139: MosCoverY: a coverage-based method to detect mosaic loss of Y

Timonina V et al., The American Journal of Human Genetics - MosCoverY is a coverage-based method that estimates mosaic loss of the Y chromosome (mLOY) from exome or whole-genome sequencing by normalizing single-copy MSY exon coverage to matched autosomal exons. The method was validated in 212,062 UK Biobank men and applied to SHCS and TCGA datasets. Key terms: mosaic loss of Y, exome sequencing, whole-genome sequencing, coverage normalization, population genomics.

Study Highlights:
MosCoverY focuses on single-copy genes in the male-specific region of chrY and normalizes exon coverage to 100 autosomal exons matched by GC content and length, then rescales to the haploid expectation. Applied to 212,062 UK Biobank men, MosCoverY identified mLOY in 5.6% and produced cell-fraction estimates that strongly correlated with mLRRY, PAR-LOY, and WGS Control-FREEC. The method replicated known associations of mLOY with age, smoking, all-cause mortality, and germline loci, was robust to downsampling, and worked on tumor exomes from TCGA. MosCoverY can be used for single-sample analysis if the same capture kit is used, but capture-kit-specific recalibration is recommended.

Conclusion:
MosCoverY enables reliable detection and quantification of mLOY from exome and WGS coverage data at population scale, facilitating epidemiological, genetic, and tumor-based analyses.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
MosCoverY: A method to estimate mosaic loss of Y chromosome from sequencing coverage data

First author:
Timonina V

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.08.016

Reference:
Timonina V., Marchal A., Abel L., Cobat A., Fellay J. MosCoverY: A method to estimate mosaic loss of Y chromosome from sequencing coverage data. The American Journal of Human Genetics (2025) 112, 1–11. https://doi.org/10.1016/j.ajhg.2025.08.016

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/moscovery-a-new-method-to-estimate-mosaic-loss-of-y-chromosome-from-sequencing-coverage-data

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited sections describing MosCoverY methodology (13 Y-exons and 100 autosomal exons, normalization, thresholding, and conversion to cell fraction), UK Biobank validation results, cross-method comparisons (mLRRY, PAR-LOY, Control-FREEC), TCGA tumor data, and SHCS/single-sample applicability along with li
- transcript topics: MosCoverY method overview; Y chromosome sequencing challenges in exome data; 13 Y exons and 100 autosomal exons normalization; Normalization to autosomal exons and scaling to 0.5; Binary mLOY threshold via IQR rule; Conversion to fraction of cells with mLOY

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- MosCoverY focuses on 13 Y-chromosome single-copy genes in X-degenerate regions and uses 100 autosomal exons matched by GC content and length for normalization.
- Normalized chrY coverage is scaled so the population median equals 0.5 (haploid Y baseline).
- Binary mLOY calls are defined by thresholding the scaled chrY coverage at Q1 - 1.5 × IQR.
- UK Biobank exome data: 212,062 male participants; MosCoverY identifies 11,897 (5.6%) mLOY carriers; mean cell fraction ~2.8%.
- Compared methods show mLRRY identifying ~5.4% and PAR-LOY ~10.1% mLOY carriers; MosCoverY exhibits higher concordance with WGS-derived Control-FREEC.
- TCGA data show higher mLOY prevalence in tumors (38%), with extremely high prevalence in papillary kidney adenocarcinoma (around 89%).

QC result: Pass.