Background selection theory overestimates effective population size for high mutation rates

Simple models from the neutral theory of molecular evolution are claimed to be flexible enough to incorporate the complex effects of background selection against linked deleterious mutations. Complexities are collapsed into an "effective" population size that specifies neutral genetic diversity. To achieve this, current background selection theory assumes linkage equilibrium among deleterious variants. Data do not support this assumption, nor do theoretical considerations when the genome-wide deleterious mutation is realistically high. We simulate genomes evolving under background selection, allowing the emergence of linkage disequilibria. With realistically high deleterious mutation rates, neutral diversity is much lower than predicted from previous analytical theory.

Deleterious protein-coding variants in diverse cattle breeds of the world

The domestication of wild animals has resulted in a reduction in effective population sizes, which can affect the deleterious mutation load of domesticated breeds. In addition, artificial selection contributes to the accumulation of deleterious mutations because of an increased rate of inbreeding among domesticated animals. Since founder population sizes and artificial selection differ between cattle breeds, their deleterious mutation load can vary. We investigated this question by using whole-genome data from 432 animals belonging to 54 worldwide cattle breeds. Our analysis revealed a negative correlation between genomic heterozygosity and nonsynonymous-to-silent diversity ratio, which suggests a higher proportion of single nucleotide variants (SNVs) affecting proteins in low-diversity breeds. Our results also showed that low-diversity breeds had a larger number of high-frequency (derived allele frequency (DAF) > 0.51) deleterious SNVs than high-diversity breeds. An opposite trend was observed for the low-frequency (DAF ≤ 0.51) deleterious SNVs. Overall, the number of high-frequency deleterious SNVs was larger in the genomes of taurine cattle breeds than of indicine breeds, whereas the number of low-frequency deleterious SNVs was larger in the genomes of indicine cattle than in those of taurine cattle. Furthermore, we observed significant variation in the counts of deleterious SNVs within taurine breeds. The variations in deleterious mutation load between taurine and indicine breeds could be attributed to the population sizes of the wild progenitors before domestication, whereas the variations observed within taurine breeds could be due to differences in inbreeding level, strength of artificial selection, and/or founding population size. Our findings imply that the incidence of genetic diseases can vary between cattle breeds.

Increasing frequency of OXA-48-producing Enterobacterales worldwide and activity of ceftazidime/avibactam, meropenem/vaborbactam and comparators against these isolates

Objectives To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance. Methods Among 55?>162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of β-lactam resistance mechanisms and MLST was performed in silico using WGS data. Results OXA-48-like-producing isolates increased from 0.5% (94/18 656) in 2016 to 0.9% (169/18?>808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of blaCTX-M-15 (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%–15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%–42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional β-lactam resistance mechanisms. Conclusions Guidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.

Harmful mutation load in the mitochondrial genomes of cattle breeds

Objective Domestication of wild animals results in a reduction in the effective population size, and this could affect the deleterious mutation load of domesticated breeds. Furthermore, artificial selection will also contribute to the accumulation of deleterious mutations due to the increased rate of inbreeding among these animals. The process of domestication, founder population size, and artificial selection differ between cattle breeds, which could lead to a variation in their deleterious mutation loads. We investigated this using mitochondrial genome data from 364 animals belonging to 18 cattle breeds of the world. Results Our analysis revealed more than a fivefold difference in the deleterious mutation load among cattle breeds. We also observed a negative correlation between the breed age and the proportion of deleterious amino acid-changing polymorphisms. This suggests a proportionally higher deleterious SNPs in young breeds compared to older breeds. Our results highlight the magnitude of difference in the deleterious mutations present in the mitochondrial genomes of various breeds. The results of this study could be useful in predicting the rate of incidence of genetic diseases in different breeds.

Nos défauts génétiques cachés

A systematic study analysing the exomes of several thousand individuals indicates that each of them carries at least one strongly deleterious mutation that is innocuous in a heterozygote but results in a severe phenotype in the homozygous state. Most of these mutations are very rare, while a few are present in 1 or 2% of the population. The frequency of at-risk couples is approximately 1.5%, but increases dramatically to 25% if the partners of the couple are first cousins. This work has important implications for carrier screening and population genetics in general.

Efficacy of platinum-based chemotherapy in advanced triple-negative breast cancer in association with homologous recombination deficiency.

e13051 Background: Previous studies have identified that at least 50% of triple negative breast cancer (TNBC) harbor mutation characteristics of homologous recombination deficiency (HRD). Thus, more sophisticated research into comprehensive genomic profiling of HRD is urgently needed. Whereas BRCA1/2-deficient advanced TNBC patients are sensitive to treatment with platinum, it is not yet clear whether HRD status could predict platinum response. Methods: 3DMed-HRD algorithm was developed based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) as previously described. HRD status was defined as HRD positive (deleterious mutation in BRCA1/2 or HRD score ≥30) or HRD negative (no deleterious mutation in BRCA1/2 and HRD score < 30). Tumor samples from 207 TNBC patients were analyzed by next-generation sequencing. Deleterious or suspected deleterious mutations were included for analysis. Among the overall cohort, 34 patients with advanced TNBC treated with chemotherapy were analyzed. Cox regression model was applied to evaluate the relationship between HRD status and clinical outcomes. Results: Deleterious BRCA1/2 mutations were detected in 22.2% (46/207) of TNBC patients as well as 54.6% (113/207) were defined as HRD positive. The most frequent mutations in HRD-positive patients were TP53 (93.5%), MYC (29.0%), PIK3R1 (22.6%), PTEN (22.6%) and MCL1 (19.4%), while TP53 (77.8%), MYC (29.6%), PIK3CA (18.5%), KMT2C (14.8%) and RIT1 (14.8%) enriched in HRD-negative patients. Mutations in DNA Damage Response (DDR), P53, Checkpoint and Receptor Tyrosine Kinase (RTK) pathways were most involved in HRD positive patients. In advanced TNBC cohort, 19 patients received platinum-based and 15 received platinum-free chemotherapy in the first-line treatment. The progression-free survival (PFS) of the platinum-based group was longer than that of the platinum-free group (media PFS 9.1 vs 2.2 months, HR 0.44, 95%CI, 0.20-0.94, P = 0.009). In HRD-positive patients, median PFS was significantly longer in platinum-based group (N = 6) than platinum-free group (N = 8) (media PFS 13.6 vs 1.9 months, HR 0.30, 95%CI, 0.09-0.95, P = 0.008). No significant difference in PFS between platinum-based and platinum-free group (p = 0.332) in patients with HRD-negative tumors. Patients with mutations in homologous recombination (HR) pathway had a worse PFS compared to wild-type in platinum-free group (1.4 vs 3.0 months, p = 0.050). Conclusions: Our findings illustrate the potential of HRD status as a marker to guide chemotherapy in advanced TNBC. In HRD positive patients, platinum-based chemotherapy might be a preferable regimen. Patients with mutations in HR pathway had a shorter PFS in platinum-free group. Prospective study with a larger sample-size is needed for further validation of our findings.

Analysis of homologous recombination DNA repair gene mutation status in patients with metastatic small cell lung cancer treated with cediranib and olaparib on NCI 9881 study.

8563 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of homologous recombination DNA repair (HRR) genes and increases sensitivity of tumors to a poly-(ADP-ribose) polymerase (PARP) inhibitor in vitro and in vivo models of breast and ovarian cancer. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumor with a deleterious mutation in HRR genes. We hypothesized that cediranib induces HRR deficient phenotype by suppressing expression of HRR genes and cediranib and olaparib combination (C+O) results in an objectives response in patients with HRR proficient (HRP) advanced solid tumors. Herein, we report the biomarker data from analyses of targeted sequencing of 84 DNA repair (DR) genes with BROCA-HR assay in patients with metastatic small cell lung cancer (mSCLC). Methods: This multi-institutional phase 2 trial enrolled patients with mSCLC previously treated with a platinum-based chemotherapy. Patients received cediranib 30mg orally (po) daily plus olaparib 200mg po twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. A tumor biopsy was obtained from the patients with safely accessible metastatic tumor. HRR deficiency (HRD) was defined as presence of a deleterious mutation in any of the 10 key HRR-related genes per BROCA-HR assay including: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, or RAD51D. Otherwise, the tumors were defined as HRR proficiency (HRP). Results: A total of 25 patients with SCLC received the study treatment. Fourteen patients had available tumor biopsy samples and/or germline available for BROCA-HR. One patient (7%) was determined to have a HRD tumor by a presence of PALB2 mutation. This patient had stable disease as a best overall response but came off study due to unequivocal clinical progression. Thirteen patients (93%) had a HRP tumor. Six of these (46%) patients had PR. Median PFS in patients with HPR tumors was 122 days. The most common gene alterations detected by BROCA-HR assay was TP53 (93%) and RB1 (79%). Other DR gene alterations noted from our study samples were MRE11, CKD12 PALB2, ERCC4, FANCB, and BAP1. Conclusions: HRD was infrequent in our mSCLC samples. C+O resulted in objective responses in 46% of mSCLC patients with HRP tumors. Mutations in TP53 and RB1 were the most common gene alterations. Further investigation in warranted to confirm this observation. Clinical trial information: NCT02498613.

Therapeutic effect of DDR pathway with different functional annotations for immune checkpoint inhibitor.

2611 Background: DNA damage response and repair (DDR) pathway-related gene mutations have been reported to predict the efficacy of immune checkpoint inhibitor (ICI). However, therapeutic effect of DDR pathway with different functional annotations is not fully studied. Here we explore the relationship of DDR pathway with different functional annotations and clinical outcomes in public cohorts of immunotherapy and chemotherapy. Methods: Genetic testing and clinical outcomes data were obtained from the public clinical cohorts across 10 tumor types. 232 DDR pathway-related gene were assigned to eight pathway according to the literature. Nine predictive models for the mutation pathogenicity were included in the analysis, of which at least five returned positive results were defined as deleterious mutations. All annotations were according to the American College of Medical Genetics (ACMG) standards and guidelines. To explore the association between DDR pathways and ICI, DDR pathway mutation is grouped. Patients, who harbored mutations in two or more DDR pathways and meanwhile had deleterious mutation in at least one DDR pathway, were enrolled in group A. Patients, who harbored deleterious mutations in only one DDR pathway or had only uncertain significance mutations, were enrolled in group B. Patients with no DDR gene mutations were enrolled in Group C. We analyzed relation of the group and survival outcomes in four public cohorts. Results: Of 4 clinical cohort analyzed, the group A treated with ICI has the best PFS or OS outcomes. However, the comparison of group B and group C is not coincide across different cohorts. Treatment is the key factor that influents the relation of DDR pathway mutations and clinical outcomes. As shown in POPLAR/OAK cohort, patients in group C has the best PFS (p=0.0381) or OS (p=0.0350) outcome when treated with chemotherapy, but patients in group A has the best PFS (p=0.0083) or OS (p=0.0222) outcome when treated with ICI. Conclusions: When treated with ICI, patients with at least one deleterious mutation and another deleterious or uncertain significance mutation has the best PFS or OS outcomes, but not for chemotherapy. Our study suggested that DDR pathway with deleterious mutations might be a potential predictive factor for immunotherapy.[Table: see text]

A deleterious mutation-sheltering theory for the evolution of sex chromosomes and supergenes

Many organisms have sex chromosomes with large non-recombining regions having expanded stepwise, the reason why being still poorly understood. Theories proposed so far rely on differences between sexes but are poorly supported by empirical data and cannot account for the stepwise suppression of recombination around sex chromosomes in organisms without sexual dimorphism. We show here, by mathematical modeling and stochastic simulations, that recombination suppression in sex chromosomes can evolve simply because it shelters recessive deleterious mutations, which are ubiquitous in genomes. The permanent heterozygosity of sex-determining alleles protects linked chromosomal inversions against expression of their recessive mutation load, leading to an accumulation of inversions around these loci, as observed in nature. We provide here a testable and widely applicable theory to explain the evolution of sex chromosomes and of supergenes in general.

Heterogeneity in viral infections increases the rate of deleterious mutation accumulation

RNA viruses have high mutation rates, with the majority of mutations being deleterious. We examine patterns of deleterious mutation accumulation over multiple rounds of viral replication, with a focus on how cellular coinfection and heterogeneity in viral output affect these patterns. Specifically, using agent-based intercellular simulations we find, in agreement with previous studies, that coinfection of cells by viruses relaxes the strength of purifying selection, and thereby increases the rate of deleterious mutation accumulation. We further find that cellular heterogeneity in viral output exacerbates the rate of deleterious mutation accumulation, regardless of whether this heterogeneity in viral output is stochastic or is due to variation in cellular multiplicity of infection. These results highlight the need to consider the unique life histories of viruses and their population structure to better understand observed patterns of viral evolution.