Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity

The UK’s COVID-19 epidemic during early 2020 was one of world’s largest and unusually well represented by virus genomic sampling. Here we reveal the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 SARS-CoV-2 genomes, including 26,181 from the UK sampled throughout the country’s first wave of infection. Using large-scale phylogenetic analyses, combined with epidemiological and travel data, we quantify the size, spatio-temporal origins and persistence of genetically-distinct UK transmission lineages. Rapid fluctuations in virus importation rates resulted in >1000 lineages; those introduced prior to national lockdown tended to be larger and more dispersed. Lineage importation and regional lineage diversity declined after lockdown, while lineage elimination was size-dependent. We discuss the implications of our genetic perspective on transmission dynamics for COVID-19 epidemiology and control.

Download Full-text

Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

Cancers ◽

10.3390/cancers13133150 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3150

Author(s):

Irene López-Oreja ◽

Heribert Playa-Albinyana ◽

Fabián Arenas ◽

Mónica López-Guerra ◽

Dolors Colomer

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Targeted Therapies ◽

Biological Pathways ◽

Lymphocytic Leukemia ◽

Pi3k Inhibitors ◽

Recurrent Mutations ◽

Treatment Responses ◽

Few Data ◽

High Degree ◽

Btk Inhibitors

Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.

Download Full-text

Variation in pleiotropic hub gene expression is associated with interspecific differences in head shape and eye size in Drosophila

Molecular Biology and Evolution ◽

10.1093/molbev/msaa335 ◽

2021 ◽

Author(s):

Elisa Buchberger ◽

Anıl Bilen ◽

Sanem Ayaz ◽

David Salamanca ◽

Cristina Matas de las Heras ◽

...

Keyword(s):

Natural Variation ◽

Compound Eye ◽

Genetic Manipulation ◽

Morphological Evolution ◽

Morphological Diversity ◽

Network Evolution ◽

Head Shape ◽

Eye Size ◽

Recurrent Mutations ◽

Repeated Evolution

Abstract Revealing the mechanisms underlying the breath-taking morphological diversity observed in nature is a major challenge in Biology. It has been established that recurrent mutations in hotspot genes cause the repeated evolution of morphological traits, such as body pigmentation or the gain and loss of structures. To date, however, it remains elusive whether hotspot genes contribute to natural variation in the size and shape of organs. Since natural variation in head morphology is pervasive in Drosophila, we studied the molecular and developmental basis of differences in compound eye size and head shape in two closely related Drosophila species. We show differences in the progression of retinal differentiation between species and we applied comparative transcriptomics and chromatin accessibility data to identify the GATA transcription factor Pannier (Pnr) as central factor associated with these differences. Although the genetic manipulation of Pnr affected multiple aspects of dorsal head development, the effect of natural variation is restricted to a subset of the phenotypic space. We present data suggesting that this developmental constraint is caused by the co-evolution of expression of pnr and its co-factor u-shaped (ush). We propose that natural variation in expression or function of highly connected developmental regulators with pleiotropic functions is a major driver for morphological evolution and we discuss implications on gene regulatory network evolution. In comparison to previous findings, our data strongly suggests that evolutionary hotspots are not the only contributors to the repeated evolution of eye size and head shape in Drosophila.

Download Full-text

The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)89090-1 ◽

1985 ◽

Vol 260 (9) ◽

pp. 5787-5796 ◽

Cited By ~ 9

Author(s):

T A Kunkel

Keyword(s):

Dna Synthesis ◽

Dna Polymerase ◽

Dna Polymerase Beta ◽

Base Substitution ◽

Deletion Mutations ◽

Polymerase Beta ◽

Mutational Specificity

Download Full-text

Contributory role of SARS-CoV-2 genomic variations and life expectancy in COVID-19 transmission and low fatality rate in Africa

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-020-00116-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Olabode E. Omotoso

Keyword(s):

Mutational Analysis ◽

Health Care Systems ◽

Selective Advantage ◽

African Population ◽

Young Generation ◽

Regulatory Policies ◽

Recurrent Mutations ◽

Mutational Hotspots ◽

Care Systems ◽

Novel Coronavirus

Abstract Background The novel coronavirus disease (COVID-19) has claimed lots of lives, posing a dire threat to global health. It was predicted that the coronavirus outbreak in the African population would be very lethal and result to economic devastation owing to the prevalence of immune-compromised population, poverty, low lifespan, fragile health care systems, poor economy, and lifestyle factors. Accumulation of mutations gives virus selective advantage for host invasion and adaptation, higher transmissibility of more virulent strains, and drug resistance. The present study determined the severe acute respiratory syndrome-2 (SARS-CoV-2) genomic variability and the contributory factors to the low COVID-19 fatality in Africa. To assess the SARS-CoV-2 mutational landscape, 924 viral sequences from the Africa region with their sociobiological characteristics mined from the Global Initiative on Sharing All Influenza Data (GISAID) database were analyzed. Results Mutational analysis of the SARS-CoV-2 sequences revealed highly recurrent mutations in the SARS-CoV-2 spike glycoprotein D614G (97.2%), concurrent R203K, and G204R (65.2%) in the nucleocapsid phosphoprotein, and P4715L (97.2%) in the RNA-dependent RNA polymerase flagging these regions as SARS-CoV-2 mutational hotspots in the African population. COVID-19 is more severe in older people (> 65 years); Africa has a low percentage of people within this age group (4.36%). The average age of the infected patients observed in this study is 46 years with only 47 infected patients (5.1%) above 65 years in Africa in comparison to 13.12% in countries in other continents with the highest prevalence of COVID-19. Conclusions Africa’s young generation, the late incidence of the disease, and adherence to public health guidelines are important indicators that may have contributed to the observed low COVID-19 deaths in Africa. However, with the easing of lockdown and regulatory policies, daily increasing incidence in most countries, and low testing and sequencing rate, the epidemiology and the true impact of the pandemic in Africa remain to be unraveled.

Download Full-text

Ichthyosis with confetti caused by new and recurrent mutations in KRT10 associated with varying degrees of keratin 10 mis-localization

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2020.02.005 ◽

2020 ◽

Vol 98 (1) ◽

pp. 35-40 ◽

Cited By ~ 1

Author(s):

Yuxue Pan ◽

Cheng Feng ◽

Huijun Wang ◽

Mingyang Lee ◽

Zhanli Tang ◽

...

Keyword(s):

Recurrent Mutations

Download Full-text

Whole-exome sequencing reveals a novel homozygous mutation in the COQ8B gene associated with nephrotic syndrome

Scientific Reports ◽

10.1038/s41598-021-92023-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mohd Fareed ◽

Vikas Makkar ◽

Ravi Angral ◽

Mohammad Afzal ◽

Gurdarshan Singh

Keyword(s):

Nephrotic Syndrome ◽

Disease Management ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Homozygous Mutation ◽

Consanguineous Family ◽

Clinical Prognosis ◽

Whole Exome ◽

Recurrent Mutations ◽

Ckd Stage

AbstractNephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

Download Full-text