scholarly journals Inference of candidate germline mutator loci in humans from genome-wide haplotype data

2016 ◽  
Author(s):  
Cathal Seoighe ◽  
Aylwyn Scally
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
1000 Genomes Project ◽  
1000 Genomes ◽  
A Genome ◽  
Haplotype Data ◽  
Candidate Loci

AbstractThe rate of germline mutation varies widely between species but little is known about the extent of variation in the germline mutation rate between individuals of the same species. Here we demonstrate that an allele that increases the rate of germline mutation can result in a distinctive signature in the genomic region linked to the affected locus, characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background of haplotypes carrying a typical proportion of derived alleles. We searched for this signature in human haplotype data from phase 3 of the 1000 Genomes Project and report a number of candidate mutator loci, several of which are located close to or within genes involved in DNA repair or the DNA damage response. To investigate whether mutator alleles remained active at any of these loci, we used de novo mutation counts from human parent-offspring trios in the 1000 Genomes and Genome of the Netherlands cohorts, looking for an elevated number of de novo mutations in the offspring of parents carrying a candidate mutator haplotype at each of these loci. We found some support for two of the candidate loci, including one locus just upstream of the BRSK2 gene, which is expressed in the testis and has been reported to be involved in the response to DNA damage.Author SummaryEach time a genome is replicated there is the possibility of error resulting in the incorporation of an incorrect base or bases in the genome sequence. When these errors occur in cells that lead to the production of gametes they can be incorporated into the germline. Such germline mutations are the basis of evolutionary change; however, to date there has been little attempt to quantify the extent of genetic variation in human populations in the rate at which they occur. This is particularly important because new spontaneous mutations are thought to make an important contribution to many human diseases. Here we present a new way to identify genetic loci that may be associated with an elevated rate of germline mutation and report the application of this method to data from a large number of human genomes, generated by the 1000 Genomes Project. Several of the candidate loci we report are in or near genes involved in DNA repair and some were supported by direct measurement of the mutation rate obtained from parent-offspring trios.

scholarly journals Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals

PLoS ONE ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. e0164212 ◽  
Author(s):  
Simon L. Girard ◽  
Cynthia V. Bourassa ◽  
Louis-Philippe Lemieux Perreault ◽  
Marc-André Legault ◽  
Amina Barhdadi ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Paternal Age ◽  
Major Portion ◽  
Healthy Individuals

scholarly journals Higher Germline Mutagenesis of Genes with Stronger Testis Expressions Refutes the Transcriptional Scanning Hypothesis

2020 ◽  
Vol 37 (11) ◽  
pp. 3225-3231
Author(s):  
Haoxuan Liu ◽  
Jianzhi Zhang
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Expression Level ◽  
Human Testis ◽  
Confounding Factors ◽  
De Novo Mutations ◽  
Gene Expressions ◽  
Specific Manner ◽  
Mammalian Testis

Abstract Why are more genes expressed in the testis than in any other organ in mammals? The recently proposed transcriptional scanning hypothesis posits that transcription alleviates mutagenesis through transcription-coupled repair so has been selected in the testis to modulate the germline mutation rate in a gene-specific manner. Here, we show that this hypothesis is theoretically untenable because the selection would be too weak to have an effect in mammals. Furthermore, the analysis purported to support the hypothesis did not control known confounding factors and inappropriately excluded genes with no observed de novo mutations. After remedying these problems, we find the human germline mutation rate of a gene to rise with its testis expression level. This trend also exists for inferred coding strand-originated mutations, suggesting that it arises from transcription-associated mutagenesis. Furthermore, the testis expression level of a gene robustly correlates with its overall expression in other organs, nullifying the need to explain the testis silencing of a minority of genes by adaptive germline mutagenesis. Taken together, our results demonstrate that human testis transcription increases the germline mutation rate, rejecting the transcriptional scanning hypothesis of extensive gene expressions in the mammalian testis.

scholarly journals Variant calling on the GRCh38 assembly with the data from phase three of the 1000 Genomes Project

2019 ◽  
Vol 4 ◽  
pp. 50 ◽  
Author(s):  
Ernesto Lowy-Gallego ◽  
Susan Fairley ◽  
Xiangqun Zheng-Bradley ◽  
Magali Ruffier ◽  
Laura Clarke ◽  
...  
Keyword(s):  
De Novo ◽  
Variant Calling ◽  
Final Phase ◽  
1000 Genomes Project ◽  
Data Set ◽  
1000 Genomes ◽  
Project Data

We present a set of biallelic SNVs and INDELs, from 2,548 samples spanning 26 populations from the 1000 Genomes Project, called de novo on GRCh38. We believe this will be a useful reference resource for those using GRCh38. It represents an improvement over the “lift-overs” of the 1000 Genomes Project data that have been available to date by encompassing all of the GRCh38 primary assembly autosomes and pseudo-autosomal regions, including novel, medically relevant loci. Here, we describe how the data set was created and benchmark our call set against that produced by the final phase of the 1000 Genomes Project on GRCh37 and the lift-over of that data to GRCh38.

scholarly journals Expression of progerin does not result in an increased mutation rate

2016 ◽  
Author(s):  
Emmanuelle Deniaud ◽  
Shelagh Boyle ◽  
Wendy Bickmore
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Mutation Rate ◽  
Genetic Defect ◽  
Lamin A ◽  
Mutant Form ◽  
Premature Ageing ◽  
Damage Response ◽  
Per Se

AbstractIn the premature ageing disease Hutchinson-Gilford progeria syndrome (HGPS) the underlying genetic defect in the lamin A gene leads to accumulation at the nuclear lamina of progerin – a mutant form of lamin A that cannot be correctly processed. This has been reported to result in defects in the DNA damage response and in DNA repair, leading to the hypothesis that, as in normal ageing and in other progeroid syndromes caused by mutation of genes of the DNA repair and DNA damage response pathways, increased DNA damage may be responsible for the premature ageing phenotypes in HGPS patients. However, this hypothesis is based upon the study of markers of the DNA damage response, rather than measurement of DNA damage per se or the consequences of unrepaired DNA damage -mutation. Here, using a mutation reporter cell line, we directly compared the inherent and induced mutation rates in cells expressing wild-type lamin A or progerin. We find no evidence for an elevated mutation rate in progerin-expressing cells. We conclude that the cellular defect in HGPS cells does not lie in the repair of DNA damage per se.

scholarly journals Nucleosome positioning stability is a significant modulator of germline mutation rate variation across the human genome

2018 ◽  
Author(s):  
Cai Li ◽  
Nicholas M. Luscombe
Keyword(s):  
Human Genome ◽  
Genome Evolution ◽  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Mutation Rates ◽  
Rate Variation ◽  
Nucleosome Organization ◽  
Local Sequence ◽  
Mutation Rate Variation

AbstractUnderstanding the patterns and genesis of germline de novo mutations is important for studying genome evolution and human diseases. Nucleosome organization is suggested to be a contributing factor to mutation rate variation across the genome. However, the small number of published de novo mutations and the low resolution of earlier nucleosome maps limited our understanding of how nucleosome organization affects germline mutation rates in the human genome. Here, we systematically investigated the relationship between nucleosome organization and fine-scale mutation rate variation by analyzing >300,000 de novo mutations from whole-genome trio sequencing and high-resolution nucleosome maps in human. We found that de novo mutation rates are elevated around strong, translationally stable nucleosomes, a previously under-appreciated aspect. We confirmed this observation having controlled for local sequence context and other potential confounding factors. Analysis of the underlying mutational processes suggests that the increased mutation rates around strong nucleosomes are shaped by a combination of low-fidelity replication, frequent DNA damage and insufficient/error-prone repair in these regions. Interestingly, strong nucleosomes are preferentially located in young SINE/LINE elements, implying frequent nucleosome re-positioning (i.e. shifting of dyad position) and their contribution to hypermutation at new retrotransposons during evolution. These findings provide novel insights into how chromatin organization affects germline mutation rates and have important implications in human genetics and genome evolution.

scholarly journals Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

2017 ◽  
Author(s):  
Jedidiah Carlson ◽  
Adam E Locke ◽  
Matthew Flickinger ◽  
Matthew Zawistowski ◽  
Shawn Levy ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Gc Content ◽  
Mutation Rates ◽  
Rate Heterogeneity ◽  
Genomic Features ◽  
Genome Wide ◽  
Wide Variability ◽  
Nucleotide Context

AbstractA detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here we use ∼36 million singleton variants from 3,560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ∼46,000 de novo mutations, and confirm our estimates are more accurate than previously published estimates based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.

XPD DNA Nucleotide Excision Repair (NER) Gene Polymorphisms Associated with DNA Repair Deficiency May Predict Better Treatment Outcomes in Secondary Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 168-168 ◽  
Author(s):  
Nataliya Kuptsova-Clarkson ◽  
Christine Ambrosone ◽  
Joli Weiss ◽  
Maria R. Baer ◽  
Lara Sucheston ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Treatment Outcomes ◽  
De Novo ◽  
Excision Repair ◽  
Variant Allele ◽  
Repair Capacity ◽  
Strand Breaks ◽  
Secondary Aml ◽  
Response To Chemotherapy

Abstract Abstract 168 The X-ray cross-complementing group 1 (XRCC1) protein plays an important role in excision and ligation of oxidized DNA bases and strand breaks, in cooperation with other enzymes in the base excision repair (BER) pathway, while XPD helicases unwind DNA prior to repair. Polymorphisms of these DNA repair genes are associated with decreased DNA repair rates and increased genotoxic damage, measured by single-strand breaks and chromosomal aberrations. Compromised repair activity may lead to accumulation of DNA damage and predispose to secondary cancers and increased treatment-related toxicity to normal tissues. It may, however, also result in decreased repair of DNA damage in malignant cells exposed to chemotherapy, facilitating their apoptosis, and therefore decreasing resistance to chemotherapy and improving treatment outcome. Functional DNA repair capacity has been found to be significantly deficient in XRCC1 399Gln and XPD 312Asn, 751Gln variant allele carriers, and NER polymorphisms, particularly ERCC2 (XPD) Lys751Gln SNP, appeared as strong determinants of in vitro toxicity to most anti-cancer agents in the NCI-60 panel of tumor cell lines. Pharmacogenetic studies of DNA repair pathways have consistently demonstrated associations between the XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes and cancer treatment outcomes, including treatment-related toxicities. Notably, the XRCC1 399Gln homozygous variant genotype has been found to decrease risk of developing both de novo and therapy-related AML, and has been associated with worse survival outcomes for other cancers. The variant glutamine allele of XPD Lys751Gln SNP has been associated with shorter disease-free survival (DFS) and overall survival (OS) for AML patients, as well as increased risk of therapy-related AML (t-AML). In this study we evaluated the role of these polymorphisms, as well as XPD haplotypes, in response to chemotherapy, OS, and toxicities in adult de novo (n=214) and secondary (n=79, including 47 with antecedent hematologic disorders and 32 with t-AML) AML patients treated with cytarabine and anthracycline-based chemotherapy regimens at Roswell Park Cancer Institute. Genotyping was performed by MALDI-TOF mass spectrometry, and logistic and proportional hazards regression models were used to evaluate relationships. Significant differential chemotherapy responses were observed in secondary, but not de novo, AML patients with variant XPD 312, XPD 751 and XPD haplotypes. In particular, among secondary AML patients, the XPD 312Asn/Asn XPD 751Gln/Gln variant was associated with eleven-fold higher odds of achieving complete remission (CR) (OR= 11.23; 95% CI, 2.23-56.63), and the odds were also increased among patients with XPD 751Gln/Gln genotypes (OR= 7.07; 95% CI, 1.42–35.18). Patients with the ‘BB/DA' (751Gln/312Asn-751Gln/312Asn/751Gln/Asp312-Lys751-Asp312) diplotype were more likely to achieve CR [OR=31.10; 95% CI: 3.98–242.88] compared to those with the AA/AC/DB diplotype in the secondary AML onset category. Additionally, in this subgroup, the XPD 751 CC, 312GA, 312AA variant genotypes and the XPD ‘BB/DA' haplotype group, which are likely to confer decreased repair function, were significantly associated with longer OS. In the whole patient population there was an association between XPD genotypes/haplotypes and chemotherapy-related toxicities, including a significantly reduced risk of nausea/vomiting (OR= 0.35, 95% CI, 0.13–0.90 for ‘BB/DA' diplotype group) and an increased incidence of infectious complications after induction chemotherapy. Overall, these findings suggest that XPD codon 312 and codon 751 variant genotypes and haplotypes containing at least one variant allele are associated with suboptimal DNA repair and may serve as predictors of more favorable AML treatment responses and diffential toxicities. With validation of results in larger samples, these findings could lead to optimizing chemotherapy AML options by treatment stratification, especially in patients with secondary AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage

2004 ◽  
Vol 24 (3) ◽  
pp. 1219-1231 ◽  
Author(s):  
Michael H. Brodsky ◽  
Brian T. Weinert ◽  
Garson Tsang ◽  
Yikang S. Rong ◽  
Nadine M. McGinnis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Drosophila Melanogaster ◽  
P53 Protein ◽  
Transcriptional Response ◽  
Protein Levels ◽  
A Genome ◽  
Apoptosis Pathways ◽  
Induced Apoptosis ◽  
Dependent Modification

ABSTRACT We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member Eiger. Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.

scholarly journals SIRT6 Inhibition As a Novel Approach for Treating Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5222-5222
Author(s):  
Michele Cea ◽  
Antonia Cagnetta ◽  
Debora Soncini ◽  
Paola Minetto ◽  
Davide Lovera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Allogeneic Bone ◽  
A Genome ◽  
Acute Myeloid

Abstract Currently available therapeutics against Acute Myeloid Leukemia (AML) have improved patient outcome. However, resistance develops even to novel therapies and patient overall survival remains low, especially for patients who are not eligible for allogeneic bone marrow transplantation. Therefore, there is an urgent need to overcome the biologic mechanisms underlying drug resistance in AML, to enhance the efficacy of existing treatments and to facilitate the design of novel approaches. Recently, our group has demonstrated that SIRT6, a NAD+-dependent histone deacetylase involved in genome maintenance, is frequently up-regulated in Multiple Myeloma and its targeting induces cancer cell killing (Cea M. et al, Blood 2016). Furthermore, gene expression analyses performed by our groups show that SIRT6 is also up-regulated in AML and confers poor prognosis in a series of 200 primary AML cases from our Hematology Clinic. Thus, these data suggested a role for SIRT6 in AML biology. High SIRT6 expression was typically observed in AML cell lines characterized by constitutive DNA damage and intense replicative stress. Likewise, primary AML cases exhibiting an intermediate-to-high chromosome instability (CIN) gene expression signature were also those with the highest SIRT6 expression, and worst prognosis. Subsequent studies demonstrated that SIRT6 silencing or its chemical inhibition, as observed in Multiple Myeloma exacerbates DNA damage in response to genotoxic agents, sensitizing AML cells to cytarabine (ARA-C) and idarubicin in vitro. Overall, enhancing genotoxic stress while concomitantly blocking DNA double-strand breaks (DSBs) repair response, may represent an innovative strategy to increase chemosensitivity of AML cells. Mechanistic studies revealed that SIRT6 acts as a genome guardian in AML cells by binding DNA damage sites and activating DNA-PKcs and CtIP by deacetylation, which in turn promotes DNA repair. Overall our data suggest that genomic instability is present in all hematologic malignancies including AML. Strategies aimed to shift the balance towards high DNA damage and reduced DNA repair by SIRT6 inhibition can decrease AML growth and may benefit patients with otherwise unfavorable outcomes. Disclosures Gobbi: Gilead: Honoraria; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

scholarly journals The quiescent X, the replicative Y and the Autosomes

2018 ◽  
Author(s):  
Guillaume Achaz ◽  
Serge Gangloff ◽  
Benoit Arcangioli
Keyword(s):  
De Novo ◽  
Yeast Cells ◽  
Simple Pattern ◽  
Maternal Lineage ◽  
1000 Genomes Project ◽  
Phase 3 ◽  
X Chromosomes ◽  
1000 Genomes ◽  
Y Chromosomes ◽  
Human Genomes

AbstractFrom the analysis of the mutation spectrum in the 2,504 sequenced human genomes from the 1000 genomes project (phase 3), we show that sexual chromosomes (X and Y) exhibit a different proportion of indel mutations than autosomes (A), ranking them X>A>Y. We further show that X chromosomes exhibit a higher ratio of deletion/insertion when compared to autosomes. This simple pattern shows that the recent report that non-dividing quiescent yeast cells accumulate relatively more indels (and particularly deletions) than replicating ones also applies to metazoan cells, including humans. Indeed, the X chromosomes display more indels than the autosomes, having spent more time in quiescent oocytes, whereas the Y chromosomes are solely present in the replicating spermatocytes. From the proportion of indels, we have inferred that de novo mutations arising in the maternal lineage are twice more likely to be indels than mutations from the paternal lineage. Our observation, consistent with a recent trio analysis of the spectrum of mutations inherited from the maternal lineage, is likely a major component in our understanding of the origin of anisogamy.

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