On the origins of Mendelian disease genes in man: the impact of gene duplication

Over 3,000 human diseases are known to be linked to heritable genetic variation, mapping to over 1,700 unique genes. Dating of the evolutionary age of these disease-associated genes has suggested that they have a tendency to be ancient, specifically coming into existence with early metazoa. The approach taken by past studies, however, assumes that the age of a disease is the same as the age of its common ancestor, ignoring the fundamental contribution of duplication events in the evolution of new genes and function. Here, we date both the common ancestor and the duplication history of known human disease-associated genes. We find that the majority of disease genes (80%) are genes that have been duplicated in their evolutionary history. Periods for which there are more disease-associated genes, for example, at the origins of bony vertebrates, are explained by the emergence of more genes at that time, and the majority of these are duplicates inferred to have arisen by whole-genome duplication. These relationships are similar for different disease types and the disease-associated gene's cellular function. This indicates that the emergence of duplication-associated diseases has been ongoing and approximately constant (relative to the retention of duplicate genes) throughout the evolution of life. This continued until approximately 390 Ma from which time relatively fewer novel genes came into existence on the human lineage, let alone disease genes. For single-copy genes associated with disease, we find that the numbers of disease genes decreases with recency. For the majority of duplicates, the disease-associated mutation is associated with just one of the duplicate copies. A universal explanation for heritable disease is, thus, that it is merely a by-product of the evolutionary process; the evolution of new genes (de novo or by duplication) results in the potential for new diseases to emerge.     

细菌素编码基因的定位分析

细菌素生物合成相关的基因经常成簇出现:结构基因、对自身产生免疫的基因及产生辅助蛋白质的基因组成操纵子结构,其中结构基因是细菌素编码基因,它可能在质粒上也可能在染色体上,为了初步定位细菌素编码基因是在质粒上还是染色体上,综述细菌素编码基因的初步定位方法,为深入研究细菌素提供依据。     

Organization of the actin multigene family of Dictyostelium discoideum and analysis of variability in the protein coding regions

There are 17 to 20 actin genes in the genome of the cellular slime mold Dictyostelium discoideum. Genomic clones of 15 of the genes have been isolated. Extensive nucleotide sequence within the protein-coding regions has been determined, including the complete nucleotide sequence of four genes representing the three distinct evolutionary groups of Dictyostelium actin genes. All are similar to mammalian cytoplasmic actins at diagnostic amino acid positions, and there is generally less variability among Dictyostelium actin genes than among Drosophila actin genes. Two genes, Actins 3-sub 1 and 3-sub 2 differ substantially from all the rest in terms of replacement amino acid substitutions and probably encode actin-related proteins rather than bona fide actins. Each contains several amino acid substitutions that should alter the secondary structure of the resulting proteins, and Actin 3-sub 2 encodes four additional amino acids at the C terminus. This gene is as divergent from other Dictyostelium actin genes as is the yeast or a soybean actin gene. At present, evidence suggests that all 15 genes examined are expressed, except the previously identified Actin 2-sub 2. We suggest that Dictyostelium might maintain a high number of functional actin genes for the purpose of regulating the level of actin synthesis within narrow limits, rather than because most genes perform different functions.     

Organisation of the Hb 1 genes of the Antarctic skate Bathyraja eatonii: new insights into the evolution of globin genes

An extensive investigation of the organisation of globin genes has greatly contributed to the understanding of universal mechanisms of gene evolution and expression. Cartilaginous fish are the first organisms that have evolved the tetrameric form of hemoglobin (Hb). So far, there has been absolute lack of data about globin genes in chondrichthyans. Bathyraja is the dominant rajid south of 60 degrees S. In the framework of the investigations on globin genes of Antarctic red-blooded and Hb-less fish we obtained the cloning of the alpha- and beta-globin cDNAs of the main Hb (Hb 1) of the skate Bathyraja eatonii. Then, a genomic fragment of 6.2 kb was isolated where the Hb 1 alpha and beta genes are linked in a tail-to-head (3' to 5') orientation. The beta-globin gene promoter region and the chromosomal organisation of the Hb 1 genes of B. eatonii have been compared to their homologues in other vertebrates. The finding of a tail-to-head linkage of the Hb 1 alpha- and beta-globin genes in B. eatonii is the first characterisation of the organisation of globin genes in chondrichthyes; such finding offers a novel contribution to the understanding of the evolution of this class of genes. Moreover, the characterisation of chondrichthyan genes is very important for gaining insight into the ancestral state of vertebrate genomes.     

Identification of the Anopheles gambiae ATP-binding cassette transporter superfamily genes

The Anopheles gambiae genome sequence has been analyzed to find ATP-binding cassette protein genes based on deduced protein similarity to known family members. A nonredundant collection of 44 putative genes was identified including five genes not detected by the original Anopheles genome project machine annotation. These genes encode at least one member of all the human and Drosophila melanogaster ATP-binding protein subgroups. Like D. melanogaster, A. gambiae has subgroup ABCH genes encoding proteins different from the ABC proteins found in other complex organisms. The largest Anopheles subgroup is the ABCC genes which includes one member that can potentially encode ten different isoforms of the protein by differential splicing. As with Drosophila, the second largest Anopheles group is the ABCG subgroup with 12 genes compared to 15 genes in D. melanogaster, but only 5 genes in the human genome. In contrast, fewer ABCA and ABCB genes were identified in the mosquito genome than in the human or Drosophila genomes. Gene duplication is very evident in the Anopheles ABC genes with two groups of four genes, one group with three genes and three groups with two head to tail duplicated genes. These characteristics argue that the A. gambiae is actively using gene duplication as a mechanism to drive genetic variation in this important gene group.     

Organization of the variable region of the immunoglobulin heavy-chain gene locus of the rat

We have mapped and annotated the variable region of the immunoglobulin heavy (IGH) gene locus of the Brown Norway (BN) rat (assembly V3.4; Rat Genomic Sequence Consortium). In addition to known variable region genes, we found 12 novel previously unidentified functional IGHV genes and 1 novel functional IGHD gene. In total, the variable region of the rat IGH locus is composed of at least 353 unique IGHV genes, 21 IGHD genes, and 5 IGHJ genes, of which 131, 14, and 4 are potentially functional genes, respectively. Of all species studied so far, the rat seems to have the highest number of functional IGHV genes in the genome. Rat IGHV genes can be classified into 13 IGHV families based on nucleotide sequence identity. The variable region of the BN rat spans a total length of approximately 4.9 Mb and is organized in a typical translocon organization. Like the mouse, members of the various IGHV gene families are more or less grouped together on the genome, albeit some members of IGHV gene families are found intermingled with each other. In the rat, the largest IGHV gene families are IGHV1, IGHV2, and IGHV5. The overall conclusion is that the genomic organization of the variable region of the rat IGH locus is strikingly similar to that of the mouse, illustrating the close evolutionary relationship between these two species.     

On the rate of DNA sequence evolution inDrosophila

Summary Analysis of the rate of nucleotide substitution at silent sites inDrosophila genes reveals three main points. First, the silent rate varies (by a factor of two) among nuclear genes; it is inversely related to the degree of codon usage bias, and so selection among synonymous codons appears to constrain the rate of silent substitution in some genes. Second, mitochondrial genes may have evolved only as fast as nuclear genes with weak codon usage bias (and two times faster than nuclear genes with high codon usage bias); this is quite different from the situation in mammals where mitochondrial genes evolve approximately 5–10 times faster than nuclear genes. Third, the absolute rate of substitution at silent sites in nuclear genes inDrosophila is about three times hihger than the average silent rate in mammals.     

Permuted tRNA genes of Cyanidioschyzon merolae, the origin of the tRNA molecule and the root of the Eukarya domain

An evolutionary analysis is conducted on the permuted tRNA genes of Cyanidioschyzon merolae, in which the 5′ half of the tRNA molecule is codified at the 3′ end of the gene and its 3′ half is codified at the 5′ end. This analysis has shown that permuted genes cannot be considered as derived traits but seem to possess characteristics that suggest they are ancestral traits, i.e. they originated when tRNA molecule genes originated for the first time. In particular, if the hypothesis that permuted genes are a derived trait were true, then we should not have been able to observe that the most frequent class of permuted genes is that of the anticodon loop type, for the simple reason that this class would derive by random permutation from a class of non-permuted tRNA genes, which instead is the rarest. This would not explain the high frequency with which permuted tRNA genes with perfectly separate 5′ and 3′ halves were observed. Clearly the mechanism that produced this class of permuted genes would envisage the existence, in an advanced stage of evolution, of minigenes codifying for the 5′ and 3′ halves of tRNAs which were assembled in a permuted way at the origin of the tRNA molecule, thus producing a high frequency of permuted genes of the class here referred. Therefore, this evidence supports the hypothesis that the genes of the tRNA molecule were assembled by minigenes codifying for hairpin-like RNA molecules, as suggested by one model for the origin of tRNA [Di Giulio, M., 1992. On the origin of the transfer RNA molecule. J. Theor. Biol. 159, 199–214; Di Giulio, M., 1999. The non-monophyletic origin of tRNA molecule. J. Theor. Biol. 197, 403–414]. Moreover, the late assembly of the permuted genes of C. merolae, as well as their ancestrality, strengthens the hypothesis of the polyphyletic origins of these genes. Finally, on the basis of the uniqueness and the ancestrality of these permuted genes, I suggest that the root of the Eukarya domain is in the super-ensemble of the Plantae and that the Rhodophyta to which C. merolae belongs are the first line of divergence.     

The non-monophyletic origin of the tRNA molecule and the origin of genes only after the evolutionary stage of the last universal common ancestor (LUCA)

A model has been proposed suggesting that the tRNA molecule must have originated by direct duplication of an RNA hairpin structure [Di Giulio, M., 1992. On the origin of the transfer RNA molecule. J. Theor. Biol. 159, 199-214]. A non-monophyletic origin of this molecule has also been theorized [Di Giulio, M., 1999. The non-monophyletic origin of tRNA molecule. J. Theor. Biol. 197, 403-414]. In other words, the tRNA genes evolved only after the evolutionary stage of the last universal common ancestor (LUCA) through the assembly of two minigenes codifying for different RNA hairpin structures, which is what the exon theory of genes suggests when it is applied to the model of tRNA origin. Recent observations strongly corroborate this theorization because it has been found that some tRNA genes are completely separate in two minigenes codifying for the 5' and 3' halves of this molecule [Randau, L., et al., 2005a. Nanoarchaeum equitans creates functional tRNAs from separate genes for their 5'- and 3'-halves. Nature 433, 537-541]. In this paper it is shown that these tRNA genes codifying for the 5' and 3' halves of this molecule are the ancestral form from which the tRNA genes continuously codifying for the complete tRNA molecule are thought to have evolved. This, together with the very existence of completely separate tRNA genes codifying for their 5' and 3' halves, proves a non-monophyletic origin for tRNA genes, as a monophyletic origin would exclude the existence of these genes which have, on the contrary, been observed. Here the polyphyletic origin of genes codifying for proteins is also suggested and discussed. Moreover, a hypothesis is advanced to suggest that the LUCA might have had a fragmented genome made up of RNA and the possibility that 'Paleokaryotes' may exist is outlined. Finally, the characteristic of the indivisibility of homology that these polyphyletic origins seem to remove at the sequence level is discussed.     

Ancestral organization of the MHC revealed in the amphibian Xenopus

With the advent of the Xenopus tropicalis genome project, we analyzed scaffolds containing MHC genes. On eight scaffolds encompassing 3.65 Mbp, 122 MHC genes were found of which 110 genes were annotated. Expressed sequence tag database screening showed that most of these genes are expressed. In the extended class II and class III regions the genomic organization, excluding several block inversions, is remarkably similar to that of the human MHC. Genes in the human extended class I region are also well conserved in Xenopus, excluding the class I genes themselves. As expected from previous work on the Xenopus MHC, the single classical class I gene is tightly linked to immunoproteasome and transporter genes, defining the true class I region, present in all nonmammalian jawed vertebrates studied to date. Surprisingly, the immunoproteasome gene PSMB10 is found in the class III region rather than in the class I region, likely reflecting the ancestral condition. Xenopus DMalpha, DMbeta, and C2 genes were identified, which are not present or not clearly identifiable in the genomes of any teleosts. Of great interest are novel V-type Ig superfamily (Igsf) genes in the class III region, some of which have inhibitory motifs (ITIM) in their cytoplasmic domains. Our analysis indicates that the vertebrate MHC experienced a vigorous rearrangement in the bony fish and bird lineages, and a translocation and expansion of the class I genes in the mammalian lineage. Thus, the amphibian MHC is the most evolutionary conserved MHC so far analyzed.     

Highly expressed and alien genes of the Synechocystis genome

Comparisons of codon frequencies of genes to several gene classes are used to characterize highly expressed and alien genes on the SYNECHOCYSTIS: PCC6803 genome. The primary gene classes include the ensemble of all genes (average gene), ribosomal protein (RP) genes, translation processing factors (TF) and genes encoding chaperone/degradation proteins (CH). A gene is predicted highly expressed (PHX) if its codon usage is close to that of the RP/TF/CH standards but strongly deviant from the average gene. Putative alien (PA) genes are those for which codon usage is significantly different from all four classes of gene standards. In SYNECHOCYSTIS:, 380 genes were identified as PHX. The genes with the highest predicted expression levels include many that encode proteins vital for photosynthesis. Nearly all of the genes of the RP/TF/CH gene classes are PHX. The principal glycolysis enzymes, which may also function in CO(2) fixation, are PHX, while none of the genes encoding TCA cycle enzymes are PHX. The PA genes are mostly of unknown function or encode transposases. Several PA genes encode polypeptides that function in lipopolysaccharide biosynthesis. Both PHX and PA genes often form significant clusters (operons). The proteins encoded by PHX and PA genes are described with respect to functional classifications, their organization in the genome and their stoichiometry in multi-subunit complexes.     

Genetic transformation of animals by the insertion of foreign genes into the zygotes

A review of literature on genetic transformation of animal (mouse and Drosophila) germ cells by microinjection of the cloned genes into the pronuclei or into the early embryos. The fate of foreign genes and mechanisms of their integration into the recipient genome are considered in detail, as well as genetic consequences of the exogenic DNA insertion. Expression of the donor genes in transgenic animals is analyzed, its irregular and unusual pattern is noted in transgenic mice. An attempt has been undertaken not only to stress obvious advances in genetic transformation of animals, but also to outline unsolved problems related to inheritance of exogenous genes, insertion mutagenesis and irregular expression of the donor genes.     

On the role of periodism in the origin of proteins

Two different views have been proposed for origins of genes (or proteins). One is that primordial genes evolved from random sequences. This view underlies the concept of modern in vitro evolution experiments that functional molecules (even proteins) evolved from random sequence-libraries. On the contrary, the second view reminds that "random sequences" would be an unusual state in which to find RNA or DNA, because it is their inherent nature to yield periodic structures during the course of semi-conservative replication. In this second view, the periodicity of DNA (or RNA) is responsible for emergence of primordial genes. Although recent reports on the variety of periodicities present in proteins, genes and genomes are consistent with the second view, it has yet to be experimentally tested. We assessed the significance of periodicities of DNA in the origin of genes by constructing such periodic DNAs. The results showed that periodic DNA produced ordered proteins at very high rates, which is in contrast to the fact that proteins with random sequences lack secondary structures. We concluded that periodicity played a pivotal role in the origin of many genes. The observation should pave the way for new experimental evolution systems for proteins.