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Although numerous approaches have been pursued to understand the function of human genes, Mendelian genetics has by far provided the most compelling and medically actionable dataset. Biallelic loss-of-function (LOF) mutations are observed in the majority of autosomal recessive Mendelian disorders, representing natural human knockouts and offering a unique opportunity to study the physiological and developmental context of these genes. The restriction of such context to 'disease' states is artificial, however, and the recent ability to survey entire human genomes for biallelic LOF mutations has revealed a surprising landscape of knockout events in 'healthy' individuals, sparking interest in their role in phenotypic diversity beyond disease causation. As I discuss in this review, the potentially wide implications of human knockout research warrant increased investment and multidisciplinary collaborations to overcome existing challenges and reap its benefits., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Technological leaps in genome sequencing have resulted in a surge in discovery of human disease genes. These discoveries have led to increased clarity on the molecular pathology of disease and have also demonstrated considerable overlap in the genetic roots of human diseases. In light of this large genetic overlap, we tested whether cross-disease research approaches lead to faster, more impactful discoveries., Methods: We leveraged several gene-disease association databases to calculate a Mutual Citation Score (MCS) for 10,853 pairs of genetically related diseases to measure the frequency of cross-citation between research fields. To assess the importance of cooperative research, we computed an Individual Disease Cooperation Score (ICS) and the average publication rate for each disease., Results: For all disease pairs with one gene in common, we found that the degree of genetic overlap was a poor predictor of cooperation (r(2)=0.3198) and that the vast majority of disease pairs (89.56%) never cited previous discoveries of the same gene in a different disease, irrespective of the level of genetic similarity between the diseases. A fraction (0.25%) of the pairs demonstrated cross-citation in greater than 5% of their published genetic discoveries and 0.037% cross-referenced discoveries more than 10% of the time. We found strong positive correlations between ICS and publication rate (r(2)=0.7931), and an even stronger correlation between the publication rate and the number of cross-referenced diseases (r(2)=0.8585). These results suggested that cross-disease research may have the potential to yield novel discoveries at a faster pace than singular disease research., Conclusions: Our findings suggest that the frequency of cross-disease study is low despite the high level of genetic similarity among many human diseases, and that collaborative methods may accelerate and increase the impact of new genetic discoveries. Until we have a better understanding of the taxonomy of human diseases, cross-disease research approaches should become the rule rather than the exception.

Historically, much of biology was studied by physicists and mathematicians. With the advent of modern molecular biology, a wave of researchers became trained in a new scientific discipline filled with the language of genes, mutants, and the central dogma. These new molecular approaches have provided volumes of information on biomolecules and molecular pathways from the cellular to the organismal level. The challenge now is to determine how this seemingly endless list of components works together to promote the healthy function of complex living systems. This effort requires an interdisciplinary approach by investigators from both the biological and the physical sciences.

This chapter provides an overview of diet-gene interaction and the role of dietary factors in human health and disease. Human master control genes that regulate processes of fundamental importance, such as cell proliferation and the immune response, are introduced and their modulation by nutraceuticals, produced by plants and photosynthetic microbes, is reviewed. Emphasis is placed on antioxidants and polyunsaturated fatty acids as regulators of master control genes. Furthermore, a case study is presented on xanthophylls, a group of carotenoids with multiple health benefits in the protection against eye disease and other chronic diseases, as well as the synergism between xanthophylls and other dietary factors. Lastly, dietary sources of the xanthophylls zeaxanthin and lutein are reviewed and their enhancement via genetic engineering is discussed.

A contrarian view suggests that the ectodermal dysplasias, including more than 200 different disorders, represent clinical variability and molecular heterogeneity as well as complex multigene heritable conditions often characterized by dysmorphogenesis of derivatives of embryonic ectoderm and beyond. Controversy exists over which syndromes do or do not belong in the classification of the clinical features that characterize ectodermal dysplasias. For example, Ellis-van Creveld syndrome is characterized by abnormalities of the teeth and hair, as well as of the skeleton and the cardiovascular system. Precision in diagnosis often is a preamble for improved patient diagnosis, treatment and desired outcomes. In tandem, molecular studies of complex epithelial-mesenchymal interactions required for ectodermal derivatives (e.g., hair, nail, skin, teeth, and exocrine glands) continue to identify and explain many signal transduction pathways and networks related to ectodermal dysplasias. Meanwhile, major international investments in fundamental biomedical research continue to yield significant benefits to the larger society. The convergence of informatics, nanotechnology, genomics, and epigenetic studies with clinical medicine and dentistry promise major progress for special needs patients such as ectodermal dysplasias. For example, investments in the molecular biology of genes and their regulation and function now provide more than 30 candidates for specific biomarkers to improve diagnosis, prognosis, treatments, therapeutics, and biomaterials for ectodermal dysplasias. Innovations in high throughput genotyping, gene mapping, single nucleotide polymorphisms (SNPs), interference RNA treatments, bioimaging, tissue engineering and related biomimetic approaches to design and fabricate biomaterials, offer enormous promise for the future of ectodermal dysplasias., ((c) 2009 Wiley-Liss, Inc.)

Purpose of Review: To highlight the development in microarray data analysis for the identification of differentially expressed genes, particularly via control of false discovery rate., Recent Findings: The emergence of high-throughput technology such as microarrays raises two fundamental statistical issues: multiplicity and sensitivity. We focus on the biological problem of identifying differentially expressed genes. First, multiplicity arises due to testing tens of thousands of hypotheses, rendering the standard P value meaningless. Second, known optimal single-test procedures such as the t-test perform poorly in the context of highly multiple tests. The standard approach of dealing with multiplicity is too conservative in the microarray context. The false discovery rate concept is fast becoming the key statistical assessment tool replacing the P value. We review the false discovery rate approach and argue that it is more sensible for microarray data. We also discuss some methods to take into account additional information from the microarrays to improve the false discovery rate., Summary: There is growing consensus on how to analyse microarray data using the false discovery rate framework in place of the classical P value. Further research is needed on the preprocessing of the raw data, such as the normalization step and filtering, and on finding the most sensitive test procedure.

Gene-finding methods are classified into homology-based bench-top approach (degenerate cDNA-PCR and cDNA selection), ab initio bench-top approach (cDNA subtraction, two-hybrid system, and exon trapping), homology-based desk-top approach (BLAST search), ab initio desk-top approach (Fgenesh and GENSCAN programs), and hybrid desk-top approach (GenomeScan program). cDNA-library screening, cDNA-PCR, and RACE are used to isolate cDNAs for complete coding sequences. Because WNT signaling molecules are potent targets for oncology, regenerative medicine, and other fields of medical science, we have cloned and characterized many human genes encoding WNT signaling molecules, including 13 out of 19 human WNT genes, and 9 out of 10 human FZD genes. We used degenerate cDNA-PCR and cDNA-library screening in the 20th century, while we use BLAST program and cDNA-PCR in the 21st century. The interval between gene-finding and manuscript-publication in my laboratory was 17.2+/-7.5 (mean +/- SD) months in the 20th century (n=13), 11.5+/-7.8 months in 2001 (n=19), and 5.5+/-1.6 months in 2002 (n=13). The interval using desk-top gene-finding approach (7.2+/-2.6 months, n=30) was significantly shorter than that using bench-top approach (19.8+/-8.0 months, n=15) (p=0.003). Gene-finding has been significantly accelerated due to paradigm shift from bench-top approach to desk-top approach. Dramatic increase of information about human genome, transcriptome and proteome accompanied by improvements of genomics, proteonics and bioinformatics technologies will accelerate paradigm shift from bench-top science to desk-top science.

The elucidation of genetic components of human diseases at the molecular level provides crucial information for developing future causal therapeutic intervention. High-throughput genome sequencing and systematic experimental approaches are fuelling strategic programs designed to investigate gene function at the biochemical, cellular and organism levels. Bioinformatics is one important tool in functional genomics, although showing clear limitations in predicting ab initio gene structures, gene function and protein folds from raw sequence data. Systematic large-scale data-set generation, using the same type of experiments that are used to decipher the function of single genes, are being applied on entire genomes. Comparative genomics, establishment of gene catalogues, and investigation of cellular and tissue molecular profiles are providing essential tools for understanding gene function in complex biological networks.

The medical research community is experiencing a marked increase in the amount of information available on genomic sequences and genes expressed by humans and other organisms. This information offers great opportunities for improving our understanding of complex diseases such as lung cancer. In particular, we should expect to witness a rapid increase in the rate of discovery of genes involved in lung cancer pathogenesis and we should be able to develop reliable molecular criteria for classifying lung cancers and predicting biological properties of individual tumors. Achieving these goals will require collaboration by scientists with specialized expertise in medicine, molecular biology, and decision-based statistical analysis.

The human body is becoming hot property, a resource to be "mined," "harvested," patented, and traded commercially for profit as well as scientific and therapeutic advances. Under the new entrepreneurial approach to the body old tensions take on new dimensions -- about consent, the fair distribution of tissues and products developed from them, the individual and cultural values represented by the body, and public policy governing the use of organs and tissues.

The "tragedy of the commons" metaphor helps explain why people overuse shared resources. However, the recent proliferation of intellectual property rights in biomedical research suggests a different tragedy, an "anticommons" in which people underuse scarce resources because too many owners can block each other. Privatization of biomedical research must be more carefully deployed to sustain both upstream research and downstream product development. Otherwise, more intellectual property rights may lead paradoxically to fewer useful products for improving human health.

Watanabe, Tsutomu (Keio University, Tokyo, Japan), Hiroshi Nishida, Chizuko Ogata, Toshihiko Arai, and Sachiko Sato. Episome-mediated transfer of drug resistance in Enterobacteriaceae. VII. Two types of naturally occurring R factors. J. Bacteriol. 88:716-726. 1964.-Naturally occurring R factors are classified into two types, fi(+) and fi(-), depending on their fi characters. The term fi is an abbreviation of fertility inhibition and fi(-) and fi(-) mean, respectively, the presence and absence of suppression of the functions of the sex factor F of Escherichia coli K-12. It was found that fi(-) R factors reduce the efficiency of plating of phages lambda and T(1) in K-12; fi(+) R factors did not have this inhibitory action. One of the fi(-) R factors reduced the efficiency of plating of phage T(7) as well. Phages lambda and T(1) underwent host-induced modifications in the host carrying some fi(-) R factors. At least two types of fi(-) R factors were recognized by the types of their restriction and host-induced modification of these phages. CaCl(2) exhibited antagonistic actions against the restrictions of phages lambda and T(1) by fi(-) R factors. Transduction of the ability to ferment galactose with HFT lysates of lambda was reduced by fi(-) R factors. Ultraviolet induction of lambda was not affected by any R factors. Furthermore, adsorption of phages lambda and T(1) was not altered by the presence of any R factors. From these results, we concluded that the suppression of progeny formation of these phages by fi(-) R factors is due to some step(s) after adsorption of the phages to the bacteria. Superinfection immunity and mutual exclusion were found between two different fi(+) R factors but not between fi(+) and fi(-) R factors. The two different fi(-) R factors were frequently genetically recombined. but fi(+) and fi(-) R factors were not genetically recombined, as indicated by findings of independent transfer of these R factors by conjugation and by transduction from the donors having these two R factors. It was assumed from these findings that fi(+) and fi(-) R factors are considerably different episomes having different resistance-transfer factors.

Barat, M. (Centre National de la Recherche Scientifique, Gif-sur-Yvette, Seine et Oise, France), C. Anagnostopoulos, and A.-M. Schneider. Linkage relationships of genes controlling isoleucine, valine, and leucine biosynthesis in Bacillus subtilis. J. Bacteriol.90:357-369. 1965.-In Bacillus subtilis, the genetic loci controlling isoleucine and valine biosynthesis are not all clustered. Some of them were located on two distinct transforming deoxyribonucleic acid "molecules." One of these molecules (the "ileilva(2-4)-met segment") carries the threonine deaminase and the dihydroxy acid dehydrase loci linked to methionine markers. The other (the "ilva(1-3)-leu segment") bears the reductoisomerase locus and one or more loci involved in leucine synthesis. A phenylalanine marker was also shown to be weakly linked to this latter group. In transduction mediated by phage PBS-1, these groups are transferred jointly with other gene clusters. The phage appears to convey chromosome fragments considerably longer than the transforming "molecules." The genetic maps of both the above segments were extended by transduction. Some groups previously studied by transformation can be placed in the following linear order: the ile-ilva(2-4)-met segment, the cluster of loci involved in aromatic amino acid synthesis (try segment), and a lysine locus. An arginine locus is cotransduced with the phe-ilva(1-2)-leu segment. Recombination frequencies between linked markers are much lower in transduction by this phage than in transformation.

Pittard, James (Yale University, New Haven, Conn.). Effect of integrated sex factor on the transduction of chromosomal genes in Escherichia coli. J. Bacteriol. 89:680-686. 1965.-Generalized transducing phage P1kc can contransduce the markers tna and ilv in Escherichia coli K-12 at a frequency of approximately 25%. When sex factor is integrated into the donor chromosome between tna and ilv, as in Hfr AB313, the entire sequence tna F ilv is not cotransduced at a detectable frequency, nor is F cotransduced with either tna or ilv. The frequency with which ilv is transduced from Hfr AB313 to female recipients is approximately one-eighth the frequency obtained when either F(+) or female strains are used as donors. This reduction of transduction frequency does not occur if the recipient is an Hfr male similar to AB313. The reduction is attributed to pairing difficulties which occur when the transduced fragment carrying the ilv genes also carries sex-factor material. When ilv(+) is transduced from a female to an ilv(-) derivative of AB313, 70% of the transductants are converted to F(+) males. A model is proposed to account for all of these observations.