scholarly journals Mutational pressure drives differential genome conservation in two bacterial endosymbionts of sap feeding insects

2020 ◽  
Author(s):  
Gus Waneka ◽  
Yumary M Vasquez ◽  
Gordon M Bennett ◽  
Daniel B Sloan
Keyword(s):  
De Novo ◽  
Evolutionary Rate ◽  
Direct Detection ◽  
Low Frequency ◽  
Sequence Evolution ◽  
De Novo Mutations ◽  
Cellular Functions ◽  
Single Nucleotide Variants ◽  
Genome Decay ◽  
Sap Feeding

Abstract Compared to free-living bacteria, endosymbionts of sap-feeding insects have tiny and rapidly evolving genomes. Increased genetic drift, high mutation rates, and relaxed selection associated with host control of key cellular functions all likely contribute to genome decay. Phylogenetic comparisons have revealed massive variation in endosymbiont evolutionary rate, but such methods make it difficult to partition the effects of mutation vs. selection. For example, the ancestor of Auchenorrhynchan insects contained two obligate endosymbionts, Sulcia and a betaproteobacterium (BetaSymb; called Nasuia in leafhoppers) that exhibit divergent rates of sequence evolution and different propensities for loss and replacement in the ensuing ~300 Ma. Here, we use the auchenorrhynchan leafhopper Macrosteles sp. nr. severini, which retains both of the ancestral endosymbionts, to test the hypothesis that differences in evolutionary rate are driven by differential mutagenesis. We used a high-fidelity technique known as duplex sequencing to measure and compare low-frequency variants in each endosymbiont. Our direct detection of de novo mutations reveals that the rapidly evolving endosymbiont (Nasuia) has a much higher frequency of single-nucleotide variants than the more stable endosymbiont (Sulcia) and a mutation spectrum that is potentially even more AT-biased than implied by the 83.1% AT content of its genome. We show that indels are common in both endosymbionts but differ substantially in length and distribution around repetitive regions. Our results suggest that differences in long-term rates of sequence evolution in Sulcia vs. BetaSymb, and perhaps the contrasting degrees of stability of their relationships with the host, are driven by differences in mutagenesis.

scholarly journals Mutational pressure drives differential genome conservation in two bacterial endosymbionts of sap feeding insects

2020 ◽  
Author(s):  
Gus Waneka ◽  
Yumary M. Vasquez ◽  
Gordon M. Bennett ◽  
Daniel B. Sloan
Keyword(s):  
De Novo ◽  
Evolutionary Rate ◽  
Direct Detection ◽  
Low Frequency ◽  
Rate Variation ◽  
Sequence Evolution ◽  
Single Nucleotide Variants ◽  
Genome Decay ◽  
Sap Feeding ◽  
Duplex Sequencing

ABSTRACTCompared to free-living bacteria, endosymbionts of sap-feeding insects have tiny and rapidly evolving genomes. Increased genetic drift, high mutation rates, and relaxed selection associated with host control of key cellular functions all likely contribute to genome decay. Phylogenetic comparisons have revealed massive variation in endosymbiont evolutionary rate, but such methods make it difficult to partition the effects of mutation vs. selection. For example, the ancestor of auchenorrhynchan insects contained two obligate endosymbionts, Sulcia and a betaproteobacterium (BetaSymb; called Nasuia in leafhoppers) that exhibit divergent rates of sequence evolution and different propensities for loss and replacement in the ensuing ∼300 Ma. Here, we use the auchenorrhynchan leafhopper Macrosteles sp. nr. severini, which retains both of the ancestral endosymbionts, to test the hypothesis that differences in evolutionary rate are driven by differential mutagenesis. We used a high-fidelity technique known as duplex sequencing to measure and compare low-frequency variants in each endosymbiont. Our direct detection of de novo mutations reveals that the rapidly evolving endosymbiont (Nasuia) has a much higher frequency of single-nucleotide variants than the more stable endosymbiont (Sulcia) and a mutation spectrum that is even more AT-biased than implied by the 83.1% AT content of its genome. We show that indels are common in both endosymbionts but differ substantially in length and distribution around repetitive regions. Our results suggest that differences in long-term rates of sequence evolution in Sulcia vs. BetaSymb, and perhaps the contrasting degrees of stability of their relationships with the host, are driven by differences in mutagenesis.SIGNIFICANCE STATEMENTTwo ancient endosymbionts in the same host lineage display stark differences in genome conservation over phylogenetic scales. We show the rapidly evolving endosymbiont has a higher frequency of mutations, as measured with duplex sequencing. Therefore, differential mutagenesis likely drives evolutionary rate variation in these endosymbionts.

scholarly journals Genome-wide DNA mutations in Arabidopsis plants after multigenerational exposure to high temperatures

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhaogeng Lu ◽  
Jiawen Cui ◽  
Li Wang ◽  
Nianjun Teng ◽  
Shoudong Zhang ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Elevated Temperatures ◽  
De Novo ◽  
Biological Evolution ◽  
Distribution Patterns ◽  
Defense Responses ◽  
Plant Evolution ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Dna Mutations

Abstract Background Elevated temperatures can cause physiological, biochemical, and molecular responses in plants that can greatly affect their growth and development. Mutations are the most fundamental force driving biological evolution. However, how long-term elevations in temperature influence the accumulation of mutations in plants remains unknown. Results Multigenerational exposure of Arabidopsis MA (mutation accumulation) lines and MA populations to extreme heat and moderate warming results in significantly increased mutation rates in single-nucleotide variants (SNVs) and small indels. We observe distinctive mutational spectra under extreme and moderately elevated temperatures, with significant increases in transition and transversion frequencies. Mutation occurs more frequently in intergenic regions, coding regions, and transposable elements in plants grown under elevated temperatures. At elevated temperatures, more mutations accumulate in genes associated with defense responses, DNA repair, and signaling. Notably, the distribution patterns of mutations among all progeny differ between MA populations and MA lines, suggesting that stronger selection effects occurred in populations. Methylation is observed more frequently at mutation sites, indicating its contribution to the mutation process at elevated temperatures. Mutations occurring within the same genome under elevated temperatures are significantly biased toward low gene density regions, special trinucleotides, tandem repeats, and adjacent simple repeats. Additionally, mutations found in all progeny overlap significantly with genetic variations reported in 1001 Genomes, suggesting non-uniform distribution of de novo mutations through the genome. Conclusion Collectively, our results suggest that elevated temperatures can accelerate the accumulation, and alter the molecular profiles, of DNA mutations in plants, thus providing significant insight into how environmental temperatures fuel plant evolution.

scholarly journals Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Elysa Jill Marco ◽  
Anne Brandes Aitken ◽  
Vishnu Prakas Nair ◽  
Gilberto da Gente ◽  
Molly Rae Gerdes ◽  
...  
Keyword(s):  
Sensory Processing ◽  
De Novo ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide

scholarly journals Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype–phenotype correlations in the Chinese population

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Yuduo Wu ◽  
Hairui Sun ◽  
Jianbin Wang ◽  
Xin Wang ◽  
Ming Gong ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Marfan Syndrome ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
De Novo ◽  
Low Frequency ◽  
Monogenic Disease ◽  
De Novo Mutations ◽  
Fbn1 Gene ◽  
Whole Exome

Abstract Marfan syndrome (MFS) is a dominant monogenic disease caused by mutations in fibrillin 1 (FBN1). Cardiovascular complications are the leading causes of mortality among MFS. In the present study, a whole-exome sequencing of MFS in the Chinese population was conducted to investigate the correlation between FBNI gene mutation and MFS. Forty-four low-frequency harmful loci were identified for the FBN1 gene in HGMD database. In addition, 38 loci were identified in the same database that have not been related to MFS before. A strict filtering and screening protocol revealed two patients of the studied group have double mutations in the FBN1 gene. The two patients harboring the double mutations expressed a prominent, highly pathological phenotype in the affected family. In addition to the FBN1 gene, we also found that 27 patients had mutations in the PKD1 gene, however these patients did not have kidney disease, and 16 of the 27 patients expressed aortic related complications. Genotype-phenotype analysis showed that patients with aortic complications are older in the family, aged between 20 and 40 years.

scholarly journals Crossovers are associated with mutation and biased gene conversion at recombination hotspots

2015 ◽  
Vol 112 (7) ◽  
pp. 2109-2114 ◽  
Author(s):  
Barbara Arbeithuber ◽  
Andrea J. Betancourt ◽  
Thomas Ebner ◽  
Irene Tiemann-Boege
Keyword(s):  
Gene Conversion ◽  
De Novo ◽  
Sequence Data ◽  
Mutagenic Effect ◽  
Human Sperm ◽  
Sequence Evolution ◽  
De Novo Mutations ◽  
Data Set ◽  
Recombination Hotspots ◽  
Biased Gene Conversion

Meiosis is a potentially important source of germline mutations, as sites of meiotic recombination experience recurrent double-strand breaks (DSBs). However, evidence for a local mutagenic effect of recombination from population sequence data has been equivocal, likely because mutation is only one of several forces shaping sequence variation. By sequencing large numbers of single crossover molecules obtained from human sperm for two recombination hotspots, we find direct evidence that recombination is mutagenic: Crossovers carry more de novo mutations than nonrecombinant DNA molecules analyzed for the same donors and hotspots. The observed mutations were primarily CG to TA transitions, with a higher frequency of transitions at CpG than non-CpGs sites. This enrichment of mutations at CpG sites at hotspots could predominate in methylated regions involving frequent single-stranded DNA processing as part of DSB repair. In addition, our data set provides evidence that GC alleles are preferentially transmitted during crossing over, opposing mutation, and shows that GC-biased gene conversion (gBGC) predominates over mutation in the sequence evolution of hotspots. These findings are consistent with the idea that gBGC could be an adaptation to counteract the mutational load of recombination.

scholarly journals Genetic Mosaicism as a Cause of Inborn Errors of Immunity

2021 ◽  
Author(s):  
Jahnavi Aluri ◽  
Megan A. Cooper
Keyword(s):  
Immune Response ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Genetic Diagnosis ◽  
Low Frequency ◽  
De Novo Mutations ◽  
Inborn Errors ◽  
Tissue Samples ◽  
Inborn Errors Of Immunity ◽  
Genetic Mosaicism

AbstractInborn errors of immunity (IEIs) are a heterogeneous group of disorders due to genetic defects in the immune response that have a broad clinical spectrum. Diagnosis of the precise genetic cause of IEI has led to improved care and treatment of patients; however, genetic diagnosis using standard approaches is only successful in ~40% of patients and is particularly challenging in “sporadic” cases without a family history. Standard genetic testing for IEI evaluates for germline changes in genes encoding proteins important for the immune response. It is now clear that IEI can also arise from de novo mutations leading to genetic variants present in germ cells and/or somatic cells. In particular, somatic mosaicism, i.e., post-zygotic genetic changes in DNA sequence, is emerging as a significant contributor to IEI. Testing for somatic mosaicism can be challenging, and both older sequencing techniques such as Sanger sequencing and newer next-generation sequencing may not be sensitive enough to detect variants depending on the platform and analysis tools used. Investigation of multiple tissue samples and specifically targeting sequence technologies to detect low frequency variants is important for detection of variants. This review examines the role and functional consequences of genetic mosaicism in IEI. We emphasize the need to refine the current exome and genome analysis pipeline to efficiently identify mosaic variants and recommend considering somatic mosaicism in disease discovery and in the first-tier of genetic analysis.

scholarly journals Paternal-age-related de novo mutations and risk for five disorders

2017 ◽  
Author(s):  
Jacob L. Taylor ◽  
Jean-Christophe P.G. Debost ◽  
Sarah U. Morton ◽  
Emilie M. Wigdor ◽  
Henrike O. Heyne ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
National Registry ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Advanced Paternal Age ◽  
Age Related ◽  
Rate Ratios

AbstractBackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.MethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.ResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01–1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).ConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

scholarly journals Genome-wide DNA mutations in Arabidopsis plants after multigenerational exposure to high temperature

2020 ◽  
Author(s):  
Zhaogeng Lu ◽  
Jiawen Cui ◽  
Li Wang ◽  
Nianjun Teng ◽  
Shoudong Zhang ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Elevated Temperatures ◽  
De Novo ◽  
Biological Evolution ◽  
Transcriptional Response ◽  
Defense Responses ◽  
Plant Evolution ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Dna Mutations

AbstractBackgroundElevated temperatures can cause physiological, biochemical, and molecular responses in plants that can greatly affect their growth and development. Mutations are the most fundamental force driving biological evolution. However, how long-term elevations in temperature influence the accumulation of mutations in plants remains unknown.ResultsHere we report that multigenerational exposure of Arabidopsis to extreme heat and moderate warming resulted in significantly increased mutation rates in single-nucleotide variants (SNVs) and small indels. We observed distinctive mutational spectra under extreme and moderately elevated temperatures, with significant increases in transition (C:G→T:A) and transversion (A:T→T:A) frequencies. Mutation occurred more frequently in intergenic regions, coding regions (especially nonsynonymous mutations), and transposable elements (TEs). At elevated temperatures, more mutations accumulated in genes associated with defense responses, DNA repair, and signaling, including the transcriptional response–related genes HSP70 and HSFA1A. Methylation was observed more frequently at mutation sites, indicating that it contributed significantly to the mutation process at elevated temperatures. Moreover, the mutations in lines and populations grown under elevated temperatures were significantly biased toward low gene density regions, special trinucleotides (GC context), tandem repeats, and adjacent simple repeats. Additionally, 24% (n = 64) of SNVs and 43% (n = 40) of indels found in all mutation accumulation lines overlapped significantly with genetic variations reported in 1001 Genomes, suggesting a non-uniform distribution of de novo mutations through the genome.ConclusionCollectively, our results suggest that elevated temperatures can accelerate the accumulation, and alter the molecular profiles, of DNA mutations in plants, thus providing significant insight into how environmental temperatures fuel plant evolution.

scholarly journals Discovery of an unusual high number of de novo mutations in sperm of older men using duplex sequencing

2021 ◽  
Author(s):  
Renato Salazar ◽  
Barbara Arbeithuber ◽  
Maja Ivankovic ◽  
Monika Heinzl ◽  
Sofia Moura ◽  
...  
Keyword(s):  
De Novo ◽  
Age Groups ◽  
Low Frequency ◽  
Congenital Disorders ◽  
Sequence Information ◽  
De Novo Mutations ◽  
Coding Region ◽  
Male Germline ◽  
Significant Difference ◽  
Duplex Sequencing

AbstractDe novo mutations (DNMs) are an important player in heritable diseases and evolution, yet little is known about the different mutagenic processes in our germline given the difficulty to reliably identify ultra-low frequency variants. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultra-deep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined ~4.5 kb of the FGFR3 coding region in sperm DNA from older and younger donors. We identified highly mutable sites with mutation frequencies 4-5 orders of magnitude higher than the genome average. Multiple mutations were found at a higher frequency, or exclusively, in older donors, suggesting that these mutations are testis exclusive mosaics expanding in the male germline with age. Also, older donors harbored more mutations associated with congenital disorders. Some mutations were found in both age groups with no significant difference, suggesting that these might result from a different mechanism (e.g., post-zygotic mosaicism). We also observed that independently of age, the frequency and deleteriousness of the mutations in sperm were elevated compared to reports in the population. Our approach is an important strategy to identify mutations that could be associated with aberrant receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.

scholarly journals Identification of de novo mutations for ARID1B haploinsufficiency associated with Coffin–Siris syndrome 1 in three Chinese families via array-CGH and whole exome sequencing

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Guanting Lu ◽  
Qiongling Peng ◽  
Lianying Wu ◽  
Jian Zhang ◽  
Liya Ma
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Array Cgh ◽  
De Novo ◽  
Current Knowledge ◽  
Comparative Genomic ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Whole Exome

Abstract Background Coffin–Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. CSS represents a small group of intellectual disability, and could be caused by at least twelve genes. The genetic background is quite heterogenous, making it difficult for clinicians and genetic consultors to pinpoint the exact disease types. Methods Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for three trios affected with intellectual disability and clinical features similar with those of Coffin–Siris syndrome. Sanger sequencing was used to verify the detected single-nucleotide variants (SNVs). Results All of the three cases were female with normal karyotypes of 46, XX, born of healthy, non-consanguineous parents. A 6q25 microdeletion (arr[hg19]6q25.3(155,966,487–158,803,979) × 1) (2.84 Mb) (case 1) and two loss-of-function (LoF) mutations of ARID1B [c.2332 + 1G > A in case 2 and c.4741C > T (p.Q1581X) in case 3] were identified. All of the three pathogenic abnormalities were de novo, not inherited from their parents. After comparison of publicly available microdeletions containing ARID1B, four types of microdeletions leading to insufficient production of ARID1B were identified, namely deletions covering the whole region of ARID1B, deletions covering the promoter region, deletions covering the termination region or deletions covering enhancer regions. Conclusion Here we identified de novo ARID1B mutations in three Chinese trios. Four types of microdeletions covering ARID1B were identified. This study broadens current knowledge of ARID1B mutations for clinicians and genetic consultors.

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