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PubMed1975

Evolution and modes of transmission of RNA tumor viruses. Parke-Davis Award lecture.

Most vertebrates contain sets of gene sequences (virogenes) which are an integral part of the chromosomal DNA and which can code, in some instances, for the production of Type C RNA tumor viruses. These genes are transmitted from parent to progeny along with other cellular genes, and their activation from a normally reressed state may be part of the mechanism by which RNA tumor viruses produce cancer. Isolates of endogenous genetically transmitted baboon Type C viruses are morphologically and biochemically related to other mammalian Type C viruses but can clearly be distinguished from the other groups (mouse, rat, cat, etc.) by immunologic and nucleic acid hybridization criteria. Within the primates, Type C viral gene sequences have evolved as the species have evolved, with virogenes from the most closely related genera and families showing the most sequence homology; all higher primate, including man, however, do have detectable virogene sequences in their normal tissues. Type C viruses have also been transferred under natural conditions between species only remotely related phylogenetically. The results show three clear examples where viral genes from one group of animals have become incorporated into the germ line of genetically distant groups of animals (inheritance of acquired genes). Infectious Type C viruses of primates, distinct from the endogenous primate virus group, have also been isolated (woolly monkey and gibbon isolates) and can be shown to produce tumors in other primates. Related viral information (nucleic acid sequences, enzymes, and antigens) have been reported in human tumors. The significance of infectious and/or genetically transmitted viruses in naturally occurring cancer is a major focus of current research. The presence of genetically transmitted viral genes in so many vertebrate species and the evidence that they have been conserved in several distinct vertebrate lineages suggests that they may provide some normal function(s) advantageous to the species carrying them and that their potential to cause cancers is a pathologic manifestation of normal, as yet undefined, physiologic processes.

Animals↗
PubMed2001

Identification of five new genes on the Y chromosome of Drosophila melanogaster.

The heterochromatic state of the Drosophila Y chromosome has made the cloning and identification of Y-linked genes a challenging process. Here, we report application of a procedure to identify Y-linked gene fragments from the unmapped residue of the whole genome sequencing effort. Previously identified Y-linked genes appear in sequenced scaffolds as individual exons, apparently because many introns have become heterochromatic, growing to enormous size and becoming virtually unclonable. A TBLASTN search using all known proteins as query sequences, tested against a blastable database of the unmapped fragments, produced a number of matches consistent with this scenario. Reverse transcription-PCR and genetic methods were used to confirm those that are expressed, Y-linked genes. The five genes reported here include three protein phosphatases (Pp1-Y1, Pp1-Y2, and PPr-Y), an occludin-related gene (ORY), and a coiled-coils gene (CCY). This brings the total to nine protein-coding genes identified on the Drosophila Y chromosome. ORY and CCY may correspond, respectively, to the fertility factors ks-1 and ks-2, whereas the three protein phosphatases represent novel genes. There remains a strong functional coherence to male function among the genes on the Drosophila Y chromosome.

Animals↗
PubMed1994

Influence of the V(D)J recombination mechanism on the formation of the primary T and B cell repertoires.

T and B cells exploit the mechanism of V(D)J recombination to make diverse or very restricted repertoires at varying times during ontogeny. Fetal repertoires are limited since there are no N nucleotides. Also, if short sequence homologies are present near the coding ends, junctions are preferentially made at that site. For gamma delta TCR, and to a lesser extent for Ig, this results in a very homogeneous population of junctions early in ontogeny. alpha beta TCR, however, have a paucity of homologous stretches, and maintain junctional diversity in the newborn. In both newborns and adults, some coding ends show very restricted nucleotide deletion, while others show heterogeneous and extensive deletion. It appears that the sequences of the coding ends have been selected through evolution as a mechanism to control repertoire formation.

Animals↗
PubMed1996

Identification of a partition and replication region in the Alcaligenes eutrophus megaplasmid pMOL28.

A 4.64 kb region of the 180 kb heavy metal resistance plasmid pMOL28 of Alcaligenes eutrophus CH34, previously shown to be able to replicate autonomously, was sequenced and analyzed. Three genes involved in plasmid maintenance were identified: parA28 and parB28 are involved in plasmid partitioning and stability, while repA28 encodes a protein required for replication. In addition to the par AB28 genes, a third locus, parS28, required in cis active partitioning was identified. The parABS28 locus of pMOL28 shows strong similarity in organization to the sop, par and rep regions, respectively, of the Escherichia coli F-factor, the E.coli P1 and P7 prophages and the Agrobacterium pTiB6S3 and pRiA4b plasmids. The ParAB28 proteins of pMOL28 also show similarity to the proteins encoded by two conserved open reading frames present in the replication regions of the Pseudomonas putida and Bacillus subtilis chromosomes. The functionality of the pMOL28 par region was examined by performing stability and incompatibility tests between pMOL28 and pMOL846 or pMOL850 which contain the 4.64 EcoRI replicon fragment of pMOL28, cloned in opposite orientations into pSUP202, which is itself unable to replicate in A. eutrophus. The RepA2 8 replication protein showed similarity to the RepL protein of P1, which is required for lytic replication of this E. coli phage. The replication origin of pMOL28, oriV28, seems to be located within the repA28 coding region, and pMOL28 replication may depend on transcriptional activation of oriV28.

Alcaligenes↗
PubMed1988

An ancient provirus has imposed androgen regulation on the adjacent mouse sex-limited protein gene.

The mouse sex-limited protein (Slp) gene is dependent on androgen for expression, unlike its homologous neighbor, which encodes the fourth component of complement (C4). We have found that the extensive identity of Slp and C4 is disrupted by an endogenous provirus inserted 2 kb upstream of Slp. The 5' LTR of this element corresponds to the previously characterized hormone-responsive enhancer associated with Slp regulation, leading to the conclusion that the provirus has conferred androgen response on the adjacent Slp gene. The provirus is extremely old, based on LTR sequence divergence, the accumulation of mutations in former retroviral-like coding regions, and its stability within the mouse genome. The association of this transposable element with Slp regulation thus provides a long-sought example of an insertional mutation that has been maintained in evolution.

Androgens↗
PubMed1995

The diversity of alleles at the hsd locus in natural populations of Escherichia coli.

In enteric bacteria three discrete families of type I restriction and modification systems (IA, IB and ID) are encoded by alleles of the serB-linked hsd locus. Probes specific for each of the three families were used to monitor the distribution of related systems in 37 of the 72 wild-type Escherichia coli strains comprising the ECOR collection. All 25 members of group A in this collection were screened; 12 were probe-positive, nine have hsd genes in the IA family, two in the IB and one in the ID. Twelve strains, representing all groups other than A, were screened; five were probe-positive, one has hsd genes in the IA family, one in the IB and three in the ID. The type ID genes are the first representatives of this family in E. coli, the probe-negative strains could have alternative families of hsd genes. The type IA and IB systems added at least five new specificities to the five already identified in natural isolates of E. coli. The distribution of alleles is inconsistent with the dendrogram of the bacterial strains derived from other criteria. This discrepancy and the dissimilar coding sequences of allelic hsd genes both imply lateral transfer of hsd genes.

Alleles↗
PubMed2004

Properties of gray and binary representations.

Representations are formalized as encodings that map the search space to the vertex set of a graph. We define the notion of bit equivalent encodings and show that for such encodings the corresponding Walsh coefficients are also conserved. We focus on Gray codes as particular types of encoding and present a review of properties related to the use of Gray codes. Gray codes are widely used in conjunction with genetic algorithms and bit-climbing algorithms for parameter optimization problems. We present new convergence proofs for a special class of unimodal functions; the proofs show that a steepest ascent bit climber using any reflected Gray code representation reaches the global optimum in a number of steps that is linear with respect to the encoding size. There are in fact many different Gray codes. Shifting is defined as a mechanism for dynamically switching from one Gray code representation to another in order to escape local optima. Theoretical results that substantially improve our understanding of the Gray codes and the shifting mechanism are presented. New proofs also shed light on the number of unique Gray code neighborhoods accessible via shifting and on how neighborhood structure changes during shifting. We show that shifting can improve the performance of both a local search algorithm as well as one of the best genetic algorithms currently available.

Algorithms↗
PubMed2004

The four Rs of RNA-directed evolution.

The way we quantify the human genome has changed markedly. The estimated percentage of the genome derived from retrotransposition has increased (now 45%; refs. 1,2), as have the estimates for alternative splicing (now 41-60% of multiexon genes), antisense transcription (now 10-20% of genes) and non-protein coding RNA (now approximately 7% of full-length cDNAs). Concomitantly, the estimated number of protein-coding genes (now approximately 24,500) has decreased. These numbers support an RNA-centric view of evolution in which phenotypic diversity arises through extensive RNA processing and widespread RNA-directed rewriting of DNA enables dissemination of 'selfish' RNAs associated with successful outcomes. The numbers also indicate important roles for sense-antisense transcription units (SATs) and coregulatory RNAs (coRNAs) in directing the read-out of genetic information, in reconciling different regulatory inputs and in transmitting epigenetic information to progeny. Together, the actions of reading, 'riting, 'rithmetic and replication constitute the four Rs of RNA-directed evolution.

Animals↗
PubMed2005

Analysis of intronic conserved elements indicates that functional complexity might represent a major source of negative selection on non-coding sequences.

The non-coding portion of human genome is punctuated by a large number of multispecies conserved sequence (MCS) elements with largely unknown function. We demonstrate that MCSs are unevenly distributed in human introns with the majority of relatively short introns (< 9 kb long) displaying no or a few MCSs and that MCS density reaching up to 10% of total size in longer introns. After correction for intron length, MCSs were found to be enriched within genes involved in development and transcription, whereas depleted in immune response loci. Moreover, many central nervous system tissues show a preferential expression of MCS-rich genes and MCS enrichment significantly correlates with gene functional complexity in terms of distinct protein domains. Analysis of human-mouse orthologous pairs indicated a significant association between intronic MCS density and conservation of protein sequence, promoter regions and untranslated sequences. Moreover, MCS density correlates with the predicted occurrence of human-mouse conserved alternative splicing events. These observations suggest that evolution acts on human genes as integrated units of coding and regulatory capacity and that functional complexity might represent a major source of negative selection on non-coding sequences. To substantiate our result, we also searched previously experimentally identified intronic regulatory elements and indicate that about half of these sequences map to an MCS; in particular, support to the notion whereby mutations in MCSs can result in human genetic diseases is provided, because three previously identified intronic pathological variations were found to occur within MCSs, and human disease and cancer genes were found significantly enriched in MCSs.

Animals↗
PubMed1996

Simple sequences and the expanding genome.

Recent analysis of the contribution of replication slippage to genome evolution shows that it has played a significant role in all species from eubacteria to humans. The overall level of repetition in genomes is related to genome size and to the degree of repetition that can be measured within individual ribosomal RNA genes, suggesting that the entire genome accepts simple sequences in a concerted manner when its size increases. Although coding sequences accept simple sequences much less readily than non-coding sequences, they accept some repeats, particularly (CAG)n, preferentially. This may have consequences for the evolution of the genes involved in trinucleotide expansion diseases and the transcriptional networks of which they may form a part.

Animals↗
PubMed2001

A test of amino acid reversibility.

In studies of molecular evolution, the assumption that protein evolution is reversible has often been made, but rarely tested. Here we use a large set of orthologous murid protein coding sequences to perform a simple test of reversibility, and find no evidence to reject the assumption of reversibility in protein evolution.

Amino Acid Substitution↗
PubMed2003

Functional constraints and frequency of deleterious mutations in noncoding DNA of rodents.

Selection against deleterious mutations imposes a mutation load on populations because individuals die or fail to reproduce. In vertebrates, estimates of genomic rates of deleterious mutations in protein-coding genes imply the existence of a substantial mutation load, but many functionally important regions of the genome are thought to reside in noncoding DNA, and the contribution of noncoding DNA to the mutation load has been unresolved. Here, we infer the frequency of deleterious mutations in noncoding DNA of rodents by comparing rates of substitution at noncoding nucleotides with rates of substitution at the fastest evolving intronic sites of adjacent genes sampled from the whole genome sequences of mouse and rat. We show that the major elements of selectively constrained noncoding DNA are within 2,500 bp upstream and downstream of coding sequences and in first introns. Our estimate of the genomic deleterious point mutation rate for noncoding DNA (0.22 per diploid per generation) is similar to that for coding DNA. Mammalian populations therefore experience a substantial genetic load associated with selection against deleterious mutations in noncoding DNA. Deleterious mutations in noncoding DNA have predominantly quantitative effects and could be an important source of the burden of complex genetic disease variation in human populations.

Animals↗
PubMed2006

Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders.

Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1.

Child, Preschool↗
PubMed2002

Evidence of gene conversion events between paralogous sequences produced by tetraploidization in Salmoninae fish.

We investigated the occurrence of gene conversions between paralogous sequences of Salmoninae derived from ancestral tetraploidization and their effect on the evolutionary history of DNA sequences. A microsatellite with long flanking regions (750 bp) including both coding and noncoding sequences was analyzed. Microsatellite size polymorphism was used to detect the alleles of both paralogous counterparts and infer linkage arrangement between loci. DNA sequencing of seven Salmoninae species revealed that paralogous sequences were highly differentiated within species, especially for noncoding regions. Ten gene conversion events between paralogous sequences were inferred. While these events appears to have homogenized regions of otherwise highly differential paralogous sequences, they amplified the differentiation among orthologous sequences. Their effects were larger on coding than on noncoding regions. As a consequence, noncoding sequences grouped by orthologous lineages in phylogenetic trees, whereas coding regions grouped by taxa. Based upon these results, we present a model showing how gene conversion events may also result in the PCR amplification of nonorthologous sequences in different taxa, with obvious complications for phylogenetic inferences, comparative mapping, and population genetic studies.

Animals↗
PubMed1992

Dissecting (CAC)5/(GTG)5 multilocus fingerprints from man into individual locus-specific, hypervariable components.

Individual components of multilocus fingerprints from man produced by (CAC)5/(GTG)5 oligonucleotides have been scrutinized to characterize their peculiar properties. Successful cloning and changes occurring during the propagation of recombinant simple repetitive DNA in prokaryotic hosts are described. The isolated locus-specific probes were characterized with respect to their formal (and population genetic) properties and their usefulness for individualization and linkage studies. The localization was determined on chromosomes 8, 9, 11, and 22. Repeat flanking sequences were characterized and analyzed for their coding potential because of significant open reading frames and apparent evolutionary conservation among vertebrates. The organization of the repeats and their flanking regions in the human genome is discussed with respect to the sequence (fine) architecture that developed during evolution. Classical "minisatellite" sequences were not detected near hypervariable (cac)n/(gtg)n repeats. The single-copy probes described herein are a convenient complement to the oligonucleotides employed for multilocus fingerprinting. Many practical applications are apparent.

Base Sequence↗
PubMed2001

Degeneracy and complexity in biological systems.

Degeneracy, the ability of elements that are structurally different to perform the same function or yield the same output, is a well known characteristic of the genetic code and immune systems. Here, we point out that degeneracy is a ubiquitous biological property and argue that it is a feature of complexity at genetic, cellular, system, and population levels. Furthermore, it is both necessary for, and an inevitable outcome of, natural selection.

Animals↗
PubMed1997

Schizophrenia and autism considered as the products of an agnosic right shift gene.

Crow (1995a) has argued that schizophrenia is caused by a gene associated with the evolution of human language and cerebral specialisation. This paper suggests a mechanism for Crow's theory which requires only one new assumption for the right shift genetic model of handedness and cerebral dominance (Annett, 1978). The proposal is that the RS+ allele, whose normal function is to induce the left hemisphere to serve speech by impairing speech-related cortex in the right hemisphere, tends to lose its directional coding. It becomes agnosic (RS+ a) for right versus left and impairs the left or right hemisphere at random. Schizophrenia is likely to develop when the RS+ a gene is paired with a normal RS+ gene but only in the 50% of cases where both hemispheres are affected. In the 50% where RS+ a affects the right hemisphere, development is normal as in the RS+ RS+ genotype. The risks for schizophrenia in monozygotic and dizygotic twins and other relatives are as expected for 50% expression of a Mendelian gene which is paired with a particular allele, but not alternative alleles at the same locus. The frequency of homozygotes for the agnosic gene is about 4 in 10,000, the rate observed for autism. A random pattern of double hemisphere deficits would give scope for a range of developmental strengths and weaknesses as observed within the spectrum of autistic disorders. Tests of the model require brain-imaging studies sensitive to individual differences in hemisphere lateralisation and a search for a genetic locus with human and nonhuman primate alleles, together with a mutant of the human form with a frequency of about 2%.

Journal Article↗