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At least 19 recordsLinked to original sources
PubMed2026

Large-scale whole-genome sequencing reveals the landscape and health implications of de novo mutations.

De novo mutations (DNMs) are an important source of congenital diseases. With delayed parenthood and assisted reproductive technology (ART) use increasing, it is essential to elucidate how these reproductive factors influence DNMs and whether resulting mutations influence offspring health. Here we performed whole-genome sequencing of 24,030 individuals from 7,851 parent-offspring families, identifying 390,924 de novo single-nucleotide variants (dnSNVs). Paternal and maternal aging exhibited distinct mutational patterns, with maternal DNM accumulation accelerating at advanced ages. Increased paternal dnSNVs partially accounted for the association between advanced parental age and shorter gestational duration. Moreover, ART showed age-independent, procedure-specific effects: intracytoplasmic sperm injection (ICSI) and ovarian stimulation were associated with increased paternal and maternal dnSNVs, respectively, and ICSI-associated paternal dnSNVs also partially accounted for the association between ICSI and shorter gestational duration. In vitro embryo manipulation was associated with increased early post-zygotic mosaic mutations, particularly C > A substitutions linked to delayed neurocognitive development at 1 year. Collectively, these findings advance understanding of the determinants and consequences of de novo mutagenesis.

Journal Article↗
PubMed1979

Gene mutations (de novo) found in electrophoretic studies of blood protein of infants with anomalous development.

Twelve proteins of enzymic and nonenzymic nature in blood samples of infants that deviate from the average population in physical development (50 premature and 177 full-term infants with rough and multiple developmental defects) were studied by electrophoresis in polyacrylamide and starch gels. The control group consisted of 500 normal newborns. In infants with developmental disorders, the frequency of rare electrophoretic protein variants was found to be about one order of magnitude higher than in the control. It has been shown for at least five cases that such variants are de novo mutations. According to these data the mutation rate is approximately 2 x 10(-3) per locus per generation for the group selected and approximately 6 x 10(-5) for the total population. Despite the fact that further specification of the estimations found is required, we consider the results obtained as evidence in favor of the efficiency of the earlier substantiated monitoring model of gene mutations in the human population [Dubinin, N.P. & Altukhov, Yu. P. (1977) in Genetic Consequences of Environmental Pollution, ed. Dubinin, N.P. (Mysl, Moscow), pp. 14-45]. This approach, which infers electrophoretic screening of blood proteins in a specially selected group of newborns, makes it possible to reduce the size of samples needed for statistically reliable estimations of the alteration of mutation rate.

Blood Group Antigens↗
PubMed2025

Investigating the interplay between prematurity and genetic variation in the context of rare developmental disorders.

BACKGROUND: Rare damaging genetic variation accounts for a substantial proportion of the risk of rare developmental disorders (DDs), but common genetic variants as well as environmental factors, including prematurity, also contribute. Little is known about the interplay between prematurity and genetic variation in influencing phenotypic outcomes in DDs, nor about how genetic factors may contribute to risk of preterm birth in DDs. METHODS: We leveraged phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. Using multivariable regression models, we compared phenotypic features and the prevalence of diagnostic genetic variation in specific genes between preterm and term individuals with DDs. We tested whether the fraction of cases attributable to de novo mutations differed between term and preterm probands. Additionally, we assessed whether associations between common variant contributions to education-related traits and prematurity are explained by direct genetic effects. RESULTS: Prematurity was associated with more severe clinical phenotypes among these DD patients, including more affected organ systems and more delayed developmental milestones. Prematurity and the presence of a monogenic diagnosis contributed additively to severity. We found that genes associated with fetal anomalies were enriched for diagnostic mutations among preterm individuals (p = 7.83 × 10-5). We also demonstrated an exome-wide enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes was higher in term than preterm cases (25% versus 20%) but DNMs in as-yet-undiscovered genes likely contribute approximately equally to both groups (14% versus 13%). Finally, we showed that the positive association between polygenic predisposition to education-related traits and gestational duration is likely to be the result of genetically influenced parental traits or confounders, rather than direct genetic effects in the child, and that a monogenic diagnosis modifies this association. CONCLUSIONS: Our findings emphasise the importance of considering environmental factors like prematurity in understanding outcomes in DDs suspected to have a genetic component, and motivate further exploration of the role that genetic variation plays in influencing prematurity.

Humans↗
PubMed2026

Loss of function of the chromatin remodeling gene INO80D leads to neurogenic features of schizophrenia.

Schizophrenia has been linked to severely damaging de novo mutations in synaptic junction proteins, neurotransmitter receptors, transcription factors, and chromatin remodeling proteins. In a patient with schizophrenia in the absence of a family history of severe mental illness, we identified de novo nonsense mutation, INO80D p.Q568X, associated with both a truncated protein and partial nonsense-mediated decay. Three experiments were undertaken to evaluate the consequences of the mutation. 1) In neural stem cells (iNSCs) differentiated from WTC11 iPSCs, CRISPRi knockdown of INO80D led to downregulation of three subunits of the AMPA-glutamate receptor, of multiple genes mutant in schizophrenia, and of genes of synaptic function. 2) INO80D p.Q568X iNSCs and neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) had significantly lower expression of neurogenesis genes compared to patient-derived cells with the mutation corrected by CRISPR-Cas9 gene editing. Patient-derived INO80D p.Q568X neurons had significantly higher expression of cell division genes compared to lines with the mutation corrected, consistent with the possibility that some of these cells may be undergoing mitosis, which is not normal for neurons. 3) Finally, on microelectrode array (MEA) plates, WTC11-derived glutamatergic neurons with reduced expression of INO80D had more rapid firing rate and increased average network burst duration, both features of neurons derived from patients with neurodevelopmental disorders. Overall, these findings suggest that partial loss of INO80D function due to de novo mutation may have disrupted normal neurodevelopment and contributed to the schizophrenia of this patient.

Humans↗
PubMed2026

MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice.

SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. De novo indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ∼21 bp. The tyrosyl-DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of de novo mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution.

Animals↗
PubMed2026

Mutation timing, accumulation, and selection in the male germline shape inheritance risk for developmental disorders.

De novo mutations (DNMs) in the paternal germline are a major cause of developmental disorders, but how mutation timing, paternal age, and spermatogonial selection jointly shape transmissible risk within individual fathers is unclear. We combined trio whole-genome sequencing from 167 families with deep targeted NanoSeq profiling of sperm from 127 fathers of children with confirmed pathogenic DNMs. Transmitted DNM burden and paternal sperm mutation burden, spectra, and selection landscape were indistinguishable from population reference cohorts. Six fathers carried pathogenic early mosaic variants detectable in sperm at variant allele fractions (VAFs) of 0.7%-14.8%, creating individual recurrence-risk outliers. However, early mosaics accounted for ∼8% of the cohort-aggregated pathogenic burden exome-wide, compared with ∼18% from known positively selected drivers and ∼74% from other rare variants accumulating with paternal age. Thus, paternal de novo disease risk is shaped primarily by universal age-associated mutation and selection, while early mosaicism creates uncommon but clinically important high-risk individuals.

DNMs↗
PubMed2026

Maternal DNA repair safeguards genome stability during the oocyte-to-embryo transition.

De novo mutations are a major source of genetic variation and disease risk, yet the developmental timing and mechanisms underlying their origin require further investigation. While germ cells have traditionally been considered the primary source of these mutations, increasing evidence suggests that a substantial fraction arise after fertilization. Here, we investigated the role of maternal DNA repair in shaping mutagenesis during this critical window by using a mouse model with oocyte-specific disruption of the homologous recombination factor RAD51 and a combination of cellular and molecular analyses. Loss of maternal RAD51 led to the accumulation of DNA double-strand breaks in oocytes without impairing their growth, meiotic maturation, or fertilization competence. In contrast, embryos derived from RAD51-deficient oocytes exhibited increased DNA damage and developmental delay during early cleavage stages. Whole-genome sequencing revealed a significant increase in de novo variants in offspring, the majority displaying intermediate allele frequencies consistent with post-zygotic mosaic mutations. These findings confirm that maternal DNA repair safeguards genome stability across the oocyte-to-embryo transition and identify early embryogenesis as a major source of de novo mutations, with implications for reproductive biology and the origins of genetic diseases.

DNA↗
PubMed1979

Periodic hypokalemic paralysis transmitted by an unaffected male with negative family history: a delayed mutation?

A pedigree is described that includes three cases of periodic hypokalemic paralysis. Apparently, the disease has arisen by de novo mutation in a father of two affected daughters, who, however, is not affected himself. This is unexpected, since in males the disorder is generally inherited as a fully dominant trait. Therefore we propose that these findings result from an early somatic or a half-chromatid mutation.

Adolescent↗
PubMed2025

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold &#x2264;30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0&#xb7;0001) and individuals older than 60 years (p=0&#xb7;0027). The median within-host genome-wide evolutionary rate was 7&#xb7;9&#x2009;&#xd7;&#x2009;10-4 substitutions per site per year (IQR 7&#xb7;0-9&#xb7;0&#x2009;&#xd7;&#x2009;10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗
PubMed2026

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset &#x2264;65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried &#x2265;1 inherited risk factor with odds ratio (OR)&#x2009;>&#x2009;1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Humans↗
PubMed2025

Distinct patterns of de novo coding variants contribute to Tourette Syndrome etiology.

Tourette syndrome (TS) is a highly heritable childhood-onset neuropsychiatric disorder characterized by persistent motor and vocal tics. While both common and rare variants contribute to TS susceptibility, the role of rare de novo mutations (DNMs) remains incompletely characterized. Here, we report findings from the largest TS whole-exome sequencing study to date, analyzing 1,466 TS trios alongside 6,714 autism spectrum disorder (ASD) trios and 5,880 unaffected sibling controls from the Simons Simplex Collection (SSC) and SPARK cohorts. Leveraging a trio-based design across these cohorts enabled calibrated assessment of DNM burden while controlling for background mutation rates. We observed a significant exome-wide enrichment of protein-truncating DNMs in TS probands, particularly within genes intolerant to loss-of-function variation (pLI &#x2265; 0.9), with little contribution from damaging missense variants. Notably, TS probands did not exhibit enrichment in previously implicated ASD or developmental delay (DD) genes, but elsewhere in the genome, suggesting a distinct rare variant architecture. Using a Bayesian statistical framework that integrates both de novo and rare inherited coding variants, we identified three candidate TS risk genes with FDR &#x2264; 0.05: PPP5C , EXOC1 , and GXYLT1 . Literature shows that they have prior links to neurodevelopmental and psychiatric disorders. These findings reveal a rare variant burden in TS that is genetically distinguishable from ASD, underscore the importance of loss-of-function mutations in TS risk, and nominate novel candidate genes for future functional investigation.

Journal Article↗
PubMed2026

Diversity at the HYP1 locus in potato cyst nematodes does not result from developmentally-programmed somatic mutations.

Most genetic diversity stems from spontaneous mutations, that is, errors in DNA repair or replication. But for dozens of organisms across the tree of life, mutations at specific loci are not spontaneous but developmentally programmed: effectively, some organisms edit their own DNA sequences. This is perhaps most common among pathogens and parasites, many of which use editing to diversify genes that produce important antigens. Plant-parasitic potato cyst nematodes are damaging agricultural pests that establish a lifelong feeding site inside the root of their host plant. We previously observed extensive diversity of rare alleles at HYP1, the most highly expressed gene that encodes a protein secreted by potato cyst nematodes during parasitism. Importantly, HYP1 alleles differ from each other by complex, in-frame rearrangements of short repeated sequence motifs within a single exon. Combining several lines of evidence, we previously hypothesized that potato cyst nematodes use developmentally-programmed mutations, or editing, to diversify HYP1 alleles in the soma. In the current work, we now test this hypothesis. We employ highly accurate long-read DNA sequencing of a simplified genetic system to identify potential rare edited alleles, we use a transgenic yeast system to describe large de novo mutations at HYP1, and we interpret our findings in light of key population genetic parameters as well as the genetic diversity surrounding HYP1 and across the genome.

Animals↗
PubMed2025

Experimental Test of Evolutionary Safety of a CRISPR-Cas9 Gene-Drive Element.

CRISPR-Cas9 gene drives (CCGDs) are powerful tools for genetic control of wild populations, with applications from disease eradication to species conservation. However, Cas9 alone and in a complex with gRNA can cause double-stranded DNA breaks at off-target sites, which could increase the mutational load and lead to unintended loss-of-heterozygosity (LOH) events. These undesired effects raise potential concerns about the long-term evolutionary safety of CCGDs, but the magnitude of these effects is unknown. To measure how the presence of a CCGD or a Cas9 alone in the genome affects the rates of LOH events and de novo mutations, we carried out a mutation accumulation experiment in yeast Saccharomyces cerevisiae. We found no detectable effects on the genome-wide rates of mutations or LOH events. Our power calculations suggest that CCGD or Cas9 affect these rates by less than 30%, which is much less than natural variation for these traits in yeast. A more detailed examination shows that CCGD or Cas9 may alter the lengths and genomic distributions of LOH events, but the statistical support for these effects is weak. Thus, our results demonstrate that CCGDs impose at most a weak additional mutational burden in the yeast model. Although mutagenic effects of gene drives need to be further evaluated in other systems, our results add credence to the proposition that the evolutionary risks posed by well designed gene drives are likely acceptable.

Journal Article↗
PubMed2026

The evolutionary origins of the parthenogenetic lizard Aspidoscelis tesselatus.

Most vertebrate species reproduce sexually. The whiptail lizards (Aspidoscelis) are a notable exception; at least 11 of the 45 recognized species are parthenogenetic. Here, we focus on one such species (Aspidoscelis tesselatus) as a case study to understand how parthenogenetic species originate and evolve. Using genome-wide sequence data and ecological niche modelling, we find that A. tesselatus likely arose from a single hybrid speciation event between A. scalaris and A. marmoratus less than 500,000 years ago. The geographic ranges of A. tesselatus and its parental species overlap currently, and niche modelling shows this zone of sympatry was even broader during the period when A. tesselatus likely formed. We additionally show evidence that A. tesselatus has a dynamic genome post-formation, with de novo mutations, introgression, and double-strand break associated events all contributing to variation within the species. These results show that asexual lineages can continue to be shaped by ongoing genomic and ecological dynamics, illuminating the processes that influence transitions in reproductive mode.

asexuality↗
PubMed2026

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.

Aneuploidy↗
PubMed2026

Widespread horizontal transfer and strong selection enhance microbial adaptation in Antarctic soils.

Terrestrial Antarctica harbors compositionally diverse and functionally distinct microbial life. Yet the eco-evolutionary processes underlying adaptation to Antarctica's polyextreme conditions remain largely unknown. Here, we address how horizontal gene transfer (HGT) and de novo mutations influence microbial adaptation in 16 Antarctic soils using combined short- and long-read datasets. Phylogenetic reconciliation and mobile genetic element analysis of 676 metagenome-assembled genomes show frequent HGT across communities. While transferred genes span diverse functional categories, those involved in energy metabolism are exchanged at higher frequency. Genes for aerotrophy, i.e. the consumption of atmospheric trace gases to provide energy, carbon, and hydration, are among the most frequently disseminated. Approximately a quarter of carbon monoxide dehydrogenases and [NiFe]-hydrogenases are predicted to be horizontally acquired and are often associated with mobile genetic elements. Analysis of polymorphisms suggests widespread purifying selection, particularly for aerotrophy genes, providing further evidence that aerotrophy is critical for microbial survival in Antarctica. Genetic variation in hydrogenases is tightly associated with predicted protein structures, with intense selection acting on critical sites preserving stability and function. Together, these findings show that previously unrecognized eco-evolutionary dynamics shape the composition and function of Antarctic microbial communities, and confirm aerotrophy is a strongly selected and horizontally disseminated trait.

Antarctic Regions↗