RESUMO
Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.
Assuntos
Predisposição Genética para Doença , Genoma Humano , Pradaria , Esclerose Múltipla , Humanos , Conjuntos de Dados como Assunto , Dieta/etnologia , Dieta/história , Europa (Continente)/etnologia , Predisposição Genética para Doença/história , Genética Médica , História do Século XV , História Antiga , História Medieval , Migração Humana/história , Estilo de Vida/etnologia , Estilo de Vida/história , Esclerose Múltipla/genética , Esclerose Múltipla/história , Esclerose Múltipla/imunologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/história , Doenças Neurodegenerativas/imunologia , Densidade DemográficaRESUMO
We performed a candidate single-nucleotide polymorphism association study of cleft lip and palate in 1992 which earned more citations than it had subjects (N = 230).
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Estudos de Associação Genética , Predisposição Genética para Doença/história , Genótipo , História do Século XX , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The study and identification of genotype-environment interactions (GxE) has been a hot topic in the field of human genetics for several decades. Yet the extent to which GxE contributes to human behavior variability, and its mechanisms, remains largely unknown. Nick Martin has contributed important advances to the field of GxE for human behavior, which include methodological developments, novel analyses and reviews. Here, we will first review Nick's contributions to the GxE research, which started during his PhD and consistently appears in many of his over 1000 publications. Then, we recount a project that led to an article testing the diathesis-stress model for the origins of depression. In this publication, we observed the presence of an interaction between polygenic risk scores for depression (the risk in our 'genotype') and stressful life events (the experiences from our 'environment'), which provided the first empirical support of this model.
Assuntos
Depressão/genética , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Genética Humana/história , Depressão/história , Predisposição Genética para Doença/história , Genótipo , História do Século XX , História do Século XXI , HumanosRESUMO
This short essay recounts the author's interactions with Nick Martin in the years they both worked with Lindon Eaves at Virginia Commonwealth University. Although coming from very different academic traditions, they became close colleagues building their young careers together. Nick generously shared his statistical genetics expertise and the author taught Nick a thing or two about psychiatric illness.
Assuntos
Predisposição Genética para Doença/história , Genética Humana/história , Transtornos Mentais/genética , História do Século XX , História do Século XXI , Humanos , Transtornos Mentais/históriaRESUMO
Blood cell concentrations for most cell types are highly heritable. Data from Nick Martin's twin registry provided much of the data for the early heritability and linkage studies of blood cell related traits and have contributed significantly to more recent genomewide association studies that have successfully identified individual genetic loci.
Assuntos
Células Sanguíneas/citologia , Locos de Características Quantitativas/genética , Estudos em Gêmeos como Assunto/história , Gêmeos/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/história , Estudo de Associação Genômica Ampla , História do Século XX , História do Século XXI , Humanos , Fenótipo , Gêmeos/históriaRESUMO
In 1917, Eugen Bleuler published an article (Mendelismus bei Psychosen, speziell bei der Schizophrenie [Mendelism in the Psychoses, especially Schizophrenia]) in response to the recently published first systematic family study of dementia praecox (DP) by Ernst Rüdin, then working under Kraepelin in Munich. Although briefly commented upon by David Rosenthal in 1978, this article has never been thoroughly reviewed or translated. Of the many themes addressed, four are especially noteworthy. First, Bleuler argues that understanding the transmission patterns of schizophrenia in families requires definitive knowledge about the boundaries of the phenotype which he argues are unknown. Rüdin's choice-Kraepelin's concept of DP-is, he asserts, too narrow. Clarifying the genetics of schizophrenia is inextricably bound up with the problem of defining the phenotype. Second, Bleuler argues for the importance of "erbschizose" (literally "inherited schizoidia") wondering whether his "4 As" or other "brain-anatomical, chemical, [or] neurological characteristics" might underlie the genetic transmission of schizophrenia. Third, Bleuler was deeply interested in the nature of the onset of schizophrenia, suggesting that environmental adversity could provoke "latent illness to become manifest." It was important, he argued, to identify such risk factors and incorporate them into genetic models. Fourth, although not optimistic that current knowledge would permit a resolution of the transmission model for schizophrenia, he finds single-locus models implausible and at several points wonders whether polygenic models might better apply. A complete translation of the article is provided.
Assuntos
Eugenia (Ciência)/história , Predisposição Genética para Doença , Psiquiatria/história , Esquizofrenia , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/história , História do Século XX , Humanos , Esquizofrenia/etiologia , Esquizofrenia/genética , Esquizofrenia/históriaRESUMO
This article examines the origins of the term "genetic disease." In the late 19 and early 20th century, an earlier idea that diseases that occur in families reflect a vague familiar "predisposition" was replaced by the view that such diseases have specific causes, while Mendelian genetics provided then clues to the patterns of their transmission. The genetictisation of inborn pathologies took a decisive turn with the redefinition, in 1959, of Down syndrome as a chromosomal anomaly, then the development of tests for the diagnosis of other hereditary pathologies. At that time, geneticists distinguished "hereditary" diseases that run in families, from "genetic" conditions that are the result of new mutations during the production of egg and sperm cells. In the latter case, the inborn impairment is produced by an anomaly in the genetic material of the cell, but is not hereditary, because it is not transmitted from one or both parents. In the late 20th and early 21st century, new genomic technologies blurred the distinction between hereditary and genetic impairments, extended the concept of genetic disease, and modified the experience of people living with such a disease.
Assuntos
Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Doenças Genéticas Inatas/história , Predisposição Genética para Doença/história , Testes Genéticos/história , Genômica/métodos , História do Século XIX , História do Século XX , História do Século XXI , HumanosRESUMO
Abstract This article examines the origins of the term "genetic disease." In the late 19 and early 20th century, an earlier idea that diseases that occur in families reflect a vague familiar "predisposition" was replaced by the view that such diseases have specific causes, while Mendelian genetics provided then clues to the patterns of their transmission. The genetictisation of inborn pathologies took a decisive turn with the redefinition, in 1959, of Down syndrome as a chromosomal anomaly, then the development of tests for the diagnosis of other hereditary pathologies. At that time, geneticists distinguished "hereditary" diseases that run in families, from "genetic" conditions that are the result of new mutations during the production of egg and sperm cells. In the latter case, the inborn impairment is produced by an anomaly in the genetic material of the cell, but is not hereditary, because it is not transmitted from one or both parents. In the late 20th and early 21st century, new genomic technologies blurred the distinction between hereditary and genetic impairments, extended the concept of genetic disease, and modified the experience of people living with such a disease.
Resumo O presente artigo tem o objetivo de examinar as origens do termo "doença genética. No final do século XIX e início do XX, a vaga ideia que a doença manifesta entre familiares refletia uma "predisposição" familiar, foi substituída pela visão que essas doenças possuem causas específicas, enquanto a genética mendeliana forneceu as pistas para os padrões de transmissão da doença. A genética das patologias congênitas deu uma guinada decisiva, em 1959, com a redefinição da Síndrome de Down como uma anomalia cromossômica e, depois, com o desenvolvimento de testes para o diagnóstico de outras patologias hereditárias. Naquela época, os geneticistas distinguiam doenças "hereditárias" como aquelas que acometiam os elementos de uma família, de condições "genéticas" que são o resultado de novas mutações ocorridas durante a produção dos óvulos e espermatozoides. Neste último caso, a deficiência inata é causada por uma anomalia do material genético da célula, porque não é transmitida por qualquer um ou ambos os pais. No final do século XX e início do XXI, as novas tecnologias genômicas obscureceram a distinção entre deficiências hereditária e a genética, estenderam o conceito da doença genética e modificaram a experiência das pessoas que vivem com esse tipo de doença.
Assuntos
Humanos , História do Século XIX , História do Século XX , História do Século XXI , Testes Genéticos/métodos , Predisposição Genética para Doença/genética , Doenças Genéticas Inatas/genética , Testes Genéticos/história , Predisposição Genética para Doença/história , Genômica/métodos , Doenças Genéticas Inatas/históriaRESUMO
BACKGROUND AND AIMS: Nucleotide Oligomerisation Domain 2 [NOD2] is a key gene of innate immunity which participates in the host defence against pathogens. Several loss-of-function NOD2 mutations are associated with Crohn's disease [CD]. Their high frequencies in populations of European ancestry suggest a model of balancing selection. Because NOD2 deficiency has been associated with a resistance to Yersinia pseudotuberculosis in mice, we hypothesised that NOD2 mutations have been selected during past plague outbreaks due to the closely related bacterium Yersinia pestis. METHODS: Contemporary frequencies of the main CD-associated NOD2 mutations [R702W, G908R, and 1007fs], measured in healthy people from European and Mediterranean countries, were collected from 60 studies via a PubMed search. Plague exposure was calculated from a dataset providing outbreaks from 1346 to 1860 in Europe and the Mediterranean Bassin. A plague index was built to capture the intensity of plague exposure in the studied geographical areas. RESULTS: NOD2 mutation frequencies were associated with the past exposure to plague. Statistical significance was obtained for the most frequent mutation [R702W, p = 0.03] and for the pooled three mutations [p = 0.023]. The association remained significant when putative demographic biases were considered. CONCLUSIONS: This result argues for a selection of CD-associated NOD2 mutations by plague outbreaks and further questioned the role of exposure to enteropathogenic Yersinia species in CD.
Assuntos
Doença de Crohn/genética , Imunidade Inata/genética , Proteína Adaptadora de Sinalização NOD2/genética , Peste/genética , População Branca/genética , Doença de Crohn/imunologia , Surtos de Doenças/história , Europa (Continente)/epidemiologia , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/história , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História Medieval , Humanos , Modelos Estatísticos , Mutação/genética , Peste/história , Peste/imunologiaRESUMO
The genomes of ancient humans, Neandertals, and Denisovans contain many alleles that influence disease risks. Using genotypes at 3,180 disease-associated loci, we estimated the disease burden of 147 ancient genomes. After correcting for missing data, genetic risk scores (GRS) were generated for nine disease categories and the set of all combined diseases. We used these genetic risk scores to examine the effects of different types of subsistence, geography, and sample age on the number of risk alleles in each ancient genome. On a broad scale, hereditary disease risks are similar for ancient hominins and modern-day humans, and the GRS percentiles of ancient individuals span the full range of what is observed in present-day individuals. In addition, there is evidence that ancient pastoralists may have had healthier genomes than hunter-gatherers and agriculturalists. We also observed a temporal trend whereby genomes from the recent past are more likely to be healthier than genomes from the deep past. This calls into question the idea that modern lifestyles have caused genetic load to increase over time. Focusing on individual genomes, we found that the overall genomic health of the Altai Neandertal is worse than 97% of present-day humans and that Ötzi, the Tyrolean Iceman, had a genetic predisposition for gastrointestinal and cardiovascular diseases. As demonstrated by this work, ancient genomes afford us new opportunities to diagnose past human health, which has previously been limited by the quality and completeness of remains.
Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Hominidae/genética , Animais , Primers do DNA , DNA Mitocondrial/classificação , DNA Mitocondrial/genética , Evolução Molecular , Biblioteca Gênica , Estudos de Associação Genética , Predisposição Genética para Doença/classificação , Predisposição Genética para Doença/história , Genômica , Geografia/classificação , Geografia/história , História Antiga , Humanos , Homem de Neandertal/genética , FilogeniaAssuntos
Síndrome do Nevo Basocelular/história , Pediatria/história , Neoplasias Cutâneas/história , Síndrome do Nevo Basocelular/genética , Criança , Predisposição Genética para Doença/história , História do Século XX , Humanos , Mutação , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
In this paper I track the history of post-1945 human genetics and genomics emphasizing the importance of ideas about risk to the scientific study and medical management of human heredity. Drawing on my own scholarship as it is refracted through important new work by other scholars both junior and senior, I explore how radiation risk and then later disease risk mattered to the development of genetics and genomics, particularly in the United States. In this context I excavate one of the central ironies of post-war human genetics: while studies of DNA as the origin and cause of diseases have been lavishly supported by public institutions and private investment around the world, the day-to-day labor of intensive clinical innovation has played a far more important role in the actual human experience of genetic disease and genetic risk for affected families. This has implications for the archival record, where clinical interactions are less readily accessible to historians. This paper then suggests that modern genomics grew out of radiation risk; that it was and remains a risk assessment science; that it is temporally embedded as a form of both prediction and historical reconstruction; and that it has become a big business focused more on risk and prediction (which can be readily marketed) than on effective clinical intervention.
Assuntos
Arquivos/história , Genética Médica/história , Armas Nucleares/história , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/história , Genômica/história , História do Século XX , Humanos , Japão , Lesões por Radiação/genética , Lesões por Radiação/história , Estados UnidosRESUMO
In an attempt to reproduce the results of an inconclusive 1927 report by the British Medical Research Council on the hereditary versus social origins of rheumatic fever, Read, Ciocco, and Taussig, from Johns Hopkins University, with the support of Frost, conducted a case-control study in 1935 and 1936. Their study, which appeared in the American Journal of Hygiene in 1938, was outstanding for its clear and tidy rationale for separating hereditary from environmental causes. The authors compared the prevalence of rheumatic fever among the relatives of 33 children admitted for "incident" rheumatic fever and 33 control children admitted in a tuberculosis clinic for reasons other than rheumatic fever. Both rheumatic fever (cases) and tuberculosis (controls) were diseases of the poor. All family members of both cases and controls, including uncles, aunts, and grandparents, were eligible for interview and physical examination. The results were compatible with the presence of an "inherited predisposition" to rheumatic fever because the disease was more prevalent among the uncles, aunts, and grandparents of case patients than among those of control patients. Methodologically, the paper by Read, Ciocco, and Taussig is an important but almost completely forgotten milestone in the evolution of case-control studies and of genetic epidemiology.
Assuntos
Febre Reumática/história , Baltimore/epidemiologia , Estudos de Casos e Controles , Criança , Métodos Epidemiológicos , Interação Gene-Ambiente , Predisposição Genética para Doença/história , História do Século XX , Humanos , Febre Reumática/epidemiologia , Febre Reumática/etiologia , Febre Reumática/genéticaRESUMO
The data on Dostoevsky's epilepsy are ambiguous and often contradictory. It prompted consideration of certain genetic aspects of the writer's pedigree for the clarification of this issue. The phenomenon of Dostoevsky's genius was for the first time contemplated from the standpoint of the contribution of genetic factors to his creative work. It was shown that Dostoevsky's ancestry can not be a source of hereditary predisposition to epilepsy. The available data question the genuine nature of his disease. Characteristic of Dostoevsky's ancestry is the wide occurrence of "creativeness" genes. Their cumulation together with a number of other factors verified in the writer can account for the phenomenon of his genius.
Assuntos
Epilepsia/história , Pessoas Famosas , Predisposição Genética para Doença/história , Genética/história , Medicina na Literatura , Personalidade , Epilepsia/genética , História do Século XIX , Humanos , Rússia (pré-1917)RESUMO
Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.
Assuntos
Predisposição Genética para Doença/genética , Predisposição Genética para Doença/história , Variação Genética/genética , Esquizofrenia/genética , Estudo de Associação Genômica Ampla/história , Estudo de Associação Genômica Ampla/métodos , Genômica , Genótipo , História do Século XX , História do Século XXI , Humanos , PubMed/estatística & dados numéricosRESUMO
The demonstration of Mycobacterium tuberculosis DNA in ancient skeletons gives researchers an insight into its evolution. Findings of the last two decades sketched the biological relationships between the various species of tubercle bacilli, the time scale involved, their possible origin and dispersal. This paper includes the available evidence and on-going research. In the submerged Eastern Mediterranean Neolithic village of Atlit Yam (9000 BP), a human lineage of M. tuberculosis, defined by the TbD1 deletion in its genome, was demonstrated. An infected infant at the site provides an example of active tuberculosis in a human with a naïve immune system. Over 4000 years later tuberculosis was found in Jericho. Urbanization increases population density encouraging M. tuberculosis/human co-evolution. As susceptible humans die of tuberculosis, survivors develop genetic resistance to disease. Thus in 18th century Hungarian mummies from Vác, 65% were positive for tuberculosis yet a 95-year-old woman had clearly survived a childhood Ghon lesion. Whole genome studies are in progress, to detect changes over the millennia both in bacterial virulence and also host susceptibility/resistance genes that determine the NRAMP protein and Killer Cell Immunoglobulin-like Receptors (KIRs). This paper surveys present evidence and includes initial findings.
Assuntos
Evolução Molecular , Genoma Bacteriano/genética , Genoma Humano/genética , Mycobacterium tuberculosis/genética , Tuberculose/genética , Animais , Proteínas de Transporte de Cátions/genética , Bovinos , Resistência à Doença/genética , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/história , Genótipo , História do Século XVIII , História do Século XIX , História Antiga , Interações Hospedeiro-Patógeno/genética , Humanos , Múmias , Paleopatologia , Tuberculose/históriaRESUMO
Leprosy is a chronic infectious disease caused by a close relative of Mycobacterium tuberculosis: Mycobacterium leprae. There have been various beliefs in its etiology with two main concepts emerging: anticontagion and contagion. From ancient times through the early Middle Ages, the miasmatic theory of leprosy was the main anticontagion view. The development of histopathologic and cytologic studies in the second half of the 19th century provided a starting point to explain the etiology of leprosy bacteriologically.