RESUMO
This perspective focuses on advances in genome technology over the last 25 years and their impact on germline variant discovery within the field of human genetics. The field has witnessed tremendous technological advances from microarrays to short-read sequencing and now long-read sequencing. Each technology has provided genome-wide access to different classes of human genetic variation. We are now on the verge of comprehensive variant detection of all forms of variation for the first time with a single assay. We predict that this transition will further transform our understanding of human health and biology and, more importantly, provide novel insights into the dynamic mutational processes shaping our genomes.
Assuntos
Variação Estrutural do Genoma , Genômica , Humanos , Genômica/métodos , Mutação em Linhagem Germinativa , Mutação , TecnologiaRESUMO
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.
Assuntos
Expressão Gênica/genética , Mutação em Linhagem Germinativa/genética , Espermatogênese/genética , Adulto , Animais , Sequência de Bases/genética , Perfilação da Expressão Gênica/métodos , Células Germinativas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Taxa de Mutação , Testículo/metabolismo , Transcrição Gênica/genética , Transcriptoma/genéticaRESUMO
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.
Assuntos
Cromatina/genética , Genoma Humano/genética , Mutação/genética , Mapeamento Cromossômico/métodos , DNA/química , Reparo do DNA/genética , Evolução Molecular , Genômica , Mutação em Linhagem Germinativa/genética , Humanos , Mutagênese/genética , Taxa de Mutação , Nucleossomos/genética , Fatores de Transcrição/genéticaRESUMO
Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.
Assuntos
Proteínas de Transporte/genética , Proteínas Nucleares/genética , Proteínas de Transporte/metabolismo , Cromatina/metabolismo , DNA , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/metabolismo , Feminino , Instabilidade Genômica , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Masculino , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Cultura Primária de Células , Reparo de DNA por RecombinaçãoRESUMO
Mutation frequencies vary along the genome, but the factors determining this variability are only partially understood. Pich et al. unravel a â¼10 bp periodicity in mutation rates at nucleosome-proximal regions that follows minor groove orientation. Opposing differential DNA damage and repair processes could shape genetic divergence irrespective of selection.
Assuntos
Mutação em Linhagem Germinativa , Nucleossomos , DNA , Genoma , Conformação de Ácido NucleicoRESUMO
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.
Assuntos
DNA/genética , Mutação em Linhagem Germinativa , Taxa de Mutação , Nucleossomos/genética , Arabidopsis/genética , DNA/química , Sequência Rica em GC , Variação Genética , Conformação de Ácido Nucleico , Nucleossomos/químicaRESUMO
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
Assuntos
Células Germinativas/metabolismo , Neoplasias/patologia , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Deleção de Genes , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Células Germinativas/citologia , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade/genética , Mutação de Sentido Incorreto , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.
Assuntos
Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Epigênese Genética , Mutação em Linhagem Germinativa , Neoplasias/genética , Neoplasias/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autofagia , Linhagem Celular Tumoral , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoterapia , Ipilimumab/farmacologia , Masculino , Melanoma/genética , Melanoma/imunologia , Antígenos Específicos de Melanoma/genética , Antígenos Específicos de Melanoma/imunologia , Camundongos , Camundongos Transgênicos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologiaRESUMO
Humans with inherited heterozygous BRCA2 mutations have an increased risk of developing cancer; however, what triggers carcinogenesis in these individuals is unclear. Tan et al. find that environmental and metabolic aldehydes pose a threat to these individuals by promoting degradation of wild-type BRCA2 protein, thereby predisposing them to genomic instability and perhaps to cancer.
Assuntos
Aldeídos , Mutação , Proteína BRCA2/genética , Neoplasias da Mama/genética , Genes BRCA1 , Instabilidade Genômica , Mutação em Linhagem Germinativa , Heterozigoto , HumanosRESUMO
Study of the biology of tumors caused by germline mutations has led to recent paradigm-changing therapy and is driving precision prevention efforts, including immune oncology and early detection research. Here, we explore recent biologic advances that are redefining the spectrum of cancers linked to various hereditary predisposition syndromes and can be leveraged to improve personalized risk assessment and develop novel interventions to prevent or intercept cancer.
Assuntos
Predisposição Genética para Doença , Neoplasias/genética , Neoplasias/prevenção & controle , Medicina de Precisão/métodos , Animais , Mutação em Linhagem Germinativa , HumanosRESUMO
We evaluated the impact of class I and class II human leukocyte antigen (HLA) genotypes, heterozygosity, and diversity on the efficacy of pembrolizumab. Seventeen pembrolizumab clinical trials across eight tumor types and one basket trial in patients with advanced solid tumors were included (n > 3,500 analyzed). Germline DNA was genotyped using a custom genotyping array. HLA diversity (measured by heterozygosity and evolutionary divergence) across class I loci was not associated with improved response to pembrolizumab, either within each tumor type evaluated or across all patients. Similarly, HLA heterozygosity at each class I and class II gene was not associated with response to pembrolizumab after accounting for the number of tests conducted. No conclusive association between HLA genotype and response to pembrolizumab was identified in this dataset. Germline HLA genotype or diversity alone is not an important independent determinant of response to pembrolizumab and should not be used for clinical decision-making in patients treated with pembrolizumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Genótipo , Mutação em Linhagem Germinativa/genética , Antígenos HLA/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Fatores Etários , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/mortalidade , Polimorfismo Genético , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Fatores Sexuais , Análise de Sobrevida , Resultado do TratamentoRESUMO
Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.
Assuntos
Doenças Autoimunes/genética , Autoimunidade/genética , Enzimas Desubiquitinantes/metabolismo , Endopeptidases/metabolismo , Inflamação/genética , Animais , Anticorpos Neutralizantes/uso terapêutico , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Linfócitos B/imunologia , Citocinas/metabolismo , Enzimas Desubiquitinantes/genética , Modelos Animais de Doenças , Endopeptidases/genética , Mutação em Linhagem Germinativa , Humanos , Inflamação/imunologia , Inflamação/terapia , Infliximab/uso terapêutico , Metionina/metabolismo , Camundongos , Camundongos Mutantes , Células Mieloides/imunologia , Poliubiquitina/metabolismo , Deleção de Sequência , Síndrome , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Carcinoma/genética , Predisposição Genética para Doença , Inflamassomos/metabolismo , Ceratose/genética , Neoplasias Cutâneas/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Proteínas Reguladoras de Apoptose/química , Carcinoma/patologia , Cromossomos Humanos Par 17/genética , Epiderme/patologia , Mutação em Linhagem Germinativa , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Inflamassomos/genética , Interleucina-1/metabolismo , Ceratose/patologia , Proteínas NLR , Comunicação Parácrina , Linhagem , Domínios Proteicos , Pirina/química , Transdução de Sinais , Neoplasias Cutâneas/patologia , SíndromeRESUMO
Definition of the specific germline immunoglobulin (Ig) alleles present in an individual is a critical first step to delineate the ontogeny and evolution of antigen-specific antibody responses. Rhesus and cynomolgus macaques are important animal models for pre-clinical studies, with four main sub-groups being used: Indian- and Chinese-origin rhesus macaques and Mauritian and Indonesian cynomolgus macaques. We applied the (Ig) gene inference tool IgDiscover and performed extensive Sanger sequencing-based genomic validation to define germline VDJ alleles in these 4 sub-groups, comprising 45 macaques in total. There was allelic overlap between Chinese- and Indian-origin rhesus macaques and also between the two macaque species, which is consistent with substantial admixture. The island-restricted Mauritian cynomolgus population displayed the lowest number of alleles of the sub-groups, yet maintained high individual allelic diversity. These comprehensive databases of germline IGH alleles for rhesus and cynomolgus macaques provide a resource toward the study of B cell responses in these important pre-clinical models.
Assuntos
Genótipo , Mutação em Linhagem Germinativa/genética , Cadeias Pesadas de Imunoglobulinas/genética , Alelos , Animais , Bases de Dados Genéticas , Modelos Animais de Doenças , Epitopos , Imunidade Humoral , Macaca fascicularis , Macaca mulatta , Filogenia , Polimorfismo Genético , Especificidade da Espécie , Recombinação V(D)JRESUMO
Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in â¼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-ß-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.
Assuntos
Mutação em Linhagem Germinativa/genética , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Genes BRCA1 , Estudo de Associação Genômica Ampla , Humanos , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Característica Quantitativa Herdável , Proteína p107 Retinoblastoma-Like/genética , Transdução de Sinais/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Germline variation and somatic mutation are intricately connected and together shape human traits and disease risks. Germline variants are present from conception, but they vary between individuals and accumulate over generations. By contrast, somatic mutations accumulate throughout life in a mosaic manner within an individual due to intrinsic and extrinsic sources of mutations and selection pressures acting on cells. Recent advancements, such as improved detection methods and increased resources for association studies, have drastically expanded our ability to investigate germline and somatic genetic variation and compare underlying mutational processes. A better understanding of the similarities and differences in the types, rates and patterns of germline and somatic variants, as well as their interplay, will help elucidate the mechanisms underlying their distinct yet interlinked roles in human health and biology.
Assuntos
Variação Genética , Mutação em Linhagem Germinativa , Humanos , Mutação , Predisposição Genética para DoençaRESUMO
Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.
Assuntos
Aneuploidia , Cromossomos Humanos X , Células Clonais , Leucócitos , Mosaicismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alelos , Doenças Autoimunes/genética , Bancos de Espécimes Biológicos , Segregação de Cromossomos/genética , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Células Clonais/metabolismo , Células Clonais/patologia , Exoma/genética , Proteínas F-Box/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Leucemia/genética , Leucócitos/metabolismo , Modelos Genéticos , Herança Multifatorial/genética , Mutação de Sentido Incorreto/genéticaRESUMO
Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) ß-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8+ T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2+ TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second ß-chain complementarity-determining region (CDR2ß). Extensive mutagenesis studies of three distinct TRBV11-2+ TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2ß loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas/imunologia , Vírus da Dengue/imunologia , Mutação em Linhagem Germinativa/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/imunologia , Dengue/genética , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA-A/química , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Humanos , Modelos Moleculares , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Sorotipagem , Ressonância de Plasmônio de SuperfícieRESUMO
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.
Assuntos
Evolução Molecular , Mutação em Linhagem Germinativa , Taxa de Mutação , Vertebrados , Animais , Feminino , Masculino , Aves/genética , Peixes/genética , Mutação em Linhagem Germinativa/genética , Mamíferos/genética , Répteis/genética , Vertebrados/genéticaRESUMO
The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.