Modern Genetics Research Articles

The spectrum and prevalence of genetic pathology among children and adolescents of the northern districts of kharkiv region

The spectrum and prevalence of genetic pathology among the population of a certain region are determined by the founder effect and microevolution factors and, therefore, are not always comparable in different countries. The study of these indicators is an important trend of modern human genetics. The purpose of the research was to study genetic and epidemiological characteristics of the pediatric population of two northern districts of the Kharkiv region, Ukraine: Bogodukhiv and Vovchansk. Total number of children aged 0–17 was 6896 in Bogodukhiv district, and 7891 in Vovchansk district on 01/01/2016. The medical records of 307 patients were analyzed in healthcare facilities of both districts and the city of Kharkiv. The subject of the study was the cases of single-gene and chromosomal diseases. The burden of genetic disorders among children and adolescents was 0.30% in both districts. The prevalence of single-gene diseases in these districts was 0.24% in Bogodukhiv district and 0.25% in Vovchansk district. There were 9 and 12 single-gene disorders with different modes of inheritance, respectively. Only two of them were common in the districts: congenital hypothyroidism and sensorineural hearing loss. The incidence of the latter is 1:985 in Bogodukhiv district and 1:1578 in Vovchansk district. Chromosomal pathology was detected in 0.06% of the patients in Bogodukhiv district and 0.05% in Vovchansk district. Down syndrome was the only nosological form of chromosomal disorders in both districts. For other five areas of Kharkiv region, the prevalence of genetic pathology ranges from 0.36% in Izyum district to 0.47% in Balakliia and Blyzniuky as have been previously reported. The incidence of single-gene disorders is 0.27% in Izyum and 0.39% in Blyzniuky, while the incidence of chromosomal disorders varies from 0.07% in Zmiiv to 0.13% in Krasnohrad. Thus, the spectrum and prevalence of single-gene and chromosomal pathology in Bogodukhiv and Vovchansk districts correspond to those in other districts of Kharkiv region and most European countries.

Epigenetic Regulation of Autophagy.

Epigenetics refers to reversible and hereditary changes in gene expression without alterations in DNA sequences, such as DNA methylation, histone modification and chromatin remodelling. It was first proposed by Waddington in the book Introduction to Modern Genetics in 1939. Autophagy includes at least four processes: autophagy induction, autophagosome formation, autophagosome fusion with lysosomes and lysosomal degradation of cytoplasmic components. The whole process is complex and dynamic, and involves at least 30 autophagy-related proteins. This degradative machinery is regulated by multiple signal molecules. Autophagy was once considered to be a cytoplasmic event; however, in recent years, emerging evidence suggests that nuclear components (transcription factors, histone modification, microRNAs, etc.) also play an important role in autophagy regulation (Baek and Kim 2017). Among them, epigenetic regulation of autophagy has gained much attention. The epigenetic machinery can not only modify autophagy-related genes but also affect some signal molecule genes that regulate autophagy, thus impacting their transcription and subsequent autophagy. This chapter focuses on the role and recent progress in autophagy regulation by DNA methylation and histone modifications. The role of non-coding RNAs such as microRNA in autophagy regulation will be covered in other chapters.

ShapeGTB: the role of local DNA shape in prioritization of functional variants in human promoters with machine learning.

MotivationThe identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes.ResultsWe demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional single nucleotide polymorphisms within promoter regions—ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (average precision 0.93 vs. 0.47–0.55). On the external validation set based on ClinVar database it displayed worse performance but was still competitive with other methods (average precision 0.47 vs. 0.23–0.42). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future.

El caminar de los genes y el reloj molecular: Realidad del Ecuador

La genética convencional y la molecular han acumulado suficientes datos sobre las poblaciones humanas mundiales; por ello, en la actualidad se puede desentrañar el origen fidedigno de cada grupo humano. Una serie de marcadores genéticos han permitido rastrear el origen y la migración humana. STRs, Indels, Mitocondrias, Cromosoma Y, entre los más usados, dan cuenta de la trayectoria de la humanidad y el poblamiento del planeta. La genética moderna nos muestra la composición poblacional de diversas variantes de genes y secuencias no informativas; asàpermiten hoy entender mejor y hasta clasificar grupos poblacionales como etnias. Aunque, el ADN es el mismo para todos los humanos, secuencias no esenciales muestran diferentes frecuencias de presentación según el grupo étnico. Adicionalmente, a través del estudio de los marcadores genéticos, podemos calcular los tiempos migratorios y el momento del origen y expansión de los humanos; lo que se llama el reloj molecular. Este artículo aborda algunos de los conocimientos actuales en genética poblacional, etnicidad y tiempos genéticos, incluso, presenta datos reales de análisis del ADN.

Molecular characterization of dromedary camel potential fertility: A new approach

Male fertility is one aspect of animal reproduction that was targeted by many biotechnology studies aiming to improve reproductive efficiency and, hence, productive capacity in different species. The current investigation aimed to determine expression of hypothetical fertility-related molecular markers in male camels. At the peak of rutting period (February), thirty ejaculates were collected from three adult dromedary bulls, Camelus dromedarius, whose reproductive history were verified over the past 10 years. Each raw ejaculate was subjected to sperm physical and morphological assessment immediately after collection. Furthermore, blood samples were obtained from each male at the peak of rutting (February) as well as out of breeding season (August) to identify potential fertility-related molecular markers by fluorescently-labeled differential display PCR (FDD). The results revealed that semen physical characteristics of each camel were in consistence with its reproductive history. Accordingly, the males were categorized into 3 fertility grades; i.e. high, medium and low prolific. Concurrently, the results of FDD successfully delineated this variation in fertility. Visualized chromatograms of differentially displayed fragments evinced detection of 24 seasonally-expressed mRNA molecules; of which 5 were expressed off the breeding season (down-regulated), and 19 molecules were expressed at the peak of rutting period (up-regulated). Furthermore, the expression of the later fragments varied concomitantly along with sperm physical characteristics as well with each male’s prolific index. These results represent the first step in utilizing modern molecular genetics techniques to identify fertility-related molecular markers in adult dromedary bulls, or even further to predict potential fertility of pre-pubertal males.

The Learning Loss Effect in Genetics: What Ideas Do Students Retain or Lose after Instruction?

Modern genetics is a relatively new domain, but it is increasingly important for students to have a firm grasp on the content, because genetic technologies are becoming more commonplace. In a previous study, we used the Learning Progression-based Assessment of Modern Genetics to assess high school students’ knowledge of genetics concepts after an intensive inquiry-based genetics instructional period. Given that this type of intensive inquiry-based instruction is unique, we are now investigating how students’ knowledge of genetics changes after instruction (i.e., learning loss effect). Using a six-measure longitudinal design, we found that students retained significant gains in five of the 12 constructs 18 months after instruction; scores were not significantly different than the pretest in seven of the constructs. Through a nonparametric analysis, we found that students are better able to retain mechanistic explanations in genetics than memorized details. This study uses an learning progression framework that examines what happens to genetics knowledge over an extended period of time after instruction and indicates that classroom time is better spent helping students construct mechanistic explanations of genetic phenomena as opposed to memorizing terminology.

ACOG Technology Assessment in Obstetrics and Gynecology No. 14 Summary: Modern Genetics in Obstetrics and Gynecology.

Knowledge of human genetics has increased dramatically, and obstetrician-gynecologists and other health care providers are increasingly called on to incorporate genetics and genetic testing into medical practice. Advances in our understanding of the molecular basis of inherited disorders have led to the development of DNA-based tests that can be used for prenatal and postnatal diagnosis, carrier testing, and aneuploidy screening. These techniques have allowed for diagnosis of a wide variety of genetic diseases ranging from aneuploidies to single-gene disorders. Once a specific pathogenic variant in a gene has been identified, direct testing for that specific variant is possible; this is the most accurate molecular diagnostic method. Counseling patients about genetic testing and results can be challenging and obstetrician-gynecologists and women's health care providers are encouraged to make use of and refer to genetics professionals when necessary. The correct interpretation of molecular genetic diagnostic testing is highly dependent on an accurate clinical diagnosis, test sensitivity, ethnic variability in variants and disease prevalence, genetic heterogeneity, reduced penetrance, and phenotypical variability. As genetics becomes a more integral part of routine medical practice, it is essential that obstetrician-gynecologists and other health care providers be aware of advances in the understanding of genetic disease and the fundamental principles of genetic screening and molecular testing. This technology assessment has been revised to reflect advances in clinical genetics related to obstetrics and gynecology, including epigenetics, sequencing, and testing.

ACOG Technology Assessment in Obstetrics and Gynecology No. 14: Modern Genetics in Obstetrics and Gynecology.

Knowledge of human genetics has increased dramatically, and obstetrician-gynecologists and other health care providers are increasingly called on to incorporate genetics and genetic testing into medical practice. Advances in our understanding of the molecular basis of inherited disorders have led to the development of DNA-based tests that can be used for prenatal and postnatal diagnosis, carrier testing, and aneuploidy screening. These techniques have allowed for diagnosis of a wide variety of genetic diseases ranging from aneuploidies to single-gene disorders. Once a specific pathogenic variant in a gene has been identified, direct testing for that specific variant is possible; this is the most accurate molecular diagnostic method. Counseling patients about genetic testing and results can be challenging and obstetrician-gynecologists and women's health care providers are encouraged to make use of and refer to genetics professionals when necessary. The correct interpretation of molecular genetic diagnostic testing is highly dependent on an accurate clinical diagnosis, test sensitivity, ethnic variability in variants and disease prevalence, genetic heterogeneity, reduced penetrance, and phenotypical variability. As genetics becomes a more integral part of routine medical practice, it is essential that obstetrician-gynecologists and other health care providers be aware of advances in the understanding of genetic disease and the fundamental principles of genetic screening and molecular testing. This technology assessment has been revised to reflect advances in clinical genetics related to obstetrics and gynecology, including epigenetics, sequencing, and testing.

Genetic Testing in Cardiovascular Medicine.

Genetic Testing in Cardiovascular Medicine.

Systematic identification and annotation of multiple-variant compound effects at transcription factor binding sites in human genome

Understanding the functional effects of genetic variants is crucial in modern genomics and genetics. Transcription factor binding sites (TFBSs) are one of the most important cis-regulatory elements. While multiple tools have been developed to assess functional effects of genetic variants at TFBSs, they usually assume that each variant works in isolation and neglect the potential “interference” among multiple variants within the same TFBS. In this study, we presented COPE-TFBS (Context-Oriented Predictor for variant Effect on Transcription Factor Binding Site), a novel method that considers sequence context to accurately predict variant effects on TFBSs. We systematically re-analyzed the sequencing data from both the 1000 Genomes Project and the Genotype-Tissue Expression (GTEx) Project via COPE-TFBS, and identified numbers of novel TFBSs, transformed TFBSs and discordantly annotated TFBSs resulting from multiple variants, further highlighting the necessity of sequence context in accurately annotating genetic variants. COPE-TFBS is freely available for academic use at http://cope.cbi.pku.edu.cn/.

Rediscovering the value of families for psychiatric genetics research.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

Vex-seq: high-throughput identification of the impact of genetic variation on pre-mRNA splicing efficiency

Understanding the functional impact of genomic variants is a major goal of modern genetics and personalized medicine. Although many synonymous and non-coding variants act through altering the efficiency of pre-mRNA splicing, it is difficult to predict how these variants impact pre-mRNA splicing. Here, we describe a massively parallel approach we use to test the impact on pre-mRNA splicing of 2059 human genetic variants spanning 110 alternative exons. This method, called variant exon sequencing (Vex-seq), yields data that reinforce known mechanisms of pre-mRNA splicing, identifies variants that impact pre-mRNA splicing, and will be useful for increasing our understanding of genome function.

INLUENCE OF ALIEN GENETIC MATERIAL ON THE MANIFESTATION OF AGRONOMICALLY IMPORTANT TRAITS OF COMMON WHEAT (T. aestivum L.)

Broadening of the genetic diversity of common wheat with respect to genes for resistance to biotic and abiotic stress factors, yield and grain quality is one of the urgent problems of modern genetics and breeding. Wild wheat relatives with diverse levels of the genome homoeology are regularly used for widening the genetic diversity of common wheat for genes that increase disease and insect resistance. Studies on the search and introduction of genetic factors determining the grain protein content and yield are also important. Although resistance genes have a prolonged protective efect on donor plants against diverse populations of pathogens, the introgression of target loci into the genome of common wheat can result in a signiicant decrease in the eiciency of the genes – up to complete loss of expression. Additionally, alien gene introgression from wild relatives occurs through whole chromosome or chromosome arm substitutions, or long translocated fragments that, together with target loci, may contain genetic material that afects other agronomically important traits. Therefore, when introducing disease resistance genes into elite wheat varieties, it is important to take into account the efects of alien substitutions and translocations on such traits as the growth habit, heading date, yield potential, grain and baking quality. Adverse efects observed with gene introgressions from wild species are commonly associated with foreign chromatin linked with target loci. However, in many cases, such efects can be the result of the genetic background of the cultivar-recipient. This article presents an overview of published data on the efect of alien introgressions on agronomically important traits of common wheat.

Using the Discovery of the Structure of DNA to Illustrate Cultural Aspects of Science

DNA is a central topic in biology courses because it is crucial to an understanding of modern genetics. Many instructors introduce the topic by means of a sanitized retelling of the history of the discovery of the structure of DNA by James Watson and Francis Crick. Historical research since 1968 has revealed that Rosalind Franklin's contributions were more significant than they are usually depicted. In light of this, we developed a two-class lesson plan that draws attention to Rosalind Franklin's role in the discovery and to the social and cultural aspects of science. The first class provides background information regarding what led scientists to recognize that DNA was the molecule of heredity. Students watch a documentary video that includes interviews with some of the surviving protagonists. Students (working in groups) are then asked to debate Franklin's role to refine their awareness of how social and cultural factors affected both the process of science and how it has been recounted. The second class has students work in groups to build a structural model of DNA through hands-on activities. The essay concludes by drawing attention to how the two-day lesson plan, developed for a college-level biology course, can be adapted for use in other settings.

Effective discovery of rare variants by pooled target capture sequencing: A comparative analysis with individually indexed target capture sequencing

Identification of all genetic variants associated with complex traits is one of the most important goals in modern human genetics. Genome-wide association studies (GWAS) have been successfully applied to identify common variants, which thus far explain only small portion of heritability. Interests in rare variants have been increasingly growing as an answer for this missing heritability. While next-generation sequencing allows detection of rare variants, its cost is still prohibitively high to sequence a large number of human DNA samples required for rare variant association studies. In this study, we evaluated the sensitivity and specificity of sequencing for pooled DNA samples of multiple individuals (Pool-seq) as a cost-effective and robust approach for rare variant discovery. We comparatively analyzed Pool-seq vs. individual-seq of indexed target capture of up to 960 genes in ∼1000 individuals, followed by independent genotyping validation studies. We found that Pool-seq was as effective and accurate as individual-seq in detecting rare variants and accurately estimating their minor allele frequencies (MAFs). Our results suggest that Pool-seq can be used as an efficient and cost-effective method for discovery of rare variants for population-based sequencing studies in individual laboratories.

OVAS: an open-source variant analysis suite with inheritance modelling

BackgroundThe advent of modern high-throughput genetics continually broadens the gap between the rising volume of sequencing data, and the tools required to process them. The need to pinpoint a small subset of functionally important variants has now shifted towards identifying the critical differences between normal variants and disease-causing ones. The ever-increasing reliance on cloud-based services for sequence analysis and the non-transparent methods they utilize has prompted the need for more in-situ services that can provide a safer and more accessible environment to process patient data, especially in circumstances where continuous internet usage is limited.ResultsTo address these issues, we herein propose our standalone Open-source Variant Analysis Sequencing (OVAS) pipeline; consisting of three key stages of processing that pertain to the separate modes of annotation, filtering, and interpretation. Core annotation performs variant-mapping to gene-isoforms at the exon/intron level, append functional data pertaining the type of variant mutation, and determine hetero/homozygosity. An extensive inheritance-modelling module in conjunction with 11 other filtering components can be used in sequence ranging from single quality control to multi-file penetrance model specifics such as X-linked recessive or mosaicism. Depending on the type of interpretation required, additional annotation is performed to identify organ specificity through gene expression and protein domains. In the course of this paper we analysed an autosomal recessive case study. OVAS made effective use of the filtering modules to recapitulate the results of the study by identifying the prescribed compound-heterozygous disease pattern from exome-capture sequence input samples.ConclusionOVAS is an offline open-source modular-driven analysis environment designed to annotate and extract useful variants from Variant Call Format (VCF) files, and process them under an inheritance context through a top-down filtering schema of swappable modules, run entirely off a live bootable medium and accessed locally through a web-browser.

Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions.

Spontaneous tumors regression has been associated with microbial infection for 100s of years and inspired the use of bacteria for anticancer therapy. Dr. William B. Coley (1862–1936), a bone- sarcoma surgeon, was a pioneer in treating his patients with both live bacterial-based and mixture of heat-killed bacteria known as “Coley’s toxins.” Unfortunately, Coley was forced to stop his work which interrupted this field for about half a century. Currently, several species of bacteria are being developed against cancer. The bacterial species, their genetic background and their infectious behavior within the tumor microenvironment are thought to be relevant factors in determining their anti-tumor effectiveness in vivo. In this perspective article we will update the most promising results achieved using bacterial therapy (alone or combined with other strategies) in clinically-relevant animal models of cancer and critically discuss the impact of the bacterial variants, route of administration and mechanisms of bacteria-cancer-cell interaction. We will also discuss strategies to apply this information using modern mouse models, molecular biology, genetics and imaging for future bacterial therapy of cancer patients.

Evolutionary and genetic features of drug targets.

In the modern drug discovery pipeline, identification of novel drug targets is a critical step. Despite rapid progress in developing biomedical techniques, it is still a great challenge to find promising new targets from the ample space of human genes. This fact is partially responsible for the situation of "more investments, fewer drugs" in the pharmaceutical industry. A series of recent researches revealed that successfully targeted genes share some common evolutionary and genetic features, which means that the knowledge accumulated in modern evolutionary biology and genetics is very helpful to identify potential drug targets and to find new drugs as well. In this article, we comprehensively summarize the links between human drug targets and genetic diseases and their evolutionary origins, with an attempt to introduce these novel concepts and their medical implications to the biomedical community.

Mendel Actually Wants to Say: Genes Are Only One Element of the Hereditary Material

The individual comes from a fertilized egg, indicating that the individual’s producer, namely the hereditary material, must be in the egg. “Modern genetics” includes the belief that genes are the hereditary material. Thus, the claim that “synthetic life” was created using a man-made genome has been made. However, molecular biology has proven that genes are only templates for individuals. The template has the controlling product’s specifications, which guide the operator to produce an individual that conforms to its given specifications. The template cannot produce the individual. It means that genes are not a producer. This compels us to review Mendel’s experiments and the original meaning of genes. This article reveals that the genes assumed by Mendel originally referred to the template rather than the producer, and that the truth regarding DNA revealed by molecular biology is identical to Mendel’s assumptions of genes. That is, both Mendel’s original literature and factual evidence show that genes are one, not all, of the elements of the hereditary material. “Modern genetics” is the product of misinterpreting Mendel, and four reasons for this historical misinterpretation are presented.

Interdisciplinary Character of Biochemistry and Analytical Biochemistry

Biochemistry is a modern frontier science with an interdisciplinary character. Biochemistry has close links with organic chemistry, which provides support for knowing the structure and properties of biomolecules. Analytical chemistry, colloidal chemistry and chelates complexes provide biochemistry with methods of identifying, separating and characterizing biomolecules as well as kinetic and thermodynamic interpretation of biochemical reactions. Biochemical processes are carried out at cellular structures, so biochemistry interferes with molecular biology first and with morphology, which can also be approached from the aspect of structural element chemistry. Physiology raises a higher level of knowledge of the laws of life phenomena, and modern genetics has in fact become biochemical genetics, because it has created the basis for the codification of the hereditary message and has established relations between nucleic acids and protein biosynthesis as a premise of self-reproduction of living organisms.