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1.
Cell ; 187(15): 3904-3918.e8, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38851187

RESUMEN

We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.


Asunto(s)
ADN Mitocondrial , Linaje , Humanos , ADN Mitocondrial/genética , Femenino , Islandia , Masculino , Mutación , Tasa de Mutación
2.
Cell ; 180(2): 248-262.e21, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31978344

RESUMEN

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary timescales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning shapes germline mutation signatures and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.


Asunto(s)
Expresión Génica/genética , Mutación de Línea Germinal/genética , Espermatogénesis/genética , Adulto , Animales , Secuencia de Bases/genética , Perfilación de la Expresión Génica/métodos , Células Germinativas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Tasa de Mutación , Testículo/metabolismo , Transcripción Genética/genética , Transcriptoma/genética
3.
Cell ; 182(3): 672-684.e11, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32697969

RESUMEN

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.


Asunto(s)
Evolución Clonal/genética , Colitis/genética , Enfermedades Inflamatorias del Intestino/genética , Tasa de Mutación , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Evolución Clonal/inmunología , Colitis/metabolismo , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Proteínas de Unión al ADN/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Humanos , Mutación INDEL , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Filogenia , Mutación Puntual , Receptores de Superficie Celular/genética , Ribonucleasas/genética , Receptores Toll-Like/genética , Factores de Transcripción/genética , Secuenciación Completa del Genoma
4.
Cell ; 177(1): 101-114, 2019 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-30901533

RESUMEN

Large-scale chromatin features, such as replication time and accessibility influence the rate of somatic and germline mutations at the megabase scale. This article reviews how local chromatin structures -e.g., DNA wrapped around nucleosomes, transcription factors bound to DNA- affect the mutation rate at a local scale. It dissects how the interaction of some mutagenic agents and/or DNA repair systems with these local structures influence the generation of mutations. We discuss how this local mutation rate variability affects our understanding of the evolution of the genomic sequence, and the study of the evolution of organisms and tumors.


Asunto(s)
Cromatina/genética , Genoma Humano/genética , Mutación/genética , Mapeo Cromosómico/métodos , ADN/química , Reparación del ADN/genética , Evolución Molecular , Genómica , Mutación de Línea Germinal/genética , Humanos , Mutagénesis/genética , Tasa de Mutación , Nucleosomas/genética , Factores de Transcripción/genética
5.
Cell ; 176(6): 1282-1294.e20, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30849372

RESUMEN

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.


Asunto(s)
Desaminasas APOBEC/genética , Neoplasias/genética , Desaminasas APOBEC/metabolismo , Línea Celular , Línea Celular Tumoral , ADN/metabolismo , Análisis Mutacional de ADN/métodos , Bases de Datos Genéticas , Exoma , Genoma Humano/genética , Xenoinjertos , Humanos , Mutagénesis , Mutación/genética , Tasa de Mutación , Retroelementos , Secuenciación del Exoma/métodos
6.
Cell ; 178(4): 820-834.e14, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31398339

RESUMEN

Delineating ecologically meaningful populations among microbes is important for identifying their roles in environmental and host-associated microbiomes. Here, we introduce a metric of recent gene flow, which when applied to co-existing microbes, identifies congruent genetic and ecological units separated by strong gene flow discontinuities from their next of kin. We then develop a pipeline to identify genome regions within these units that show differential adaptation and allow mapping of populations onto environmental variables or host associations. Using this reverse ecology approach, we show that the human commensal bacterium Ruminococcus gnavus breaks up into sharply delineated populations that show different associations with health and disease. Defining populations by recent gene flow in this way will facilitate the analysis of bacterial and archaeal genomes using ecological and evolutionary theory developed for plants and animals, thus allowing for testing unifying principles across all biology.


Asunto(s)
Clostridiales/genética , Flujo Génico , Microbiota/genética , Adaptación Fisiológica/genética , Alelos , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/microbiología , Transferencia de Gen Horizontal , Genoma Bacteriano , Humanos , Modelos Genéticos , Tasa de Mutación , Filogenia , Polimorfismo de Nucleótido Simple , Prochlorococcus/genética , Sulfolobus/genética , Vibrio/genética
7.
Cell ; 175(4): 1074-1087.e18, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388444

RESUMEN

Mutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and phase of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosome-bound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.


Asunto(s)
ADN/genética , Mutación de Línea Germinal , Tasa de Mutación , Nucleosomas/genética , Arabidopsis/genética , ADN/química , Secuencia Rica en GC , Variación Genética , Conformación de Ácido Nucleico , Nucleosomas/química
8.
Cell ; 175(7): 1946-1957.e13, 2018 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-30415839

RESUMEN

Directed evolution is a powerful approach for engineering biomolecules and understanding adaptation. However, experimental strategies for directed evolution are notoriously labor intensive and low throughput, limiting access to demanding functions, multiple functions in parallel, and the study of molecular evolution in replicate. We report OrthoRep, an orthogonal DNA polymerase-plasmid pair in yeast that stably mutates ∼100,000-fold faster than the host genome in vivo, exceeding the error threshold of genomic replication that causes single-generation extinction. User-defined genes in OrthoRep continuously and rapidly evolve through serial passaging, a highly straightforward and scalable process. Using OrthoRep, we evolved drug-resistant malarial dihydrofolate reductases (DHFRs) in 90 independent replicates. We uncovered a more complex fitness landscape than previously realized, including common adaptive trajectories constrained by epistasis, rare outcomes that avoid a frequent early adaptive mutation, and a suboptimal fitness peak that occasionally traps evolving populations. OrthoRep enables a new paradigm of routine, high-throughput evolution of biomolecular and cellular function.


Asunto(s)
Adaptación Fisiológica/genética , Genoma Fúngico , Modelos Genéticos , Tasa de Mutación , Saccharomyces cerevisiae/genética , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
9.
Cell ; 171(5): 1029-1041.e21, 2017 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-29056346

RESUMEN

Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.


Asunto(s)
Neoplasias/genética , Neoplasias/patología , Humanos , Mutación INDEL , Inestabilidad de Microsatélites , Modelos Genéticos , Tasa de Mutación , Neoplasias/inmunología , Mutación Puntual , Polimorfismo de Nucleótido Simple , Selección Genética
10.
Annu Rev Genet ; 57: 391-410, 2023 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-38012024

RESUMEN

The ciliate genus Paramecium served as one of the first model systems in microbial eukaryotic genetics, contributing much to the early understanding of phenomena as diverse as genome rearrangement, cryptic speciation, cytoplasmic inheritance, and endosymbiosis, as well as more recently to the evolution of mating types, introns, and roles of small RNAs in DNA processing. Substantial progress has recently been made in the area of comparative and population genomics. Paramecium species combine some of the lowest known mutation rates with some of the largest known effective populations, along with likely very high recombination rates, thereby harboring a population-genetic environment that promotes an exceptionally efficient capacity for selection. As a consequence, the genomes are extraordinarily streamlined, with very small intergenic regions combined with small numbers of tiny introns. The subject of the bulk of Paramecium research, the ancient Paramecium aurelia species complex, is descended from two whole-genome duplication events that retain high degrees of synteny, thereby providing an exceptional platform for studying the fates of duplicate genes. Despite having a common ancestor dating to several hundred million years ago, the known descendant species are morphologically indistinguishable, raising significant questions about the common view that gene duplications lead to the origins of evolutionary novelties.


Asunto(s)
Paramecium , Paramecium/genética , Evolución Molecular , Genómica , Genoma , Tasa de Mutación
11.
Nature ; 633(8030): 608-614, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39261734

RESUMEN

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing1. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility1, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan-that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.


Asunto(s)
Envejecimiento , Predisposición Genética a la Enfermedad , Menopausia , Tasa de Mutación , Neoplasias , Ovario , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Envejecimiento/genética , Envejecimiento/patología , Daño del ADN/genética , Fertilidad/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genoma Humano/genética , Mutación de Línea Germinal/genética , Menarquia/genética , Menopausia/genética , Neoplasias/genética , Ovario/metabolismo , Ovario/patología , Factores de Tiempo , Biobanco del Reino Unido , Reino Unido/epidemiología
12.
Nature ; 634(8034): 617-625, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39232174

RESUMEN

The adoption of agriculture triggered a rapid shift towards starch-rich diets in human populations1. Amylase genes facilitate starch digestion, and increased amylase copy number has been observed in some modern human populations with high-starch intake2, although evidence of recent selection is lacking3,4. Here, using 94 long-read haplotype-resolved assemblies and short-read data from approximately 5,600 contemporary and ancient humans, we resolve the diversity and evolutionary history of structural variation at the amylase locus. We find that amylase genes have higher copy numbers in agricultural populations than in fishing, hunting and pastoral populations. We identify 28 distinct amylase structural architectures and demonstrate that nearly identical structures have arisen recurrently on different haplotype backgrounds throughout recent human history. AMY1 and AMY2A genes each underwent multiple duplication/deletion events with mutation rates up to more than 10,000-fold the single-nucleotide polymorphism mutation rate, whereas AMY2B gene duplications share a single origin. Using a pangenome-based approach, we infer structural haplotypes across thousands of humans identifying extensively duplicated haplotypes at higher frequency in modern agricultural populations. Leveraging 533 ancient human genomes, we find that duplication-containing haplotypes (with more gene copies than the ancestral haplotype) have rapidly increased in frequency over the past 12,000 years in West Eurasians, suggestive of positive selection. Together, our study highlights the potential effects of the agricultural revolution on human genomes and the importance of structural variation in human adaptation.


Asunto(s)
Agricultura , Amilasas , Evolución Molecular , Dosificación de Gen , Genoma Humano , Haplotipos , Selección Genética , Humanos , Agricultura/historia , Agricultura/estadística & datos numéricos , Amilasas/genética , Amilasas/química , Dosificación de Gen/genética , Duplicación de Gen/genética , Sitios Genéticos/genética , Genoma Humano/genética , Haplotipos/genética , Historia Antigua , Tasa de Mutación , Polimorfismo de Nucleótido Simple/genética , Caza/estadística & datos numéricos , Eliminación de Gen , ADN Antiguo/análisis
13.
Nature ; 615(7951): 285-291, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36859541

RESUMEN

The germline mutation rate determines the pace of genome evolution and is an evolving parameter itself1. However, little is known about what determines its evolution, as most studies of mutation rates have focused on single species with different methodologies2. Here we quantify germline mutation rates across vertebrates by sequencing and comparing the high-coverage genomes of 151 parent-offspring trios from 68 species of mammals, fishes, birds and reptiles. We show that the per-generation mutation rate varies among species by a factor of 40, with mutation rates being higher for males than for females in mammals and birds, but not in reptiles and fishes. The generation time, age at maturity and species-level fecundity are the key life-history traits affecting this variation among species. Furthermore, species with higher long-term effective population sizes tend to have lower mutation rates per generation, providing support for the drift barrier hypothesis3. The exceptionally high yearly mutation rates of domesticated animals, which have been continually selected on fecundity traits including shorter generation times, further support the importance of generation time in the evolution of mutation rates. Overall, our comparative analysis of pedigree-based mutation rates provides ecological insights on the mutation rate evolution in vertebrates.


Asunto(s)
Evolución Molecular , Mutación de Línea Germinal , Tasa de Mutación , Vertebrados , Animales , Femenino , Masculino , Aves/genética , Peces/genética , Mutación de Línea Germinal/genética , Mamíferos/genética , Reptiles/genética , Vertebrados/genética
14.
Nature ; 621(7978): 355-364, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37612510

RESUMEN

The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date1 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 chromosomes2. 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 established1 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.


Asunto(s)
Cromosomas Humanos Y , Evolución Molecular , Humanos , Masculino , Cromosomas Humanos Y/genética , Genoma Humano/genética , Genómica , Tasa de Mutación , Fenotipo , Eucromatina/genética , Seudogenes , Variación Genética/genética , Cromosomas Humanos X/genética , Regiones Pseudoautosómicas/genética
15.
Nature ; 620(7974): 607-614, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37495687

RESUMEN

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. 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.


Asunto(s)
Neoplasias de la Mama , Linaje de la Célula , Células Clonales , Evolución Molecular , Mutagénesis , Mutación , Adolescente , Adulto , Femenino , Humanos , Adulto Joven , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Linaje de la Célula/genética , Células Clonales/metabolismo , Células Clonales/patología , Epigénesis Genética , Células Epiteliales/citología , Células Epiteliales/metabolismo , Epitelio/patología , Microdisección , Tasa de Mutación , Premenopausia , Microambiente Tumoral
16.
Annu Rev Genet ; 54: 1-24, 2020 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-32663048

RESUMEN

Spermatogonial stem cells (SSCs) are generally characterized by excellent DNA surveillance and repair, resulting in one of the lowest spontaneous mutation rates in the body. However, the barriers to mutagenesis can be overwhelmed under two sets of circumstances. First, replication errors may generate age-dependent mutations that provide the mutant cells with a selective advantage, leading to the clonal expansions responsible for dominant genetic diseases such as Apert syndrome and achondroplasia. The second mechanism centers on the vulnerability of the male germline to oxidative stress and the induction of oxidative DNA damage in spermatozoa. Defective repair of such oxidative damage in the fertilized oocyte results in the creation of mutations in the zygote that can influence the health and well-being of the offspring. A particular hot spot for such oxidative attack on chromosome 15 has been found to align with several mutations responsible for paternally mediated disease, including cancer, psychiatric disorders, and infertility.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Mutación/genética , Animales , Cromosomas Humanos Par 15/genética , Daño del ADN/genética , Humanos , Masculino , Tasa de Mutación , Neoplasias/genética , Oocitos/crecimiento & desarrollo , Espermatozoides/crecimiento & desarrollo
17.
Nature ; 604(7906): 517-524, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35418684

RESUMEN

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.


Asunto(s)
Longevidad , Tasa de Mutación , Animales , Humanos , Longevidad/genética , Mamíferos/genética , Mutagénesis/genética , Mutación
18.
Nature ; 602(7895): 101-105, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35022609

RESUMEN

Since the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences1. Here we test this assumption with large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome-mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. With independent genomic mutation datasets, including from the largest Arabidopsis mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes. Observed mutation frequencies around genes in turn accurately predict patterns of genetic polymorphisms in natural Arabidopsis accessions (r = 0.96). That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies. Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias2 reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution.


Asunto(s)
Arabidopsis/genética , Evolución Molecular , Modelos Genéticos , Mutagénesis , Mutación , Selección Genética/genética , Epigenoma/genética , Epigenómica , Frecuencia de los Genes , Genes Esenciales/genética , Genes de Plantas/genética , Genoma de Planta/genética , Tasa de Mutación , Polimorfismo Genético/genética
19.
Nature ; 604(7907): 714-722, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35444284

RESUMEN

Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , Neuronas , Envejecimiento , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , ADN , Exones , Genómica , Hipocampo/citología , Humanos , Tasa de Mutación , Neuronas/patología , Nucleótidos , Corteza Prefrontal/citología , Secuenciación Completa del Genoma
20.
Nature ; 606(7915): 725-731, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35676473

RESUMEN

Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral1-5. Here, to experimentally verify this presumption, we constructed 8,341 yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 endogenous genes with diverse functions and expression levels and measured their fitness relative to the wild type in a rich medium. Three-quarters of synonymous mutations resulted in a significant reduction in fitness, and the distribution of fitness effects was overall similar-albeit nonidentical-between synonymous and nonsynonymous mutations. Both synonymous and nonsynonymous mutations frequently disturbed the level of mRNA expression of the mutated gene, and the extent of the disturbance partially predicted the fitness effect. Investigations in additional environments revealed greater across-environment fitness variations for nonsynonymous mutants than for synonymous mutants despite their similar fitness distributions in each environment, suggesting that a smaller proportion of nonsynonymous mutants than synonymous mutants are always non-deleterious in a changing environment to permit fixation, potentially explaining the common observation of substantially lower nonsynonymous than synonymous substitution rates. The strong non-neutrality of most synonymous mutations, if it holds true for other genes and in other organisms, would require re-examination of numerous biological conclusions about mutation, selection, effective population size, divergence time and disease mechanisms that rely on the assumption that synoymous mutations are neutral.


Asunto(s)
Genes Fúngicos , Aptitud Genética , Saccharomyces cerevisiae , Mutación Silenciosa , Secuencia de Aminoácidos , Codón sin Sentido/genética , Evolución Molecular , Genes Fúngicos/genética , Aptitud Genética/genética , Tasa de Mutación , ARN de Hongos/análisis , ARN de Hongos/biosíntesis , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Selección Genética , Mutación Silenciosa/genética
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