uppsala, Sweden.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus

Principal component analysis of Y chromosome specific SNP variation between haplogroups.A. The figure shows the graphical representation of the first two eigenvectors after PCA analysis. Y-axis corresponds to the first vector explaining 24.1% of the variation and X-axis explains 13.4% of the remaining variation. Each dot represents the results from one individual and the colour represent each HG as denoted by letters in the figure. The plus symbols in black denote individuals for which HG determination was ambiguous. The black triangles denote individuals for which no HG could be assigned. B. The results from the individuals carrying the blue-grey dupl are represented in blue, while the results from individuals carrying “blue-grey like dupl.” are in red. All cases are included within the NO-M214(xM175) haplogroup. In total 11 individuals carry these variants (Table 1) but they are superimposed in the figure, due to high similarity between their HG.
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pone.0137223.g004: Principal component analysis of Y chromosome specific SNP variation between haplogroups.A. The figure shows the graphical representation of the first two eigenvectors after PCA analysis. Y-axis corresponds to the first vector explaining 24.1% of the variation and X-axis explains 13.4% of the remaining variation. Each dot represents the results from one individual and the colour represent each HG as denoted by letters in the figure. The plus symbols in black denote individuals for which HG determination was ambiguous. The black triangles denote individuals for which no HG could be assigned. B. The results from the individuals carrying the blue-grey dupl are represented in blue, while the results from individuals carrying “blue-grey like dupl.” are in red. All cases are included within the NO-M214(xM175) haplogroup. In total 11 individuals carry these variants (Table 1) but they are superimposed in the figure, due to high similarity between their HG.

Mentions: Principal component analysis was performed as described in Methods with data from 1506 individuals belonging to 12 haplogroups. We found that the first and second eigenvectors explained 24.1% and 13.4% of the variability between groups. In general, the HGs are clearly segregated by this analysis, particularly R-M207, E-M96 and I-M170. Haplogroups NO-M214(xM175), KLT-M9(xM526), F-M89(xM1329), G-M201, J-M304 and O-M175 exhibit larger similarity between each other, but they can still be distinguished (Fig 4A).


Microarray Analysis of Copy Number Variants on the Human Y Chromosome Reveals Novel and Frequent Duplications Overrepresented in Specific Haplogroups.

Johansson MM, Van Geystelen A, Larmuseau MH, Djurovic S, Andreassen OA, Agartz I, Jazin E - PLoS ONE (2015)

Principal component analysis of Y chromosome specific SNP variation between haplogroups.A. The figure shows the graphical representation of the first two eigenvectors after PCA analysis. Y-axis corresponds to the first vector explaining 24.1% of the variation and X-axis explains 13.4% of the remaining variation. Each dot represents the results from one individual and the colour represent each HG as denoted by letters in the figure. The plus symbols in black denote individuals for which HG determination was ambiguous. The black triangles denote individuals for which no HG could be assigned. B. The results from the individuals carrying the blue-grey dupl are represented in blue, while the results from individuals carrying “blue-grey like dupl.” are in red. All cases are included within the NO-M214(xM175) haplogroup. In total 11 individuals carry these variants (Table 1) but they are superimposed in the figure, due to high similarity between their HG.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554990&req=5

pone.0137223.g004: Principal component analysis of Y chromosome specific SNP variation between haplogroups.A. The figure shows the graphical representation of the first two eigenvectors after PCA analysis. Y-axis corresponds to the first vector explaining 24.1% of the variation and X-axis explains 13.4% of the remaining variation. Each dot represents the results from one individual and the colour represent each HG as denoted by letters in the figure. The plus symbols in black denote individuals for which HG determination was ambiguous. The black triangles denote individuals for which no HG could be assigned. B. The results from the individuals carrying the blue-grey dupl are represented in blue, while the results from individuals carrying “blue-grey like dupl.” are in red. All cases are included within the NO-M214(xM175) haplogroup. In total 11 individuals carry these variants (Table 1) but they are superimposed in the figure, due to high similarity between their HG.
Mentions: Principal component analysis was performed as described in Methods with data from 1506 individuals belonging to 12 haplogroups. We found that the first and second eigenvectors explained 24.1% and 13.4% of the variability between groups. In general, the HGs are clearly segregated by this analysis, particularly R-M207, E-M96 and I-M170. Haplogroups NO-M214(xM175), KLT-M9(xM526), F-M89(xM1329), G-M201, J-M304 and O-M175 exhibit larger similarity between each other, but they can still be distinguished (Fig 4A).

Bottom Line: In a set of 1718 males, we found 25 different CNV patterns, many of which are novel.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.Our results demonstrate that currently available genome-wide SNP platforms can be used to identify duplications and deletions in the human Y chromosome.

View Article: PubMed Central - PubMed

Affiliation: Department of Organismal Biology, EBC, Uppsala University, Uppsala, Sweden.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus