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1.
Nat Commun ; 12(1): 1434, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664264

RESUMEN

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.


Asunto(s)
Aneuploidia , Variaciones en el Número de Copia de ADN/genética , Genoma Humano/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Progresión de la Enfermedad , Exoma/genética , Humanos , Mutación INDEL/genética , Melanocitos/patología , Mutación Puntual/genética , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma Completo , Secuenciación Completa del Genoma
2.
EBioMedicine ; 65: 103246, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33647767

RESUMEN

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.


Asunto(s)
/patología , Péptidos/genética , Receptores Androgénicos/genética , Anciano , Estudios de Casos y Controles , Cuidados Críticos/estadística & datos numéricos , Femenino , Genoma Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Índice de Severidad de la Enfermedad , España , Testosterona/sangre
3.
Am J Hum Genet ; 108(3): 395-399, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33667393

RESUMEN

This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.


Asunto(s)
Consanguinidad , Genética Médica/tendencias , Genética de Población/tendencias , Genoma Humano/genética , Humanos , Anotación de Secuencia Molecular
4.
Nat Commun ; 12(1): 1861, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767199

RESUMEN

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.


Asunto(s)
Genoma Humano/genética , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Mieloma Múltiple/genética , Mieloma Múltiple Quiescente/genética , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/patología , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Mieloma Múltiple Quiescente/patología , Secuenciación Completa del Genoma
5.
Evol Anthropol ; 30(2): 113-121, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788352

RESUMEN

The relationship history of evolutionary anthropology and genetics is complex. At best, genetics is a beautifully integrative part of the discipline. Yet this integration has also been fraught, with punctuated, disruptive challenges to dogma, periodic reluctance by some members of the field to embrace results from analyses of genetic data, and occasional over-assertions of genetic definitiveness by geneticists. At worst, evolutionary genetics has been a tool for reinforcing racism and colonialism. While a number of genetics/genomics papers have disproportionately impacted evolutionary anthropology, here we highlight the 2002 presentation of an elegantly powerful approach for identifying "signatures" of past positive selection from haplotype-based patterns of genetic variation. Together with technological advances in genotyping methods, this article transformed our field by facilitating genome-wide "scans" for signatures of past positive selection in human populations. This approach helped researchers test longstanding evolutionary anthropology hypotheses while simultaneously providing opportunities to develop entirely new ones. Genome-wide scans for signatures of positive selection have since been conducted in diverse worldwide populations, with striking findings of local adaptation and convergent evolution. Yet there are ethical considerations with respect to the ubiquity of these studies and the cross-application of the genome-wide scan approach to existing datasets, which we also discuss.


Asunto(s)
Antropología Física/ética , Genética de Población/ética , Genoma Humano/genética , Selección Genética/genética , Adaptación Biológica/genética , Antropología Física/organización & administración , Evolución Molecular , Haplotipos/genética , Humanos , Metagenómica/ética , Publicaciones/estadística & datos numéricos
6.
Nature ; 592(7852): 80-85, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33692543

RESUMEN

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation-within a few cell divisions of the zygote-of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.


Asunto(s)
Mosaicismo , Mutagénesis , Mutación , Placenta/metabolismo , Biopsia , Masa Celular Interna del Blastocisto/citología , Femenino , Genoma Humano/genética , Humanos , Mesodermo/citología , Tasa de Mutación , Placenta/citología , Embarazo , Trisomía/genética , Trofoblastos/citología , Trofoblastos/metabolismo , Cigoto/citología
7.
Am J Hum Genet ; 108(3): 517-524, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33667394

RESUMEN

Tuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia.


Asunto(s)
ADN Antiguo/análisis , Polimorfismo Genético/genética , TYK2 Quinasa/genética , Tuberculosis/genética , Restos Mortales , Europa (Continente) , Femenino , Genoma Humano/genética , Historia Antigua , Humanos , Masculino , Tuberculosis/historia , Tuberculosis/microbiología
8.
Nat Genet ; 53(4): 435-444, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33686287

RESUMEN

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.


Asunto(s)
/genética , Sistemas CRISPR-Cas , Genoma Humano/genética , Estudio de Asociación del Genoma Completo/métodos , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Líquido del Lavado Bronquioalveolar/citología , /virología , Línea Celular Tumoral , Células Cultivadas , Coronavirus Humano 229E/genética , Epidemias , Células Epiteliales/virología , Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Provirus/fisiología , Internalización del Virus
9.
Rev. Hosp. Ital. B. Aires (2004) ; 41(1): 37-42, mar. 2021. ilus, tab
Artículo en Español | LILACS | ID: biblio-1178964

RESUMEN

El término CRISPR, por su acrónimo en inglés refiere a Clustered Regularly Interspaced Short Palindromic Repeats, es decir, repeticiones palindrómicas cortas, agrupadas y regularmente esparcidas, por sus características en el genoma, pertenece naturalmente al sistema de defensa de bacterias y arqueas. Este ha sido adaptado biotecnológicamente para la edición del ADN de células eucariotas, incluso de células humanas. El sistema CRISPR-Cas para editar genes consta, en forma generalizada, de dos componentes: una proteína nucleasa (Cas) y un ARN guía (sgRNA). La simplicidad del complejo lo hace una herramienta molecular reprogramable capaz de ser dirigida y de editar cualquier sitio en un genoma conocido. Su principal foco son las terapias para enfermedades hereditarias monogénicas y para el cáncer. Sin embargo, además de editor de genes, la tecnología CRISPR se utiliza para edición epigenética, regulación de la expresión génica y método de diagnóstico molecular. Este artículo tiene por objetivo presentar una revisión de las aplicaciones de la herramienta molecular CRISPR-Cas, particularmente en el campo biomédico, posibles tratamientos y diagnósticos, y los avances en investigación clínica, utilizando terapia génica con CRISPR/Cas más relevantes hasta la fecha. (AU)


CRISPR are Clustered Regularly Interspaced Short Palindromic Repeats, which naturally belong to the defense system of bacteria and archaea. It has been biotechnologically adapted for editing the DNA of eukaryotic cells, including human cells. The CRISPR-Cas system for editing genes generally consists of two components, a nuclease protein (Cas) and a guide RNA (sgRNA). The simplicity of the complex makes it a reprogrammable molecular tool capable of being targeted and editing any site in a known genome. Its main focus is therapies for monogenic inherited diseases and cancer. However, in addition to gene editor, CRISPR technology is used for epigenetic editing, regulation of gene expression, and molecular diagnostic methods. This article aims to present a review of the applications of the CRISPR-Cas molecular tool, particularly in the biomedical field, possible treatments and diagnoses, and the advances in clinical research, using the most relevant CRISPR-Cas gene therapy to date. (AU)


Asunto(s)
Humanos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Sistemas CRISPR-Cas/genética , Biotecnología , Terapia Genética/métodos , Expresión Génica , Genoma Humano/genética , Regulación de la Expresión Génica , Epigenómica/tendencias , Proteínas Asociadas a CRISPR/genética , Proteínas Asociadas a CRISPR/uso terapéutico , Enfermedades Genéticas Congénitas/terapia , Neoplasias/terapia
17.
Viruses ; 13(2)2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557409

RESUMEN

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions.


Asunto(s)
Carcinoma Hepatocelular/genética , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/genética , Integración Viral , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , ADN Viral/genética , Frecuencia de los Genes , Genoma Humano/genética , Genoma Viral/genética , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/genética , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Programas Informáticos
18.
Nat Commun ; 12(1): 1264, 2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627654

RESUMEN

The recent development of imputation methods enabled the prediction of human leukocyte antigen (HLA) alleles from intergenic SNP data, allowing studies to fine-map HLA for immune phenotypes. Here we report an accurate HLA imputation method, CookHLA, which has superior imputation accuracy compared to previous methods. CookHLA differs from other approaches in that it locally embeds prediction markers into highly polymorphic exons to account for exonic variability, and in that it adaptively learns the genetic map within MHC from the data to facilitate imputation. Our benchmarking with real datasets shows that our method achieves high imputation accuracy in a wide range of scenarios, including situations where the reference panel is small or ethnically unmatched.


Asunto(s)
Antígenos HLA/metabolismo , Alelos , Grupo de Ascendencia Continental Asiática , Diabetes Mellitus Tipo 1/genética , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Genotipo , Antígenos HLA/genética , Humanos , Modelos Teóricos , Fenotipo , Polimorfismo de Nucleótido Simple/genética
19.
Methods Mol Biol ; 2243: 1-25, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33606250

RESUMEN

Increasingly affordable sequencing technologies are revolutionizing the field of genomic medicine. It is now feasible to interrogate all major classes of variation in an individual across the entire genome for less than $1000 USD. While the generation of patient sequence information using these technologies has become routine, the analysis and interpretation of this data remains the greatest obstacle to widespread clinical implementation. This chapter summarizes the steps to identify, annotate, and prioritize variant information required for clinical report generation. We discuss methods to detect each variant class and describe strategies to increase the likelihood of detecting causal variant(s) in Mendelian disease. Lastly, we describe a sample workflow for synthesizing large amount of genetic information into concise clinical reports.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Variación Genética/genética , Genoma Humano/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Genómica/métodos , Humanos , Secuenciación Completa del Genoma/métodos
20.
Methods Mol Biol ; 2243: 27-58, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33606251

RESUMEN

The next-generation sequencing (NGS) technology has revolutionized research in genetics and genomics, resulting in massive NGS data and opening more fronts to answer unresolved issues in genetics. NGS data are usually stored at three levels: image files, sequence tags, and alignment reads. The sizes of these types of data usually range from several hundreds of gigabytes to several terabytes. Biostatisticians and bioinformaticians are typically working with the aligned NGS read count data (hence the last level of NGS data) for data modeling and interpretation.To horn in on the use of NGS technology, researchers utilize it to profile the whole genome to study DNA copy number variations (CNVs) for an individual subject (or patient) as well as groups of subjects (or patients). The resulting aligned NGS read count data are then modeled by proper mathematical and statistical approaches so that the loci of CNVs can be accurately detected. In this book chapter, a summary of most popularly used statistical methods for detecting CNVs using NGS data is given. The goal is to provide readers with a comprehensive resource of available statistical approaches for inferring DNA copy number variations using NGS data.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Genoma Humano/genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos
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