Field Of Human Genetics Research Articles

Mammalian Cell Tissue Culture.

Cultured mammalian cells are used extensively in the field of human genetics. It requires a number of special skills in order to be able to preserve the structure, function, behavior, and biology of the cells in culture. This unit describes the basic skills required to maintain and preserve cell cultures: maintaining aseptic technique, preparing media with the appropriate characteristics, passaging, freezing and storage, recovering frozen stocks, and counting viable cells. © 2017 by John Wiley & Sons, Inc.

From sexless to sexy: Why it is time for human genetics to consider and report analyses of sex

Science has come a long way with regard to the consideration of sex differences in clinical and preclinical research, but one field remains behind the curve: human statistical genetics. The goal of this commentary is to raise awareness and discussion about how to best consider and evaluate possible sex effects in the context of large-scale human genetic studies. Over the course of this commentary, we reinforce the importance of interpreting genetic results in the context of biological sex, establish evidence that sex differences are not being considered in human statistical genetics, and discuss how best to conduct and report such analyses. Our recommendation is to run stratified analyses by sex no matter the sample size or the result and report the findings. Summary statistics from stratified analyses are helpful for meta-analyses, and patterns of sex-dependent associations may be hidden in a combined dataset. In the age of declining sequencing costs, large consortia efforts, and a number of useful control samples, it is now time for the field of human genetics to appropriately include sex in the design, analysis, and reporting of results.

Knowledge-driven binning approach for rare variant association analysis: application to neuroimaging biomarkers in Alzheimer\u2019s disease

BackgroundRapid advancement of next generation sequencing technologies such as whole genome sequencing (WGS) has facilitated the search for genetic factors that influence disease risk in the field of human genetics. To identify rare variants associated with human diseases or traits, an efficient genome-wide binning approach is needed. In this study we developed a novel biological knowledge-based binning approach for rare-variant association analysis and then applied the approach to structural neuroimaging endophenotypes related to late-onset Alzheimer’s disease (LOAD).MethodsFor rare-variant analysis, we used the knowledge-driven binning approach implemented in Bin-KAT, an automated tool, that provides 1) binning/collapsing methods for multi-level variant aggregation with a flexible, biologically informed binning strategy and 2) an option of performing unified collapsing and statistical rare variant analyses in one tool. A total of 750 non-Hispanic Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort who had both WGS data and magnetic resonance imaging (MRI) scans were used in this study. Mean bilateral cortical thickness of the entorhinal cortex extracted from MRI scans was used as an AD-related neuroimaging endophenotype. SKAT was used for a genome-wide gene- and region-based association analysis of rare variants (MAF (minor allele frequency) < 0.05) and potential confounding factors (age, gender, years of education, intracranial volume (ICV) and MRI field strength) for entorhinal cortex thickness were used as covariates. Significant associations were determined using FDR adjustment for multiple comparisons.ResultsOur knowledge-driven binning approach identified 16 functional exonic rare variants in FANCC significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In addition, the approach identified 7 evolutionary conserved regions, which were mapped to FAF1, RFX7, LYPLAL1 and GOLGA3, significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In further analysis, the functional exonic rare variants in FANCC were also significantly associated with hippocampal volume and cerebrospinal fluid (CSF) Aβ1–42 (p-value < 0.05).ConclusionsOur novel binning approach identified rare variants in FANCC as well as 7 evolutionary conserved regions significantly associated with a LOAD-related neuroimaging endophenotype. FANCC (fanconi anemia complementation group C) has been shown to modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Our results warrant further investigation in a larger independent cohort and demonstrate that the biological knowledge-driven binning approach is a powerful strategy to identify rare variants associated with AD and other complex disease.

Survey of Metaheuristics and Statistical Methods for Multifactorial Diseases Analyses

The identification of the interactions of polymorphisms with other genetic or environmental factors for the detection of multifactorial diseases has now become both a challenge and an objective for geneticists. Unlike monogenic Mendelian diseases, the classical methods have not become too efficient for the identification of these interactions, especially with the exponential increase in the number of genetic interactions as well as the number of combinations of genotypes. Several methods have been proposed for the detection of susceptibility variants such as metaheuristics and statistical methods. Using metaheuristics, we focus on the feature selection of variables, and more precisely on the determination of the genes that increase the susceptibility to the disease, especially as these methods are more suitable for the description of complex data. Statistical methods are divided into two submethods including linkage studies and association studies. Generally these two methods are used one after the other since they are complementary. The linkage study is used initially because its objective is the localization of the chromosomal regions containing the gene(s) involved in the disease. Then, in a second step, the association study is set up to specify precisely the location of the gene. In this paper, we will present a survey of metaheuristics and statistical methods integrated in the field of human genetics and specifically multifactorial diseases in order to help genetics to find interaction between genes and environemental factor involved in those diseases.

Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing.

BackgroundNGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD).MethodsA cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken.ResultsGenetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation.ConclusionThe diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes.

Erratum: Guidelines for diagnostic next-generation sequencing

We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for the evaluation and validation of next-generation sequencing (NGS) applications for the diagnosis of genetic disorders. The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients' representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here. The background document and full guidelines are available as supplementary material. They include many examples to assist the laboratories in the implementation of NGS and accreditation of this service. The work and ideas presented by others in guidelines that have emerged elsewhere in the course of the past few years were also considered and are acknowledged in the full text. Interestingly, a few new insights that have not been cited before have emerged during the preparation of the guidelines. The most important new feature is the presentation of a 'rating system' for NGS-based diagnostic tests. The guidelines and statements have been applauded by the genetic diagnostic community, and thus seem to be valuable for the harmonization and quality assurance of NGS diagnostics in Europe.

BIRC3 as a yet underestimated prognostic marker of malignancies

Working in the field of human genetics since >20 years the announcement and publication of a discovery of a new candidate gene for a specific genetic disorder is not that unusual to me. In contrary, even though the whole exome of human was announced to be sequenced in 2001 already (1), candidate genes for inborn as well as acquired diseases were not becoming less since that time ( Figure 1 ). Knowing the field, this is not surprising. Even though human genome project (HUGO) told us where genes may be located within the 46 human chromosomes, HUGO per se was never able to tell us what the function of all these genes is. To find out about this, studies in patients are necessary to identify which genes are impaired in connection with which disorder or disease; and such studies need to be followed or accompanied by functional studies.

An Introduction to Genome-Wide Association Studies: GWAS for Dummies

Although the genetic origin of many human diseases and phenotypes has been long and widely recognized, identification of the causative gene alleles has been limited, slow, and cumbersome. This has changed substantially with the introduction of genome-wide association studies (GWASs) a decade ago, fueled by studies and reference projects of human genetic diversity and the development of novel DNA analysis technology applicable to high-throughput and large-scale data generation. Although GWASs essentially combine epidemiological study designs with molecular genetic analysis techniques, it has also fundamentally changed the way in which research was done in human genetics by the introduction of large consortia of collaborating investigators. GWASs have over flooded many clinical and basic research areas with gene discoveries, including those in reproductive medicine. This review describes aspects of GWAS methodology and how this field of human genetics is developing.

Mini-Workshop: Recent Developments in Statistical Methods with Applications to Genetics and Genomics

Recent progress in high-throughput genomic technologies has revolutionized the field of human genetics and promises to lead to important scientific advances. With new improvements in massively parallel biotechnologies, it is becoming increasingly more efficient to generate vast amounts of information at the genomics, transcriptomics, proteomics, metabolomics etc. levels, opening up as yet unexplored opportunities in the search for the genetic causes of complex traits. Despite this tremendous progress in data generation, it remains very challenging to analyze, integrate and interpret these data. The resulting data are high-dimensional and very sparse, and efficient statistical methods are critical in order to extract the rich information contained in these data. The major focus of the mini-workshop, entitled “Recent Developments in Statistical Methods with Applications to Genetics and Genomics”, has been on integrative methods. Relevant research questions included the optimal study design for integrative genomic analyses; appropriate handling and pre-processing of different types of omics data; statistical methods for integration of multiple types of omics data; adjustment for confounding due to latent factors such as cell or tissue heterogeneity; the optimal use of omics data to enhance or make sense of results identified through genetic studies; and statistical and computational strategies for analysis of multiple types of high-dimensional data.

Reflections on the Field of Human Genetics: A Call for Increased Disease Genetics Theory.

Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant.

Improving Genomic Literacy Among Cardiovascular Practitioners via a Flipped-Classroom Workshop at a National Meeting.

The enormous progress in the field of human genetics since the completion of the Human Genome Project—most notably the identification of both rare and common variants associated with a plethora of clinical traits and diseases through novel methodologies, such as the genome-wide association study and next-generation DNA sequencing—has revolutionized our understanding of human health. At the same time, this progress threatens to outstrip the ability to apply these discoveries to clinical care for the benefit of patients. One significant barrier is a lack of genomic literacy among clinical practitioners,1–4 not surprising given that many advances in genetics and genomics have emerged recently, well after the completion of formal training by most practitioners. Published examples of attempts to enhance the teaching of clinical genomics to medical learners have largely been lecture based. For example, the Stanford University’s Department of Pathology created a Genomic Medicine course for their residents and fellows that comprised a series of 10 lectures that were also made available online.5 In another example, the Tufts University School of Medicine’s medical school curriculum added a lecture on the science and technology of genomic testing and incorporated a homework assignment in which students analyzed the results of genome testing of anonymous patients.6 Neither of these educational innovations address the considerable need to educate active practitioners about genetics and genomics in a way that does not rely on traditional lecture-based classroom learning—an impracticality for busy professionals—but rather draws from best practices in adult education, including the growing recognition of the superiority of active-learning approaches in science, technology, engineering, and mathematics education, such as the so-called flipped classroom.7 In 2010, through the Program Directors Section of the Association of Pathology Chairs, the Training Residents in Genomics (TRIG) working group (WG) was formed to create teaching tools …

A true mentor and pioneer in medical genetics.

I still remember very vividly the first lecture that I ever heard from Prof. Peter Beighton. This was shortly after he arrived in Cape Town in 1972. Were it not for Peter, I do not think that I would ever have entered the field of human genetics. With his enthusiasm and brilliant presentation, and the capability of evoking excitement and dreams, Peter Beighton inspired me. Shortly after I had heard that lecture, I presented myself at the Department of Human Genetics, which was newly established and the first in Africa. I asked him whether I could participate in any research projects. I was particularly drawn to his research projects, as it appeared that they opened up new possibilities for understanding biology in different populations, which might have relevance for the general population. Peter's stories of his hiking through the Sahara Desert with the Tuareg, and his stories from different populations in Africa, inspired me and elucidated for me for the first time the power of studying rare families and their ability to inform general rules of biology.

Emerging targeted drug therapies in skeletal dysplasias.

Quantum advances have occurred in the field of human genetics in the six decades since Watson and Crick expressed their "wish to suggest a structure for the salt of deoxyribose nucleic acid." These culminated with the human genome project, which has opened up myriad possibilities, including that of individualized genetic medicine, the ability to deliver medical advice, management, and therapy tailored to an individual's genetic blueprint. Advances in genetic diagnostic capabilities have been rapid, to the point where the genome can be sequenced for several thousand dollars. Crucially, it has facilitated the identification of targets for "precision" treatments to combat genetic diseases at their source. This manuscript will review the innovative, pathogenesis-based therapies that are revolutionizing management of skeletal dysplasias, giving patients and families new options and outcomes. © 2016 Wiley Periodicals, Inc.

What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants?

Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease.

2015 ASHG Awards and Addresses

ThehighestandmostprestigioushonorthatTheAmericanSociety of Human Genetics (ASHG) can bestow on any sci-entist is the William Allan Award. This honor is awardedeach year in memory of William Allan to a scientist whohas had far-reaching and substantial scientific contribu-tions to the field of human genetics and who has thusdemonstrated a sustained period of productivity over theirlifetime. William Allan was a physician, an educator, andone of the early pioneers of American human genetics. Itis a special treat for me today to introduce to you the 2013recipient of this award: Aravinda Chakravarti.In1954inCalcutta,Aravindawasbornthethirdsoninafamily who placed a high value on the importance of edu-cation. He was a particularly precocious child but even at ayoung age never shied away from voicing his opinion. Hereceived his Bachelor of Statistics in 1974 from the IndianStatistical Institute, Calcutta, and immigrated to theUnited States, where in 1979 he received his Ph.D. whileworking with Masatoshi Nei at the University of Texas.From 1985 to 1993, Aravinda was a faculty member ofthe Department of Human Genetics at the University ofPittsburgh; he joined the faculty of Case Western ReserveUniversity in 1994 and later the Johns Hopkins UniversitySchool of Medicine in 2000. He is currently the directorof the Center for Complex Disease Genomics of theMcKusick-Nathans Institute of Genetic Medicine and aprofessor of medicine, pediatrics, and molecular biologyand genetics at Johns Hopkins.Aravinda’s contributions to science have shown aremarkablebreadthanddepth.Hehasmadeseminalcontri-butions to the discovery of the gene associated with cysticfibrosis,

Analysis of Downs syndrome with molecular techniques for future diagnoses.

Down syndrome (DS) is a genetic disorder appeared due to the presence of trisomy in chromosome 21 in the G-group of the acrocentric region. DS is also known as non-Mendelian inheritance, due to the lack of Mendel’s laws. The disorder in children is identified through clinical symptoms and chromosomal analysis and till now there are no biochemical and molecular analyses. Presently, whole exome sequencing (WES) has largely contributed in identifying the new disease-causing genes and represented a significant breakthrough in the field of human genetics and this technique uses high throughput sequencing technologies to determine the arrangement of DNA base pairs specifying the protein coding regions of an individual’s genome. Apart from this next generation sequencing and whole genome sequencing also contribute for identifying the disease marker. From this review, the suggestion was to perform the WES is DS children to identify the marker region.

Severe infectious diseases of childhood as monogenic inborn errors of immunity

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

Human genetics: international projects and personalized medicine.

In this article, we present the progress driven by the recent technological advances and new revolutionary massive sequencing technologies in the field of human genetics. We discuss this knowledge in relation with drug response prediction, from the germline genetic variation compiled in the 1000 Genomes Project or in the Genotype-Tissue Expression project, to the phenome-genome archives, the international cancer projects, such as The Cancer Genome Atlas or the International Cancer Genome Consortium, and the epigenetic variation and its influence in gene expression, including the regulation of drug metabolism. This review is based on the lectures presented by the speakers of the Symposium "Human Genetics: International Projects & New Technologies" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held on the 20th and 21st of April 2015.

Direito fundamental à liberdade de pesquisa genética e à proteção de dados pessoais: os princípios da prevenção e da precaução como garantia do direito à vida privada

O artigo analisa os direitos fundamentais de liberdade de pesquisa e da proteção de dados pessoais no campo da genética humana, propõe a aplicação dos princípios da precaução de da prevenção. Avalia a legislação brasileira na matéria objeto da pesquisa como medida de garantia à privacidade dos dados pessoais e das informações colhidas na investigação científica, situação que se agrava no meio no mundo digital e virtual por ser este um espaço praticamente de rápido desenvolvimento. Enfoca a limitação de direitos fundamentais, partindo da concepção de que não são absolutos. Propõe a aplicação dos princípios da precaução e da prevenção no meio ambiente virtual. Adotou-se os métodos dedutivo e dialético, tendo-se como premissa maior os direitos fundamentais relacionados e previstos na legislação brasileira; o método dialético foi empregado porque a questão é objeto de constante debate sendo necessário o confronto de correntes doutrinárias e a normativa brasileira.

The Pathogenesis and Therapy of Muscular Dystrophies.

Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics.