Antitype

“ For example, a computer program would not be able to recognize the fact that there is a significant similarity between the PAX6 mutations that result in “small eyed” mice, “opaque cornea” in humans, a “malformed retina” in zebrafish, and “eyeless” Drosophila (Figure 1) .
Representation of phenotypes.Phenotypes of wild-type (top) and PAX6 ortholog mutations (bottom) in human, mouse, zebrafish, and fly can be described with the EQ method. EQ annotations of the abnormal phenotypes are listed below each set of images per organism. ”

“ Although many MODs curate phenotype data using the EQ method, no such annotations existed for human disease genes. Because we required annotations of human diseases in the EQ style for comparison, we proceeded to annotate a small set of gene records from OMIM: ATP2A1, EPB41, EXT2, EYA1, FECH, PAX2, SHH, SOX9, SOX10, TTN, and TNNT2. These 11 genes were selected because they were known to be causal for a variety of human diseases and had known mutant orthologs in flies, mice, and/or fish with corresponding EQ descriptions available for comparative analysis. ”

“ Our understanding of gene function is often informed by comparing the phenotypic consequences of mutation with the canonical “wild-type” in a single organism, as well as between mutants of orthologous genes in different organisms. In particular, model organisms have provided great insight into gene function in humans. The importance and need for automating these cross-species comparisons has become imperative as large-scale mutagenesis screens are conducted in model organisms. ”

“ 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) . ”

“ Other parameters are the same as for the right side of Figure 3: w1 = 3.0, w2 = 2, and k = 2. When Nμ ≪ 1, the above description does not hold. Mutations occur so rarely, that the population is very likely to fix or lose each mutation before the next one arises. In this case, it no longer makes sense to talk about a quasispecies—there is no mutation–selection balance, but instead a fixed type, the wild-type, with possibly some recent mutants. The wild-type essentially undergoes a random walk in genotype space, in which it tends to “hang out” more often in areas with high fitness [18] . ”

“ 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. ”

“ 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. ”

“ 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. ”

“ However, ubiquitous expression is not a comprehensive indicator of essentiality, and genes with housekeeping functions may not necessarily have lethal knockout phenotypes. Our work, thus, demonstrates that when essentiality, as inferred by mouse knockout phenotypes, is considered explicitly, disease genes themselves display differing characteristics based on their essentiality status. ”

“ 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. ”

“ Diseases also contribute their share towards this double elimination. Some, like tuberculosis, work against the upland type, while the fevers and alcohol weed out the lowlanders. The action of this double elimination can be shown by using the Mendelian law of crosses. When parents of mixed breeds unite, the children are one fourth pure of each pure type and one half of the mixed type. If none of the pure types survived, the next generation, being children of the mixed type, would again be one fourth of each of the pure types and one half of the mixed type. ”

“ Each of these types breeds true. “Each has arisen independently and suddenly. Every 437part of the body has been affected by one or another of these mutations.” To arrange these mutations arbitrarily into graded series would give the impression of an evolutionary series, but this is directly contrary to the known facts concerning their origin, for each mutation “originated independently from the wild type.” “Evolution has taken place by the incorporation into the race of those mutations that are beneficial to the life and reproduction of the individual.” ”

“ The recognition that disease genes are not a homogenous subset of human genes, and that essential genes cannot be excluded from consideration as candidates for all types of human disease genes, will aid in the identification of candidate disease gene loci for a variety of human 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ For a specific disease, the prediction result will be limited by existing knowledge about the disease, including the number of known disease genes and their relationships within the existing data sources. We have used the concept of disease families in order to increase the number of known disease genes in each family. Some recent studies have considered relationships/similarities between diseases/phenotypes [29] and have utilized phenotype similarities in their gene prioritization approach [30] – [31] . We will investigate approaches to incorporate phenotype similarities into our framework. ”

“ Also, when we did not consider specific gene loci and ranked all genes globally by our score, we could identify genes that show high extent of pleiotropy and participate in the physiological pathogenic processes of many diseases [28] . In addition, the successful identification of the common genes involved in many diseases in the context of network indicates the phenotypic interdependency, cooccurrence and shared pathophysiology between different disorders. This study provides a novel, effective and easy-implemented algorithm for the prioritization of candidate disease genes. ”

“ While severe mutant alleles that eliminate protein function represent the null state and confer lethality, hypomorphic alleles simply reduce protein function below an optimal level, resulting in a phenotype recognized as disease. In this manner, lethal genes can have mutations that only reduce protein function and therefore present as disease in the human population, allowing for inheritance of these more mild alleles in genetic diseases. ”

“ Abstract A novel method for quantifying the similarity between phenotypes by the use of ontologies can be used to search for candidate genes, pathway members, and human disease models on the basis of phenotypes alone.==Abstract== Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. ”

“ Specifically, if a group of genes shows a consistent pattern of different expression levels in sick subjects and a control group, then that gene is likely a strong candidate of playing a pathogenic role. ”

“ 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. ”

“ We searched the Morbid map of the Online Mendelian Inheritance in Man (OMIM) database [33] and identified 359 genes associated with the 40 distinct diseases in our microarray data, in which one disease was associated with at least one gene. As listed in Table S2, the disease with the most known causing genes is cardiomyopathy, with 32 disease genes known. A total of 318 of the 359 genes were found to present in the protein-protein interaction network constructed from STRING, and these genes were used to validate our algorithm (see Table S2) . ”

“ Here we set the vector x in Eq. (4) as the vector of the absolute values of the logarithm of the ratio of the expression levels of this microarray set, and W as the normalized interaction-weight matrix in STRING (See Material and Method) . In the cases when one disease corresponds to more than one experiment (disease-control datasets) we summed up the s-score vectors corresponding to the disease. Then we ranked the genes in each candidate-gene set of a disease according to their s-scores and got their r-ratios (see the Materials and Methods section) . ”