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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

qPCR validation of the newly discovered P6 duplication.Amplification plots for a female (green), a control male (purple) and a male with P6 dupl. (blue) are shown for markers RH38681 (A), sY1081 (B) and sY933 (C). D. Intensity signal plot (Log 2 ratio) for an individual with P6 dupl. showing that markers sY1081 and sY933 are positioned within the duplicated region, while RH38681 is located outside.
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pone.0137223.g003: qPCR validation of the newly discovered P6 duplication.Amplification plots for a female (green), a control male (purple) and a male with P6 dupl. (blue) are shown for markers RH38681 (A), sY1081 (B) and sY933 (C). D. Intensity signal plot (Log 2 ratio) for an individual with P6 dupl. showing that markers sY1081 and sY933 are positioned within the duplicated region, while RH38681 is located outside.

Mentions: In addition, the last variant was named Palindrome 6 duplication (P6 dupl), started at position 18.279.605 (UCSC genome browser hg19) and ended at position 18.843.147. This duplication has not been previously described (Fig 2J). In the Norwegian population, five individuals displayed this variant, two of which also had a CNV in the AZFc region, including one b2/b3 del and one gr/gr dupl. We confirmed detected variants using STS markers for PCR analysis. sY1191 and sY1192 did not amplify in individuals with b2/b3 del and blue-grey dupl while they produced amplification bands in individuals with gr/gr del. Marker sY1291 amplified positively in individuals with b2/b3 del and blue-grey dupl while it was negative for gr/gr del (data not shown). For confirmation experiments of the newly discovered P6 dupl. we used a qPCR approach including markers RH38681, sY1081 and sY933 (Fig 3).


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)

qPCR validation of the newly discovered P6 duplication.Amplification plots for a female (green), a control male (purple) and a male with P6 dupl. (blue) are shown for markers RH38681 (A), sY1081 (B) and sY933 (C). D. Intensity signal plot (Log 2 ratio) for an individual with P6 dupl. showing that markers sY1081 and sY933 are positioned within the duplicated region, while RH38681 is located outside.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137223.g003: qPCR validation of the newly discovered P6 duplication.Amplification plots for a female (green), a control male (purple) and a male with P6 dupl. (blue) are shown for markers RH38681 (A), sY1081 (B) and sY933 (C). D. Intensity signal plot (Log 2 ratio) for an individual with P6 dupl. showing that markers sY1081 and sY933 are positioned within the duplicated region, while RH38681 is located outside.
Mentions: In addition, the last variant was named Palindrome 6 duplication (P6 dupl), started at position 18.279.605 (UCSC genome browser hg19) and ended at position 18.843.147. This duplication has not been previously described (Fig 2J). In the Norwegian population, five individuals displayed this variant, two of which also had a CNV in the AZFc region, including one b2/b3 del and one gr/gr dupl. We confirmed detected variants using STS markers for PCR analysis. sY1191 and sY1192 did not amplify in individuals with b2/b3 del and blue-grey dupl while they produced amplification bands in individuals with gr/gr del. Marker sY1291 amplified positively in individuals with b2/b3 del and blue-grey dupl while it was negative for gr/gr del (data not shown). For confirmation experiments of the newly discovered P6 dupl. we used a qPCR approach including markers RH38681, sY1081 and sY933 (Fig 3).

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