Developmental and temporal characteristics of clonal sperm mosaicism.

Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.

Sub-GOFA: A tool for Sub-Gene Ontology function analysis in clonal mosaicism using semantic (logical) similarity.

Clonal mosaicism (a detectable post-zygotic mutational event in cellular subpopulations) is common in cancer patients. Detected segments of clonal mosaicism are usually bundled into large-locus regions for statistical analysis. However, low-frequency genes are overlooked and are not sufficient to elucidate qualitative differences between cancer patients and non-patients. Therefore, it is of interest to develop and describe a tool named Sub-GOFA for Sub-Gene Ontology function analysis in clonal mosaicism using semantic similarity. Sub-GOFA measures the semantic (logical) similarity among patients using the sub-GO network structures of various sizes segmented from the gene ontology (GO) for clustering analysis. The sub-GO's root-terms with significant differences are extracted as disease-associated genetic functions. Sub-GOFA selected a high ratio of cancer-associated genes under validation with acceptable threshold.

Loss of Y chromosome: An emerging next-generation biomarker for disease prediction and early detection?

As human life expectancy increases substantially and aging is the primary risk factor for most chronic diseases, there is an urgent need for advancing the development of post-genomic era biomarkers that can be used for disease prediction and early detection (DPED). Mosaic loss of Y chromosome (LOY) is the state of nullisomy Y in sub-groups of somatic cells acquired from different post-zygotic development stages and onwards throughout the lifespan. Multiple large-cohort based epidemiology studies have found that LOY in blood cells is a significant risk factor for future mortality and various diseases in males. Many features intrinsic to LOY analysis may be leveraged to enhance its use as a non-invasive, sensitive, reliable, high throughput-biomarker for DPED. Here, we review the emerging literatures in LOY studies and highlight ten strengths for using LOY as a novel biomarker for genomics-driven DPED diagnostics. Meanwhile, the current limitations in this area are also discussed. We conclude by identifying some important knowledge gaps regarding the consequences of malsegregation of the Y chromosome and propose further steps that are required before clinical implementation of LOY. Taken together, we think that LOY has substantial potential as a biomarker for DPED, despite some hurdles that still need to be addressed before its integration into healthcare becomes acceptable.