Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.
<p>The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| 格式: | Journal article |
| 語言: | English |
| 出版: |
Nature Publishing Group
2017
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| _version_ | 1826297566394843136 |
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| author | Wright, D Day, F Kerrison, N Zink, F Cardona, A Sulem, P Thompson, D Sigurjonsdottir, S Gudbjartsson, D Helgason, A Chapman, J Jackson, S Langenberg, C Wareham, N Scott, R Thorsteindottir, U Ong, K Stefansson, K Perry, J |
| author_facet | Wright, D Day, F Kerrison, N Zink, F Cardona, A Sulem, P Thompson, D Sigurjonsdottir, S Gudbjartsson, D Helgason, A Chapman, J Jackson, S Langenberg, C Wareham, N Scott, R Thorsteindottir, U Ong, K Stefansson, K Perry, J |
| author_sort | Wright, D |
| collection | OXFORD |
| description | <p>The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P<5x10-8) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10-6). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.</p> |
| first_indexed | 2024-03-07T04:33:36Z |
| format | Journal article |
| id | oxford-uuid:cf28dac2-a0b4-465d-a1a9-be7f3e69b57c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:33:36Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:cf28dac2-a0b4-465d-a1a9-be7f3e69b57c2022-03-27T07:40:42ZGenetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cf28dac2-a0b4-465d-a1a9-be7f3e69b57cEnglishSymplectic Elements at OxfordNature Publishing Group2017Wright, DDay, FKerrison, NZink, FCardona, ASulem, PThompson, DSigurjonsdottir, SGudbjartsson, DHelgason, AChapman, JJackson, SLangenberg, CWareham, NScott, RThorsteindottir, UOng, KStefansson, KPerry, J<p>The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P<5x10-8) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10-6). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.</p> |
| spellingShingle | Wright, D Day, F Kerrison, N Zink, F Cardona, A Sulem, P Thompson, D Sigurjonsdottir, S Gudbjartsson, D Helgason, A Chapman, J Jackson, S Langenberg, C Wareham, N Scott, R Thorsteindottir, U Ong, K Stefansson, K Perry, J Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. |
| title | Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. |
| title_full | Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. |
| title_fullStr | Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. |
| title_full_unstemmed | Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. |
| title_short | Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. |
| title_sort | genetic variants associated with mosaic y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility |
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