Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells.

Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.

A mutation rate model at the basepair resolution identifies the mutagenic effect of polymerase III transcription.

De novo mutations occur at substantially different rates depending on genomic location, sequence context and DNA strand. The success of methods to estimate selection intensity, infer demographic history and map rare disease genes, depends strongly on assumptions about the local mutation rate. Here we present Roulette, a genome-wide mutation rate model at basepair resolution that incorporates known determinants of local mutation rate.

The origin of human mutation in light of genomic data.

Despite years of active research into the role of DNA repair and replication in mutagenesis, surprisingly little is known about the origin of spontaneous human mutation in the germ line. With the advent of high-throughput sequencing, genome-scale data have revealed statistical properties of mutagenesis in humans. These properties include variation of the mutation rate and spectrum along the genome at different scales in relation to epigenomic features and dependency on parental age.

Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations.

Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis.

Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence.

Clustering of mutations has been observed in cancer genomes as well as for germline de novo mutations (DNMs). We identified 1,796 clustered DNMs (cDNMs) within whole-genome-sequencing data from 1,291 parent-offspring trios to investigate their patterns and infer a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these clusters consisted of more individual mutations with larger intermutational distances than those of paternal clusters.

Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma.

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand.

Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome.

Evolution of Local Mutation Rate and Its Determinants.

Unlabelled: Mutation rate varies along the human genome, and part of this variation is explainable by measurable local properties of the DNA molecule. Moreover, mutation rates differ between orthologous genomic regions of different species, but the drivers of this change are unclear. Here, we use data on human divergence from chimpanzee, human rare polymorphism, and human de novo mutations to predict the substitution rate at orthologous regions of non-human mammals.

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context.

APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions.

Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained.

APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication.

APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mutations occur as clusters ("kataegis") in single-stranded DNA produced during repair of double-stranded breaks (DSBs).

Polymerase ζ Activity Is Linked to Replication Timing in Humans: Evidence from Mutational Signatures.

Replication timing is an important determinant of germline mutation patterns, with a higher rate of point mutations in late replicating regions. Mechanisms underlying this association remain elusive. One of the suggested explanations is the activity of error-prone DNA polymerases in late-replicating regions.

Extraordinary Genetic Diversity in a Wood Decay Mushroom.

Populations of different species vary in the amounts of genetic diversity they possess. Nucleotide diversity π, the fraction of nucleotides that are different between two randomly chosen genotypes, has been known to range in eukaryotes between 0.0001 in Lynx lynx and 0.

Gene age predicts the strength of purifying selection acting on gene expression variation in humans.

Gene expression levels can be subject to selection. We hypothesized that the age of gene origin is associated with expression constraints, given that it affects the level of gene integration into the functional cellular environment. By studying the genetic variation affecting gene expression levels (cis expression quantitative trait loci [cis-eQTLs]) and protein levels (cis protein QTLs [cis-pQTLs]), we determined that young, primate-specific genes are enriched in cis-eQTLs and cis-pQTLs.

Crossing-over in a hypervariable species preferentially occurs in regions of high local similarity.

Recombination between double-stranded DNA molecules is a key genetic process which occurs in a wide variety of organisms. Usually, crossing-over (CO) occurs during meiosis between genotypes with 98.0-99.

Prevalence of multinucleotide replacements in evolution of primates and Drosophila.

Evolution of sequences mostly involves independent changes at different sites. However, substitutions at neighboring sites may co-occur as multinucleotide replacement events (MNRs). Here, we compare noncoding sequences of several species of primates, and of three species of Drosophila fruit flies, in a phylogenetic analysis of the replacements that occurred between species at nearby nucleotide sites.

Heterogeneity of the transition/transversion ratio in Drosophila and Hominidae genomes.

Mutation rate varies between sites in the genome. Part of this variation can be explained by well-recognized short nucleotide contexts, but a large component of this variation remains cryptic. We used data on interspecies divergence and intraspecies polymorphism in Drosophila and Hominidae to analyze variation of the average rate of the 12 possible kinds of single-nucleotide mutations and in the transition/transversion ratio κ at single-nucleotide resolution.