Retroposed new genes out of the X in Drosophila

New genes that originated by various molecular mechanisms are an essential component in understanding the evolution of genetic systems. We investigated the pattern of origin of the genes created by retroposition in Drosophila. We surveyed the whole Drosophila melanogaster genome for such new retrogenes and experimentally analyzed their functionality and evolutionary process. These retrogenes, functional as revealed by the analysis of expression, substitution, and population genetics, show a surprisingly asymmetric pattern in their origin. There is a significant excess of retrogenes that originate from the X chromosome and retropose to autosomes; new genes retroposed from autosomes are scarce. Further, we found that most of these X-derived autosomal retrogenes had evolved a testis expression pattern. These observations may be explained by natural selection favoring those new retrogenes that moved to autosomes and avoided the spermatogenesis X inactivation, and suggest the important role of genome position for the origin of new genes.     

The origin of intestinal stem cells in Drosophila

Renewing tissues in the adult organism such as the gastrointestinal (GI) epithelium depend on stem cells for epithelial maintenance and repair. Yet, little is known about the developmental origins of adult stem cells and their niches. Studies of Drosophila adult midgut precursors (AMPs), a population of endodermal progenitors, demonstrate that adult intestinal stem cells (ISCs) arise from the AMP lineage and provide insight into the stepwise process by which the adult midgut epithelium is established during development. Here, I review the current literature on AMPs, where local, inductive and long-range humoral signals have been found to control progenitor cell behavior. Future studies will be necessary to determine the precise mechanism by which adult intestinal stem cells are established in the endodermal lineage.     

Longevity determination genes in Drosophila melanogaster

Identification of longevity mutants is crucial for genetic approach to dissect the molecular mechanism of aging and longevity determination. In Drosophila melanogaster, several mutations have been shown to extend the longevity: methuselah encoding a putative G-protein coupled receptor, Indy encoding a sodium dicarboxylate cotransporter, chico encoding insulin receptor substrate, and InR encoding the insulin-like receptor. Extended longevity phenotypes were also observed in transgenic flies overexpressing antioxidant enzymes, Cu/Zn superoxide dismutase and Catalase, Cu/Zn SOD only, or a molecular chaperone, hsp70. Pleiotropism of mutations is a limitation associated with conventional mutagenesis for efficient detection of longevity determination genes. Using a conditional misexpression system, we identified Drosophila POSH (DPOSH), a scaffold protein containing RING finger and four SH3 domains, whose ubiquitous overexpression in adult stage extends the longevity. Neural-specific overexpression of DPOSH is sufficient to extend the longevity, whereas overexpression in non-neural tissues during development induces apoptosis through activation of JNK/SAPK pathway.     

HLA genes in Macedonians and the sub-Saharan origin of the Greeks

HLA alleles have been determined in individuals from the Republic of Macedonia by DNA typing and sequencing. HLA-A, -B, -DR, -DQ allele frequencies and extended haplotypes have been for the first time determined and the results compared to those of other Mediterraneans, particularly with their neighbouring Greeks. Genetic distances, neighbor-joining dendrograms and correspondence analysis have been performed. The following conclusions have been reached: 1) Macedonians belong to the "older" Mediterranean substratum, like Iberians (including Basques), North Africans, Italians, French, Cretans, Jews, Lebanese, Turks (Anatolians), Armenians and Iranians, 2) Macedonians are not related with geographically close Greeks, who do not belong to the "older" Mediterranenan substratum, 3) Greeks are found to have a substantial relatedness to sub-Saharan (Ethiopian) people, which separate them from other Mediterranean groups. Both Greeks and Ethiopians share quasi-specific DRB1 alleles, such as *0305, *0307, *0411, *0413, *0416, *0417, *0420, *1110, *1112, *1304 and *1310. Genetic distances are closer between Greeks and Ethiopian/sub-Saharan groups than to any other Mediterranean group and finally Greeks cluster with Ethiopians/sub-Saharans in both neighbour joining dendrograms and correspondence analyses. The time period when these relationships might have occurred was ancient but uncertain and might be related to the displacement of Egyptian-Ethiopian people living in pharaonic Egypt.     

Age-dependent chromosomal distribution of male-biased genes in Drosophila

We investigated the correlation between the chromosomal location and age distribution of new male-biased genes formed by duplications via DNA intermediates (DNA-level) or by de novo origination in Drosophila. Our genome-wide analysis revealed an excess of young X-linked male-biased genes. The proportion of X-linked male-biased genes then diminishes through time, leading to an autosomal excess of male-biased genes. The switch between X-linked and autosomal enrichment of male-biased genes was also present in the distribution of both protein-coding genes on the D. pseudoobscura neo-X chromosome and microRNA genes of D. melanogaster. These observations revealed that the evolution of male-biased genes is more complicated than the previously detected one-step X→A gene traffic and the enrichment of the male-biased genes on autosomes. The pattern we detected suggests that the interaction of various evolutionary forces such as the meiotic sex chromosome inactivation (MSCI), faster-X effect, and sexual antagonism in the male germline might have shaped the chromosomal distribution of male-biased genes on different evolutionary time scales.It has been observed that male-biased genes in Drosophila are overrepresented on autosomes (Parisi et al. 2003; Ranz et al. 2003). Consistent with this result, a dynamic process that can explain the nonrandom autosomal distribution has also been observed, in which autosomal new genes with X-linked parental genes are often male-biased. Specifically, a significant excess of autosomal testis-expressed retrogenes were identified as RNA-duplicates of X-linked parental genes (Betran et al. 2002). Recently, similar X→A gene traffic was observed in the DNA-level duplication and relocation data set of the Drosophila genus (Vibranovski et al. 2009b), and was further confirmed for DNA-level duplications in the D. pseudoobscura neo-X chromosome (Meisel et al. 2009). In addition, selective extinction of neo-X linked male-biased genes also occurred in D. pseudoobscura (Sturgill et al. 2007). These three lines of genome-wide investigation support a common pattern of out-of-X traffic for male-biased genes, resulting in an enrichment of these genes on autosomes in the long term.Various hypotheses have been proposed to explain the chromosomal distribution of sex-biased genes. The sexual antagonism hypothesis (Rice 1984) predicts an increase of X-linked sexually antagonistic genes in a population over a wide range of parameters (e.g., recessive mutations advantageous for males and disadvantageous for females). With the assumption of a modifier gene that may restrict expression to the advantageous sex, X-linked antagonistic genes would be more likely to be involved in the evolution of sexually dimorphic traits (Rice 1984; Vicoso and Charlesworth 2006). In autosomal inheritance, when the advantageous effect on one sex is greater than the disadvantageous effect on the other sex, sexually antagonistic genes can spread in the population (Rice 1984). Although sexual antagonism has often been used to explain the evolution of sex-biased genes (Betran et al. 2002; Parisi et al. 2003; Ranz et al. 2003; Meisel et al. 2009), recent reports questioned the association between sex-biased expression and sexual antagonism (Vicoso and Charlesworth 2009; Innocenti and Morrow 2010). On the other hand, meiotic sex chromosome inactivation (MSCI) in spermatogenesis predicts X demasculinization via selection favoring autosomal male-biased genes, if the X chromosome is inactive during meiosis (Lifschytz and Lindsley 1972; Betran et al. 2002; Hense et al. 2007; Vibranovski et al. 2009a, 2010). Thus, if sex-biased expression were a proxy for sexual antagonism, sexually antagonistic selection is compatible with a paucity of X-linked somatic male-biased genes (Parisi et al. 2003). Additionally, the existence of MSCI-based selection is supported by the recent finding that autosomal genes retroposed from the X chromosome frequently demonstrate complementary expression in meiosis compared to their X-linked parental genes (Vibranovski et al. 2009a).However, a number of X-linked evolutionarily young genes have been identified recently (Arguello et al. 2006; Levine et al. 2006; Chen et al. 2007), all of which are male-biased. In order to understand whether these cases represent a general pattern, we examined the chromosomal distribution of male-biased genes of different evolutionary ages. Unexpectedly, we observed that the X chromosome has undergone an initial enrichment of young male-biased genes through intrachromosomal origination. However, as gene age increases, this excess gradually diminishes and is finally reversed, resulting in an overrepresentation of male-biased genes on the autosomes. This dynamic suggests a significant impact of the evolutionary time scale on the different mechanisms responsible for the evolution of male-biased genes. Here, we discuss how different evolutionary forces may impact the chromosomal distribution of male-biased genes with different ages.     

An evolutionary analysis of orphan genes in Drosophila

Orphan genes are protein-coding regions that have no recognizable homolog in distantly related species. A substantial fraction of coding regions in any genome sequenced consists of orphan genes, but the evolutionary and functional significance of orphan genes is not understood. We present a reanalysis of the Drosophila melanogaster proteome that shows that there are still between 26% and 29% of all proteins without a significant match with noninsect sequences, and that these orphans are underrepresented in genetic screens. To analyze the characteristics of orphan genes in Drosophila, we used sequence comparisons between cDNAs retrieved from two Drosophila yakuba libraries and their corresponding D. melanogaster orthologs. We find that a cDNA library from adults yields twice as many orphan genes as such a library from embryos. The orphan genes evolve on average more than three times faster than nonorphan genes, although the width of the evolutionary rate distribution is similar for the two classes. In particular, some orphan genes show very low substitution rates that are comparable to otherwise highly conserved genes. We propose a model suggesting that orphans may be involved in the evolution of adaptive traits, and that slow-evolving orphan genes may be particularly interesting candidate genes for identifying lineage-specific adaptations.     

On the origin of cancer

In this paper, I present a highly unorthodox and provocative hypothesis, namely that cancer is an evolutionarily derived phenomenon, dormant in every human cell and actively triggered in certain individuals. Cancer is shown to help maintain the integrity of the common gene pool through active elimination of individuals, thus serving a definite advantage for the survival of the species. Those individuals who are less capable of maintaining the integrity of their genome are stopped from inheriting defective genes, and even more important, from bequeathing defective deoxyribonucleic acid conservation traits to their offspring.Genome stability is a primary prerequisite for survival. The spread of deteriorated, imperfect genes should have a disastrous effect on a species' chances for survival. Although we tend to focus our attention on mutations as evolution's driving force, the stability of the deoxyribonucleic acid molecule is what really maintains life on our planet. When observing evolution's end product, we tend to forget that the extreme stability of the genetic material is a genetic quality by itself, a product of a long evolutionary process. The hypothesis presented here is that the selection pressure imposed by cancer is one of the mechanisms leading to this stability.     

Myotropic peptides in Drosophila melanogaster and the genes that encode them

Myotropic peptides are structurally dissimilar; thus, they comprise different families. The cellular expressions of myotropins suggest they act as hormones, transmitters, and modulators of numerous biological processes. Drosophila melanogaster allatostatin (AST), FMRFamide-containing, dromyosuppressin (DMS), and drosulfakinin (DSK) peptides represent four different myotropin families. A different gene encodes each of these four myotropin families. D. melanogaster AST, FMRFamide-containing, DMS, and DSK peptides are present in neural and gut tissue, but are not all expressed in the same cells. These four families of myotropins affect spontaneous contractions of gut, heart, and/or reproductive tissue, but their effects are dissimilar in magnitude and time course. Based on their structures, genes, distributions, and activities, the synthesis and release of these D. melanogaster myotropins are likely governed by different sensory inputs and regulatory mechanisms. The differences in structures, precursors, cellular expressions, and activities are consistent with the conclusion that they do not play redundant roles in their effects on the frequency of muscle contractions. Orthologs of these D. melanogaster myotropins exist in other animal species; thus, research on the mechanisms involved in their production and processing, functions, and signaling may be widely applicable. Here, we review research on D. melanogaster AST, FMRFamide-containing, myosuppressin, and sulfakinin peptides.     

Homeobox genes,fossils, and the origin of species

Ever since Darwin there has been a history of debate on the tempo and mode of evolution. Is speciation a gradual process involving the accumulation of minute variations extant within a species, or is it rapid, the result of major organismal reorganization? Does one define a species on the basis of genes, morphology, or geographic or reproductive isolation? In this communication I present a model of evolutionary change that is based on the Mendelian inheritance of mutations in regulatory genes and the fact that most nonlethal mutations arise in the recessive state. Since the new recessive allele will spread through many generations without expression until there is a critical mass of heterozygotes capable of producing homozygotes for the mutation, the novel feature thus produced will appear abruptly in the population and in more than one individual. This picture of punctuation is consistent with the fossil record, which typically fails to provide evidence of smoothly transitional states of morphological change. Given that the first of their kind in the fossil record are organisms in which their novel characteristics are often more fully expressed or complex than in their descendants, it would seem that, after the mutation involving a regulatory gene is introduced, the general tendency is for its effects to become diminished. Among the implications for speciation is that this process does not depend on either reproductive isolation or genetic incompatibility. Rather, barring effects on reproductive organs or behavior, homozygotes for a novelty should be able to breed with heterozygotes and homozygotes for the wild state of the original population. This, in turn, suggests that the species barrier between individuals is probably a matter of mate recognition. Anat Rec (New Anat): 257:15–31, 1999. © 1999 Wiley‐Liss, Inc.     

On the origin of respiratory waves in circulation

Summary The origin of the respiratory waves which modulate arterial blood pressure recordings and photoplethysmograms was investigated. The thoracic pump and the respiratory center were considered as possible generators of the respiratory influence. The complex of factors responsible for the production of modulating waves was separated into generators of the input signal, the resultant input signal and the system influenced by the signal.While testing the separate activities of the generators, it was found that input signals could be obtained exclusively from the peripheral generator under natural as well as artificial functioning. Input signals from the central generator, however, were obtained only at an increased level of functioning, as, for example, during the accumulation of excess CO₂. The activities of the two generators were tested separately and simultaneously, at a uniform and variable pace, and the forementioned conditions prevailed also during their joint activity. It was therefore deduced that the respiratory waves originate primarily from the peripheral generator in the course of natural respiration.Partially in fulfillment of the M.Sc. thesis (Hebrew) of the first author at the Technion—Israel Institute of Technology, Haifa, Israel