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International Journal of Molecular... Jun 2023Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM's morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin-proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.
Topics: Humans; Carrier Proteins; Mutation; Cardiomyopathy, Hypertrophic; Mutation, Missense; Cytoskeletal Proteins; Death, Sudden, Cardiac
PubMed: 37445689
DOI: 10.3390/ijms241310510 -
Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.Nature Genetics Aug 2023Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals...
Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.
Topics: Humans; Cell-Free Nucleic Acids; Prospective Studies; Mutation; Neoplasms; Mutation Rate; Lung Neoplasms
PubMed: 37500728
DOI: 10.1038/s41588-023-01446-3 -
Brain : a Journal of Neurology Jul 2023Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased kw in the whole brain (β = -0.634, P = 0.001), normal-appearing white matter (β = -0.599, P = 0.002) and temporal lobe (β = -0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (β = 0.458, P = 0.001; β = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.
Topics: Humans; Blood-Brain Barrier; CADASIL; Brain; Cerebral Small Vessel Diseases; Cerebral Infarction
PubMed: 36625892
DOI: 10.1093/brain/awac500 -
Nature Aug 2023Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development....
Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
Topics: Adolescent; Adult; Female; Humans; Young Adult; Breast Neoplasms; Cell Lineage; Clone Cells; Epigenesis, Genetic; Epithelial Cells; Epithelium; Evolution, Molecular; Microdissection; Mutagenesis; Mutation; Mutation Rate; Premenopause; Tumor Microenvironment
PubMed: 37495687
DOI: 10.1038/s41586-023-06333-9 -
Frontiers in Veterinary Science 2023
PubMed: 37675076
DOI: 10.3389/fvets.2023.1273650 -
Nature Sep 2023The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic...
The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.
Topics: Humans; Male; Chromosomes, Human, Y; Genome, Human; Genomics; Mutation Rate; Phenotype; Evolution, Molecular; Euchromatin; Pseudogenes; Genetic Variation; Chromosomes, Human, X; Pseudoautosomal Regions
PubMed: 37612510
DOI: 10.1038/s41586-023-06425-6 -
Journal of Theoretical Biology Sep 2023The cost of germline maintenance gives rise to a trade-off between lowering the deleterious mutation rate and investing in life history functions. Therefore, life...
The cost of germline maintenance gives rise to a trade-off between lowering the deleterious mutation rate and investing in life history functions. Therefore, life history and the mutation rate coevolve, but this coevolution is not well understood. We develop a mathematical model to analyse the evolution of resource allocation traits, which simultaneously affect life history and the deleterious mutation rate. First, we show that the invasion fitness of such resource allocation traits can be approximated by the basic reproductive number of the least-loaded class; the expected lifetime production of offspring without deleterious mutations born to individuals without deleterious mutations. Second, we apply the model to investigate (i) the coevolution of reproductive effort and germline maintenance and (ii) the coevolution of age-at-maturity and germline maintenance. This analysis provides two resource allocation predictions when exposure to environmental mutagens is higher. First, selection favours higher allocation to germline maintenance, even if it comes at the expense of life history functions, and leads to a shift in allocation towards reproduction rather than survival. Second, life histories tend to be faster, characterised by individuals with shorter lifespans and smaller body sizes at maturity. Our results suggest that mutation accumulation via the cost of germline maintenance can be a major force shaping life-history traits.
Topics: Humans; Mutation Rate; Basic Reproduction Number; Body Size; Life History Traits; Mutation Accumulation
PubMed: 37598761
DOI: 10.1016/j.jtbi.2023.111598 -
Research Square Jul 2023Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species...
Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight (contrary to Peto's Paradox) and somatic mutation rate, but decreases with gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.
PubMed: 37461608
DOI: 10.21203/rs.3.rs-3117313/v1 -
Cells Jan 2024Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their... (Review)
Review
Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their mutation frequency in premalignant tissue is expected to exceed the basal mutation rate. In old terms, that translates to "the survival of the fittest" and implies that a selective process underlies the frequency of cancer driver mutations. In that sense, each tissue is its own niche that creates a molecular selective pressure that may favor the propagation of a mutation or not. At the heart of this stands one of the biggest riddles in cancer biology: the tissue-predisposition to cancer driver mutations. The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.
Topics: Humans; Precancerous Conditions; Disease Susceptibility; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Mutation Rate
PubMed: 38247798
DOI: 10.3390/cells13020106