The clock-like accumulation of germline and somatic mutations can arise from the interplay of DNA damage and repair

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(6), P. e3002678 - e3002678

Published: June 17, 2024

The rates at which mutations accumulate across human cell types vary. To identify causes of this variation, are often decomposed into a combination the single-base substitution (SBS) “signatures” observed in germline, soma, and tumors, with idea that each signature corresponds to one or small number underlying mutagenic processes. Two such signatures turn out be ubiquitous types: SBS 1, consists primarily transitions methylated CpG sites thought caused by spontaneous deamination, more diffuse 5, is unknown etiology. In cancers, attributed these 2 accumulates linearly age diagnosis, thus have been termed “clock-like.” better understand clock-like behavior, we develop mathematical model includes DNA replication errors, unrepaired damage, damage repaired incorrectly. We show mutational can exhibit behavior because divisions occur constant rate and/or remain over time, distinct sources teased apart comparing lineages divide different rates. With goal mind, analyze accumulation multiple types, including soma as well male female germline. find no detectable increase 1 neurons only very weak assigned but significant time rapidly dividing cells, suggesting driven rounds occurring relatively fixed rate. contrast, 5 increases all postmitotic ones, indicating it independently divisions; observation points errors repair key mechanism. Thus, two “clock-like” likely origins, set division, other

Language: Английский

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Chasing Sequencing Perfection: Marching Toward Higher Accuracy and Lower Costs

Genomics Proteomics & Bioinformatics, Journal Year: 2024, Volume and Issue: 22(2)

Published: March 11, 2024

Next-generation sequencing (NGS), represented by Illumina platforms, has been an essential cornerstone of basic and applied research. However, the error rate 1 per 1000 bp (10-3) represents a serious hurdle for research areas focusing on rare mutations, such as somatic mosaicism or microbe heterogeneity. By examining high-fidelity methods developed in past decade, we summarized three major factors underlying errors corresponding 12 strategies mitigating these errors. We then proposed novel framework to classify 11 preexisting representative according combinatory identified trends that emerged during methodological developments. further extended this analysis eight long-read methods, emphasizing reduction strategies. Finally, suggest two promising future directions could achieve comparable even higher accuracy with lower costs both NGS sequencing.

Language: Английский

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A tale of two strands: Decoding chromatin replication through strand-specific sequencing

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 238 - 261

Published: Jan. 1, 2025

Language: Английский

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Somatic mutations acquired during life: state of the art and implications for the kidney

Kidney International, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Direct measurement of the male germline mutation rate in individuals using sequential sperm samples

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 15, 2025

Mutations that accumulate in the human male germline with age are a major driver of genetic diversity and contribute to diseases. However, aging-related mutation rates have not been measured directly cells (sperm) at level individuals. We developed study design which we recalled 23 sperm donors prior banked samples provide new samples. The old sequential were separated by long timespans, ranging from 10 33 years. profiled these high-fidelity duplex sequencing demonstrate direct yields cohort-wide patterns consistent family-based (trio) studies. In every individual, detected an increase burden between two samples, yielding individual-specific measurements rate. Deep whole-genome individuals followed targeted validation remarkably stable mosaicism clonal mutations likely arose during embryonic development, suggesting did substantially impact spermatogonial stem cell pools Our application deep provides insight into processes germline. germline, can lead diseases offspring. Here, authors collect they profile processes.

Language: Английский

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DNA lesions piece together impossible trees

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

DNA lesions can persist through multiple cell cycles, resulting in mutational strand asymmetry, multiallelic variation, and somatic mosaicism. But for how long do these persist? Recent work from Spencer Chapman et al. shows that they last months to years, even arising endogenous exposures utero.

Language: Английский

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Error-corrected flow-based sequencing at whole-genome scale and its application to circulating cell-free DNA profiling

Nature Methods, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Language: Английский

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Germline mutation rates and fine-scale recombination parameters in zebra finch

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(4), P. e1011661 - e1011661

Published: April 15, 2025

Most of our understanding the fundamental processes mutation and recombination stems from a handful disparate model organisms pedigree studies mammals, with little known about other vertebrates. To gain broader comparative perspective, we focused on zebra finch ( Taeniopygia castanotis ), which, like birds, differs mammals in its karyotype (which includes many micro-chromosomes), mechanism by which is directed to genome, aspects ontogenesis. We collected genome sequences three generation pedigrees that provide information 80 meioses, inferring 202 single-point de novo mutations, 1,088 crossovers, 275 non-crossovers. On basis, estimated sex-averaged rate 5.0 × 10 -9 per base pair generation, par have similar time (~2–3 years). Also as found paternal germline bias at later stages gametogenesis (of 1.7:1) but no discernible difference between sexes early development. Examining patterns, crossover macro-chromosomes 0.93 cM/Mb, pronounced enrichment crossovers near telomeres. In contrast, non-crossover rates are more uniformly distributed. micro-chromosomes, substantially higher (3.96 cM/Mb), accordance homeostasis, both events At finer scale, overlap CpG islands often than expected chance, absence PRDM9. Estimates degree GC-biased gene conversion (59%), mean tract length (~32 bp), non-crossover-to-crossover ratio (5.4:1) all comparable those reported primates mice. Therefore, properties resolutions remain over large phylogenetic distances.

Language: Английский

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Advances in single-cell DNA sequencing enable insights into human somatic mosaicism

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Language: Английский

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Sperm from infertile, oligozoospermic men have elevated mutation rates

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 22, 2024

Abstract Male infertility is associated with elevated rates of aneuploidy and DNA breaks in spermatozoa germline precursors. This common condition not well understood poor individual familial somatic health relative to fertile men. To further understand the extent source genome instability, we used error-corrected duplex sequencing test whether impaired spermatogenesis relatively poorer oligozoospermic men are linked single nucleotide de novo mutation frequencies their sperm blood, respectively. We observed a significant 1.34 2.01-fold increase age-adjusted infertile, Conversely, consistently blood were found. Gain-of-function mutations clonal Mendelian disorders accumulate age at similar rate normozoospermic These results implicate hypermutation as hallmark feature oligozoospermia point age-independent processes affecting spermatogonial stem cell biology that may underlie spermatogenic impairment before after puberty. Our findings also underscore importance investigating tissue-specific mechanisms driving association between reduced reproductive infertile

Language: Английский

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