Genetic disorder

“ The early science of genetics became the basis of State laws that provided for the sterilization of persons having presumed genetic "defects" such as mental retardation, mental disease, epilepsy, blindness, and hearing loss, among other conditions. ”

“ With the completion of the Human Genome Project, we will have unprecedented knowledge about the cause of such genetic diseases as muscular dystrophy and Alzheimer's and greater hope of preventing them in the future. ”

“ We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. ”

“ The similar physiology and genome structure between the mouse and human facilitate ortholog comparison and functional identification between the two species. To determine if differences exist between essential and non-essential disease genes we examined several parameters in our analyses, including the physiological systems affected by each disease gene, the connectivity of each gene in protein-protein interaction networks, and the genetic mechanisms by which genes cause human disease. ”

“ Even where the mutational variation appears to be one of gain, as happens when a positive character appears de novo in the phenotype, or when a dilute parental character is intensified in the offspring, it is, nevertheless, interpretable as a result of germinal loss, the loss, namely, total or partial, of a genetic inhibitor. Such inhibitive genes or factors are known to exist. ”

“ I consider it unsurprising that when people develop the very same disease conditions as their parents. they wrongly assume the cause is genetic inheritance, when actually it was just because they were putting their feet under the same table as their parents. ”

“ A well-known example is Phenylketonuria, where the function of the gene encoding the PAH enzyme was studied with respect to the mechanism of the disease [3] . However, we are still far from fully understanding disease causation, especially regarding complex diseases such as cancer [2] . Even for mendelian diseases this is not fully achieved because phenotypic outcome cannot be predicted solely based on the genotype [3] . It has become evident, that many human diseases cannot be attributed to malfunction of single genes but arise due to complex interactions among multiple genetic variants [4] . ”

“ At the end of the day, how a disease is caused and thus how it can be treated can only be studied on the basis of the entire body of knowledge including all genes that are associated with the disease and their interactions through biological pathways. However, with the unprecedented wealth of information available, it is extremely difficult to obtain a complete picture of the genetic basis of diseases. In order to obtain such a complete picture, data integration from different sources is required. ”

“ Response to selection for disease resistance can also be improved. Implementation of a progeny-testing system when a marker trait has a low heritability will improve the accuracy of identifying superior parents and increase the rate of genetic progress. ”

“ By examining mutations in these organisms, one can identify candidate genes that cause disease in humans, and develop models to better understand human disease and gene function. A fundamental roadblock for analysis is, however, the lack of a computational method for describing and comparing phenotypes of mutant animals and of human diseases when the genetic basis is unknown. ”

“ Abstract Many diseases have complex genetic causes, where a set of alleles can affect the propensity of getting the disease. The identification of such disease genes is important to understand the mechanistic and evolutionary aspects of pathogenesis, improve diagnosis and treatment of the disease, and aid in drug discovery. ”

“ In such an imaginary situation, the ratio of cancer-developing mice may not appear to correspond to any of the known Mendelian ratios, because superimposed on the genetic situation there would be added results depending on the frequency of mutation when a specific gene is present. ”

“ Most importantly, our results suggest that the reciprocal search will work, where we will be able to identify animal models of human disease (or disease pathways) where the human gene is not yet known. In order to implement this, we intend to annotate the remainder of OMIM using the EQ method on OMIM phenotype synopses, and supplement the database with other disease data, to provide the necessary phenotypes for comparison. Because a mutated gene in an animal model is more readily available or identifiable, our method may hasten the identification of the genetic basis of human diseases. ”

“ Trauma are not diseases and modern medicine has become quite skilled at putting traumatized bodies back together. Genetic abnormality may be another undesirable physical condition that is beyond the purview of natural medicine. However, the expression of contra-survival genetics can often be controlled by nutrition. And the expression of poor genetics often results from poor nutrition, and thus is similar to a degenerative disease condition, and thus is well within the scope of natural medicine. ”

“ Given that the genetic basis of human disease is often unknown, this method provides a means for identifying candidate genes, pathway members, and disease models by computationally identifying similar phenotypes within and across species. ”

“ Gene alleles with reduced function, called hypomorphic alleles, therefore can generate different phenotypes from those of null alleles. Although null or severe loss-of-function mutations in essential genes may indeed contribute to spontaneous miscarriages, hypomorphic mutations in the same genes can contribute to less severe abnormalities that are recognized as human disease. Therefore, the human orthologs of genes required for embryonic development in the mouse can cause disease in mutated forms through a variety of mechanisms. ”

“ Abstract A greater understanding of the causes of human disease can come from identifying characteristics that are specific to disease genes. However, a full understanding of the contribution of essential genes to human disease is lacking, due to the premise that these genes tend to cause developmental abnormalities rather than adult disease. We tested the hypothesis that human orthologs of mouse essential genes are associated with a variety of human diseases, rather than only those related to miscarriage and birth defects. ”

“ However, great challenges exist because many common diseases are caused by multiple disease genes with small to moderate effects. Even diseases that show Mendelian inheritance may involve multiple genes due to heterogeneity. Gene-gene interactions, as well as gene-environment interactions, also play an important role in the development of diseases. Classifications of diseases, which are mostly based on observed phenotypes, may not necessarily reflect their underlying mechanisms. ”

“ We also detected a difference in the mode of inheritance of disease genes when classified according to essentiality. We find that disease lethal genes are more likely to demonstrate an autosomal dominant mode of inheritance. This reflects the tendency for disease to occur in the heterozygous state in these individuals, and that homozygosity for disease mutations would present a more severe phenotype causing lethality. Human disease mutations are not often nulls, and essentiality and disease can be considered on a spectrum with respect to mutant alleles. ”

“ Human Social Genomics
Initial indications that social environments might significantly affect the functional activity of the human genome came from studies dissecting leukocyte gene expression profiles into genetic and environmental components [8] , [9] . Gibson and colleagues found that ∼5% of genes expressed in leukocytes showed appreciable genetic regulation (e.g., via expression quantitative trait loci) , whereas >50% showed significant differences in expression across pastoral, rural, and urban social environments [9] . ”

“ The authors of one study therefore conclude that essential genes are not human disease genes [9] , as mutations prevent viability. However, this assumption fails to consider the impact of alleles on gene function. Genes have been defined as essential due to the phenotype of mouse knockouts, which result from a deletion of the protein-coding region of the gene from the genome. These mouse mutants therefore are null alleles, and represent the phenotype caused by complete absence of functional protein. However, point mutations in these same genes do not necessarily fully remove protein function. ”

“ Research proved long ago that artificial mutations could be produced in the genetic material of the cell. What is not so widely known is that the series of tests in the clinics of the Genetic Center, which every expectant mother undergoes in the second month of pregnancy, are actually a course of treatment. ”

“ If one can control the matings, so that out-breeding takes place each time, the result would undoubtedly be like that in our diagram; but what chance is there for a recessive character, that is neither beneficial nor injurious, if left to itself, to contaminate widely the race with its gene? The answer is that for any one defect there is hardly any chance at all. On the other hand, there is always a possibility that a defect may become widespread despite the chances against each in turn. ”

“ A trait with low heritability should not be assumed to be unaffected by genetics. In fact, any trait that differs between breeds or responds to heterosis has a significant genetic component. Heterosis is the difference in performance of crossbred animals from the average performance of purebred animals and is attributed to genes with dominant and epistatic action. Traits most affected by heterosis are those pertaining to fitness (longevity, reproduction rate, etc.) ”

“ Given that several genes known to cause lethality in mouse knockouts also cause human disease due to point mutations or genomic rearrangements, we hypothesise that essential genes form an important group of disease genes that will have different characteristics from non-essential disease genes. As mouse targeted deletions provide a source of experimental analysis of null alleles, we used data on lethal and viable mouse knockouts as a proxy for human essential genes. ”

“ It is important to note that the essentiality classification is based upon mouse null alleles, whereas human disease alleles are rarely null mutations. Therefore, when a gene is referred to as “disease lethal” it is not an indication that the human diseases associated with mutations in that gene are lethal, but rather that complete removal of protein function causes lethality in mouse. Importantly, in contrast to prior studies [5] , we considered all disease genes for which there is no mouse knockout data available as a separate group of “unknown” disease genes (DU, n = 1172) . ”

“ This classification, however, over-estimates the size of the non-essential gene group, due to the inclusion of genes with no reported knockout data. As currently only approximately 9% of mouse genes have been knocked out (Dataset S1) , it is very likely that disease genes with no known mouse knockout phenotype would include both lethal and viable genes. Therefore, to include genes with no knockout data in the viable gene group confounds the analysis, and could lead to erroneous conclusions about the relative importance of lethal and viable genes in human disease. ”

“ Some gene mutations produce characteristics so undesirable that it is difficult to imagine any reasonable change in environmental conditions that would make them beneficial. There are mutations that lead to the nondevelopment of hands and feet, to the production of blood that will not clot, to serious malformations of essential organs, and so on. ”

“ Indeed our study reveals that DL genes are more highly associated with diseases that affect multiple physiological systems. This finding suggests that disease lethal genes have pleiotrophic functions. ”

“ We do not know how widespread recessive genes are in the human germ-plasm. The fact that defective individuals appear in certain communities may be safely interpreted to mean that individuals bearing the same gene have at last come together. On the other hand, the absence of such individuals from the community, at large, may only mean that the chance of suitable combinations is small, and does not mean necessarily that the gene in question is confined to the community within which the defects have been recorded. ”

“ DV genes primarily affect systems that are not required for basic survival of the organism. For example, while a high percentage of disease viable genes are associated with psychiatric and immune system diseases, they are under-represented among cardiovascular diseases. ”

“ We obtained the human–mouse orthology and mouse viable/lethal phenotype data from Mouse Genome Informatics (http://www.informatics.jax.org) [26] , to give 2,360 human genes with information about lethality status of the mouse knockout of their ortholog in the whole genome, without consideration of whether the gene is annotated as a human disease gene. ”

“ In man and in domesticated animals we find that individuals appear occasionally that are defective in one or another respect. Some of the defects are inherited. Rarely a new one appears that has not been seen before. But the majority of them are reappearances of characters that have been carried under the surface as recessive genes in the germ-plasm. Today we recognize that each of these modifications, if recessive, has first arisen as a mutational change in a single gene before it appeared on the surface as a character by the coming together of two such genes. ”