OA Genetics http://www.oapublishinglondon.com/oa-genetics OA Genetics Advances in the genetic aspects linking folate metabolism to the maternal risk of birth of a child with Down syndrome. http://www.oapublishinglondon.com/article/392 In 1999 it was first hypothesized that maternal polymorphisms of genes involved in folate metabolism might represent maternal risk factors for the birth of a child with Down syndrome (DS). Several research papers have been produced worldwide to address that question, and recent meta-analyses of the literature suggest that at least two polymorphisms, namely MTHFR c.677C>T and MTRR c.66A>G, are associated with increased maternal risk for trisomy 21. Moreover, there is indication for an additive contribution of variants in folate pathway genes to the maternal risk for having a birth with DS. In addition, lack of folate supplementation at periconception, in combination with genetic polymorphisms of folate pathway genes, might represent maternal risk factors for congenital heart defects in the DS child. Despite those results are extremely encouraging, several factors, such as ethnicity, age, dietary habits, latitude, and many others could modulate those interactions and we are still far away from a complete understanding of the complex relationship between folate metabolism and chromosome 21 nondisjunction. 09/25/2020 04:58:16 pm Copy number variations—is there a biological difference between submicroscopic and microscopically visible ones? http://www.oapublishinglondon.com/article/852 Introduction:Copy number variations (CNVs) are nowadays most often understood as submicroscopic gains or losses of chromosomal material, either connected with a disease or just one of the many possible genetic variants in man. However, besides such submicroscopic CNVs already decades ago chromosome analysis revealed the existence of cytogenetic visible copy number variations (CG-CNVs); first discovered were the chromosomal heteromorphisms, more recently euchromatic variants (EVs) and unbalanced chromosome abnormalities without phenotypic consequences (UBCA). Recently, for submicroscopic CNVs (MG-CNVs) a so-called two-hit model suggested. This suggests that the combination of per se harmless size variants may be led to clinical aberrations if they are present together in a patient. A literature based comparison of CG-CNVs and MG-CNVs revealed that, biologically, besides size, these two groups of CNVs do not really differ. Both may be present as heterochromatic (gene-poor to gene-free) and euchromatic CNV-variants. Identical regions have even been reported as CG-CNV and a MG-CNV independently. Conclusion:Yet CG-CNVs, especially chromosomal heteromorphisms are by far not considered enough in evaluation of routine cytogenetic analysis as well as in array-comparative genomic hybridization analysis. 09/25/2020 04:58:16 pm Approximation Bayesian computation. http://www.oapublishinglondon.com/article/853 Approximation Bayesian computation [ABC] is an analysis approach that has arisen in response to the recent trend to collect data that is of a magnitude far higher than has been historically the case. This has led to many existing methods become intractable because of difficulties in calculating the likelihood function. ABC circumvents this issue by replacing calculation of the likelihood with a simulation step in which it is estimated in one way or another. In this review we give an overview of the ABC approach, giving examples of some of the more popular specific forms of ABC. We then discuss some of the areas of most active research and application in the field, specifically, choice of low-dimensional summaries of complex datasets and metrics for measuring similarity between observed and simulated data. Next, we consider the question of how to do model selection in an ABC context. Finally, we discuss an area of growing prominence in the ABC world, use of ABC methods in genetic pathway inference. 09/25/2020 04:58:16 pm From quantitative trait locus mapping to genomic selection: the roadmap towards a systematic genetics. http://www.oapublishinglondon.com/article/862 Introduction: Mendelian theory of inheritance explains qualitative traits that are controlled by single genetic locus, while modern quantitative genetic theory states that complex traits are influenced by many factors including main effects of many quantitative trait loci (QTLs), epistatic effects involving more than one QTLs, environmental effects and the effects of gene-environment interactions. QTL mapping identifies important QTLs that reveal genetic basis of complex traits, serve as a map for functional gene cloning, and assist breed line selection. Discussion:We introduced different breeding populations, genetic models and statistical methods for QTL mapping. Genetic background, model principles, and computational algorithms and techniques were reviewed. We specifically discussed the whole-genome QTL mapping that simultaneously estimates genetic effects associated with markers of entire genome. The fact that the whole-genome approach avoids evaluation of multiple models and model selection while enables genomic selection that predicts genetic merits for a quantitative trait has drawn great attention in research community, and will be an effective tool in breeding line selection.  Conclusion: While traditional QTL mapping was designed with the availability of marker density and model capability in recent two decades, whole-genome QTL mapping is the result of advancement in generating high density molecular markers and development in high-dimensional sparse modeling algorithms. Whole-genome QTL mapping and genomic selection together lead to a systematic genetics that will increase genetic gain and revolutionize crop and livestock breeding. 09/25/2020 04:58:16 pm Aberrant translation of proteins implicated in Alzheimer’s disease pathology. http://www.oapublishinglondon.com/article/918 Introduction Control of protein manufacture at the point of translation is a crucial step in the regulation of gene expression and has shown to be important to many neurological processes e.g. synaptic plasticity and memory formation. The aim of this review is to discuss new and exciting research which identifies putative mechanisms of regulation of proteins associated with Alzheimer’s disease (AD). Discussion Aberrant translation has been linked with neurodegenerative conditions such as AD, however it is not fully understood how this aberrant protein synthesis occurs or how this may be sustained in AD. Cell stressors such as oxidative stress may enhance the translation of AD associated proteins e.g. Amyloid precursor protein, and new research suggests that the cell survival response e.g. eif2-alpha phosphorylation may inadvertently up-regulate the translation of proteins such as BACE1; a process mediated in this instance by an upstream open reading frame located within the BACE1 5’UTR. Conclusion The research discussed in this review article has identified that in addition to regulation at the point of transcription and post-translational protein processing, the levels of proteins which negatively associate with AD pathology may also be controlled at the point of translation. Stressors such as oxidative stress may drive the transcription of APP; the cleavage of APP and may also enhance the translational efficiency of both APP and the secretase responsible for cleaving APP into its cytotoxic Abeta42 fragment. We suggest that selectively inhibiting the translation machinery in combination with reducing the levels of oxidative stress may represent a new therapeutic avenue for the treatment of AD. 09/25/2020 04:58:16 pm Epigenetics, evolution, and embodiment: On the conceptual vacuity of evolutionary psychology. http://www.oapublishinglondon.com/article/919 We summarize briefly contemporary scientific advances in evolutionary biology and epigenetics, and discuss their implications for revising scholarly understanding of human development, especially when framed within relational developmental systems theories (RDST). We contrast the evidence in support of a relationally-integrated approach to biological and behavioral (psychological and social) processes with the claims about links between evolution and human development emanating from an area of social/behavioral science, Evolutionary Psychology (EP). We note the conceptual and empirical problems of EP and, in turn, highlight the empirical utility of RDST-framed, integrated biological and developmental science research. We make recommendations for future, multidisciplinary research framed by RDST, and point to the implications of data derived from such work for applications to social policies and programs. 09/25/2020 04:58:16 pm Penalised regression methods in genetic research. http://www.oapublishinglondon.com/article/920 Complex human diseases usually have multifactorial causes, and may develop as a result of the collective effects of multiple genetic variants, complex gene-gene/gene-environment interactions, rare sequence variants, copy number alterations, epigenetic modifications, etc. Understanding the genetic etiology of complex human diseases require a comprehensive assessment of these causes. Recently, penalized regression methods have gained popularity in genetic research, aiming to detect genetic, epigenetic and environmental factors contributing to complex human diseases. In this article, we attempt to provide a brief overview of these methods in light of their applications in various contexts of genetic research. 09/25/2020 04:58:16 pm Where is the gender in behaviour genetics? The need for social epidemiology in research on gene–environment interactions. http://www.oapublishinglondon.com/article/927 Introduction. Despite evidence of pervasive gender differences in morbidity and mortality, as well as gender-specific genetic association in some diseases, research on candidate gene-environment interaction is rarely informed by social science perspectives on gender and health. Omitting basic theories of gender stratification from the study of social-environmental moderation of genetics may contribute to problems with replication and false positive results in GxE research. Discussion.A framework for studying gender-moderated GxE effects (i.e. GxExGender) is advocated. Because GxE may be conditioned on gender or other social statuses associated with systematic inequalities in risks and resources, modeling interactions between genotype and one proximal indicator of the social environment is overly simplistic. Gender can moderate GxE through at least three pathways: 1) By stratifying men and women into different environments, 2) By differentially shaping the experiences of men and women in similar environments, and 3) By influencing distinct biological, psychological, or behavioral responses to similar experiences. The importance of endophenotypes in identifying the timing and sequencing of gender moderation is discussed, and methodological considerations are offered to guide future research. Conclusion. In cases where social environments are reflective of gender difference or inequality, hypotheses on GxE must be gender-specific, presenting both unique challenges and enormous potential for the significance of social epidemiology in transdisciplinary agendas on health and behavior. 09/25/2020 04:58:16 pm The genetics of cardiomyopathy, new technologies and the path to personalised medicine. http://www.oapublishinglondon.com/article/959 Introduction Cardiomyopathy is defined as a weakening of the heart muscle which reduces the ability of the heart to pump blood. Inherited cardiomyopathies (CMs) include hypertrophic, dilated, arrythmogenic right ventricular, restrictive and unclassified cardiomyopathies. The discovery of numerous disease causing genes has demonstrated these CMs have a substantial genetic aetiology. Molecular genetic diagnosis in individuals with CM facilitates medical interventions to prevent serious complications such as heart failure and arrhythmia. In addition, it enables cascade testing to identify additional at risk family members and the provision of informed counselling. Traditionally, issues of genetic heterogeneity, clinical variability and reduced penetrance have meant that molecular genetic screening was time consuming and costly. However, modern genomic technologies, in particular Next Generation Sequencing (NGS), support comprehensive and rapid molecular genetic screening for CM.  Conclusion Considerable progress in understanding the biology of CM has been driven in part by gene identification, which has been accelerated dramatically by NGS technology. NGS coupled with increased understanding of disease biology is making personalised medicine a reality. Despite the advances in technology, limitations remain in data quality, analysis and interpretation. A portion of patients with CM still remain undiagnosed due in part to the difficulty identifying casual variants amongst the many genetic variants identified by NGS. This has highlighted the need to advance current databases and improve collaboration between the laboratory and clinic. The aim of this article is to provide an overview of the genetics and pathogenesis of CM. We will also discuss how new genetic technologies are being utilised to accelerate gene discovery and molecular genetic diagnosis and increase the potential for personalised medicine for individuals with CM. 09/25/2020 04:58:16 pm The potential for next-generation sequencing to characterise the genetic variation underlying non-syndromic cleft lip and palate phenotypes. http://www.oapublishinglondon.com/article/987 Next generation sequencing is revolutionising the study of genetic variation and its role in disease. Individual DNA samples can now be sequenced cost-effectively enabling analysis of the complete spectrum of genetic variation. This technology has the potential to contribute significantly to the understanding of nonsyndromic cleft lip and/or palate. This condition occurs with relatively high frequency and only a proportion of the underlying genetic causal factors have been identified. Many of the genes implicated have been found through genome-wide association studies but further progress is limited because these approaches consider only common genetic variants and neglect rarer variation. Because many of the causal genetic variants remain unknown the role of gene-environment and gene-gene interaction is difficult to characterise. The identification of novel, low frequency, variants will provide new insights into the biological mechanisms and pathways involved in the condition. Sequence-based analysis will also be invaluable for fine mapping causal variants in the larger regions already identified by linkage and association studies for which positive identification of causal genetic variants has proven difficult. This review considers the available evidence for the genes involved and current understanding of how genetic variation interacts with environmental factors known to influence risk. Only by characterising the underlying genetic factors will the effort to understand gene-environment interaction and underlying functional processes be successful. Success with next generation sequencing will lead to improvements in prediction, prevention and treatment for cleft lip and palate patients. 09/25/2020 04:58:16 pm Mucopolysaccharidosis III: Molecular genetics and genotype-phenotype correlations. http://www.oapublishinglondon.com/article/1469 Sanfilippo Syndrome or Mucopolysaccharidosis III (MPS III) is a group of lysosomal storage diseases resulting from a deficiency of one of four lysosomal enzymes: Type A - heparan N-sulfatase (SGSH), Type B - α-N-acetylglucosaminidase (NAGLU), Type C - acetyl CoA α-glucosaminide acetyltransferase (HGSNAT) and Type D - N-acetylglucosamine-6-sulfatase (GNS). Each of these enzymes is necessary for degradation of heparan sulfate. Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifestations. Currently treatment is limited to supportive care.  MPS IIIA and IIIB are the most common subtypes of MPS III and will be further discussed in this review. The integral genes underlying both these diseases have been cloned and characterized. Through genetic analysis of the cDNA from MPS IIIA and B, researchers have begun to link many genetic mutations to their resultant phenotypes, and discern geographic differences in mutational variation. Here, we highlight many of the known MPS IIIA and B mutations and present them in the context of ethnic and geographic differences in an attempt to discern genotype-phenotype correlations and patterns of inheritance. 09/25/2020 04:58:16 pm Preimplantation genetic screening: Pitfalls and opportunities. http://www.oapublishinglondon.com/article/1558 Preimplantation genetic screening is an increasingly utilized as a tool to optimize the efficiency of IVF in a variety of clinical situations. Initial data from PGS was discouraging using florescence in situ hybridization (FISH) and cleavage stage biopsy. However, more recently the trophectoderm biopsy at the blastocyst stage of embryonic development coupled with evaluation of all 23 chromosome pairs has yielded encouraging clinical results. 09/25/2020 04:58:16 pm