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PubMed1997

Will genetics really revolutionize the drug discovery process?

Genetics has played only a modest role in drug discovery, but new technologies will radically change this. Whole genome sequencing will identify new drug discovery targets, and emerging methods for the determination of gene function will increase the ability to select robust targets. Detection of single nucleotide polymorphisms and common polymorphisms will enhance the investigation of polygenic diseases and the use of genetics in drug development. Oligonucleotide arraying technologies will allow analysis of gene expression patterns in novel ways.

Drug Design↗
PubMed2000

Evolutionary lineages of RT1.Ba in the Australian Rattus.

In this study, the evolutionary history of the variable second exon of RT1.Ba and its adjoining intron b are compared across a number of species and subspecies of the Australian RATTUS: Three lineages are identified in the second intron across a range of Rattus species. Two of these lineages, separated by the insertion of a probable rodent short interspersed nucleotide element and by point mutations outside the indel region, are both found in each of the major clades of the endemic Australian RATTUS: This pattern of ancestral polymorphism is reflected in the adjoining exon 2 sequences, although phylogenetic constraints confirm that the clustering is not identical to that of the associated intron sequences. In addition, the coding sequences show evidence of the retention of ancestral polymorphism, with identical exon sequences found in two divergent species, and some indication of gene conversion detected for the exon sequences.

Amino Acid Sequence↗
PubMedDate not supplied

Sequence polymorphism of the Salmonella plasmid virulence factor D (SpvD) in Salmonella enterica isolates of animal origin.

The nucleotide sequence encoding the Salmonella plasmid virulence factor D (SpvD) was determined in 17 Salmonella strains that were different in O and H antigen patterns, animal host and geographical origin, and year of isolation. Nucleotide sequence comparison revealed the existence of at least nine spvD alleles resulting in 8 SpvD protein variants although the nucleotide sequences were highly similar (identity 98.8-100%). The spvD gene products differed from each other in up to 4 amino acid residues only with the exception of the carboxy-terminally truncated SpvD variant of one S. Gallinarum field isolate. The highly conserved primary structure of SpvD in epidemiologically relevant salmonellae suggests that this virulence factor is a promising antigen candidate for diagnostic purposes (i.e. antibody detection in infected animals) but also for immunoprophylaxis in farm animal species.

ADP Ribose Transferases↗
PubMed2000

Nucleotide polymorphism at the RpII215 gene in Drosophila subobscura. Weak selection on synonymous mutations.

Nucleotide variation in an 8.1-kb fragment encompassing the RpII215 gene, which encodes the largest subunit of the RNA polymerase II complex, is analyzed in a sample of 11 chromosomes from a natural population of Drosophila subobscura. No amino acid polymorphism was detected among the 157 segregating sites. The observed numbers of preferred and unpreferred derived synonymous mutations can be explained by neutral mutational processes. In contrast, preferred mutations segregate at significantly higher frequency than unpreferred mutations, suggesting the action of natural selection. The polymorphism to divergence ratio is different for preferred and unpreferred changes, in agreement with their beneficial and deleterious effects on fitness, respectively. Preferred and unpreferred codons are nonrandomly distributed in the RpII215 gene, leading to a heterogeneous distribution of polymorphic to fixed synonymous differences across this coding region. This intragenic variation of the polymorphism/divergence ratio cannot be explained by different patterns of gene expression, mutation, or recombination rates, and therefore it indicates that selection coefficients for synonymous mutations can vary extensively across a coding region. The application of nucleotide composition stationarity tests in coding and flanking noncoding regions, assumed to behave neutrally, allows the detection of the action of natural selection when stationarity holds in the noncoding region.

Animals↗
PubMed2005

Signatures of reproductive isolation in patterns of single nucleotide diversity across inbred strains of mice.

Reproductive isolation is often caused by the disruption of genic interactions that evolve in geographically separate populations. Identifying the genomic regions and genes involved in these interactions, known as "Dobzhansky-Muller incompatibilities," can be challenging but is facilitated by the wealth of genetic markers now available in model systems. In recent years, the complete genome sequence and thousands of single nucleotide polymorphisms (SNPs) from laboratory mice, which are largely genetic hybrids between Mus musculus and M. domesticus, have become available. Here, we use these resources to locate genomic regions that may underlie reproductive isolation between these two species. Using genotypes from 332 SNPs that differ between wild-derived strains of M. musculus and M. domesticus, we identified several physically unlinked SNP pairs that show exceptional gametic disequilibrium across the lab strains. Conspecific alleles were associated in a disproportionate number of these cases, consistent with the action of natural selection against hybrid gene combinations. As predicted by the Dobzhansky-Muller model, this bias was differentially attributable to locus pairs for which one hybrid genotype was missing. We assembled a list of potential Dobzhansky-Muller incompatibilities from locus pairs that showed extreme associations (only three gametic types) among conspecific alleles. Two SNPs in this list map near known hybrid sterility loci on chromosome 17 and the X chromosome, allowing us to nominate partners for disrupted interactions involving these genomic regions for the first time. Together, these results indicate that patterns produced by speciation between M. musculus and M. domesticus are visible in the genomes of lab strains of mice, underscoring the potential of these genetic model organisms for addressing general questions in evolutionary biology.

Animals↗
PubMed2002

16S-23S rDNA intergenic spacer region polymorphism of Lactococcus garvieae, Lactococcus raffinolactis and Lactococcus lactis as revealed by PCR and nucleotide sequence analysis.

The intergenic spacer region (ISR) between the 16S and 23S rRNA genes was tested as a tool for differentiating lactococci commonly isolated in a dairy environment. 17 reference strains, representing 11 different species belonging to the genera Lactococcus, Streptococcus, Lactobacillus, Enterococcus and Leuconostoc, and 127 wild streptococcal strains isolated during the whole fermentation process of "Fior di Latte" cheese were analyzed. After 16S-23S rDNA ISR amplification by PCR, species or genus-specific patterns were obtained for most of the reference strains tested. Moreover, results obtained after nucleotide analysis show that the 16S-23S rDNA ISR sequences vary greatly, in size and sequence, among Lactococcus garvieae, Lactococcus raffinolactis, Lactococcus lactis as well as other streptococci from dairy environments. Because of the high degree of inter-specific polymorphism observed, 16S-23S rDNA ISR can be considered a good potential target for selecting species-specific molecular assays, such as PCR primer or probes, for a rapid and extremely reliable differentiation of dairy lactococcal isolates.

Base Sequence↗
PubMed1997

[Differentiation of mumps virus strains by polymerase chain reaction and silver stained single-strand conformation polymorphism analysis].

The cDNA fragments amplified through nested RT-PCR from the small hydrophobic (SH) protein gene and its flanking region of the five wild mumps viruses and Enders strain were subjected to single-strand conformation polymorphism (SSCP) analysis by using silver staining. These five wild isolates could be divided into three SSCP patterns and they were differentiated from the Enders strain. Two wild strains which have 3.4% heterology of the nucleotide acid sequence could be distinguished by the method. The results were well correlated with sequence analysis of the SH gene segments, indicating high applicability of the silver staining SSCP analysis for differentiation of mumps virus strains. Furthermore, the method, which is not only quick, sensitive, safe and reliable, but also reproducible and inexpensive, can be used in the molecular epidemiology study of mumps viruses.

Base Sequence↗
PubMed1995

Dynamics of Mhc evolution in birds and crocodilians: amplification of class II genes with degenerate primers.

Genes of the major histocompatibility complex (Mhc) are the most polymorphic functional loci in mammalian populations, but little is known of Mhc variability in natural populations of nonmammalian vertebrates. To help extend such studies to birds and relatives, we present a pair of degenerate primers that amplify polymorphic segments of one chain (the beta chain) of the class II genes from the major histocompatibility complex (Mhc) of archosaurs (birds+crocodilians). The primers target two conserved regions lying within portions of the antigen-binding site (ABS) encoded by the second exon and amplify multiple genes from both genomic DNA and cDNA. The pattern of nucleotide substitution in ABS codons of 51 sequences amplified and cloned from five species of passerine birds and an alligator (Alligator mississippiensis) indicates that archosaurian class II beta genes are subject to selective forces similar to those operating in mammalian populations. Hybridization of a genomic clone generated by the primers revealed highly polymorphic bands in a sample of Florida scrub jays (Aphelocoma coerulescens coerulescens). Because the primers amplify only part of the ABS from multiple class II genes, they will be useful primarily for generating species specific clones, thereby providing a critical inroad to more detailed structural and evolutionary studies.

Alligators and Crocodiles↗
PubMed2000

Adaptive evolution of a candidate gene for aging in Drosophila.

Examination of the phenotypic effects of specific mutations has been extensively used to identify candidate genes affecting traits of interest. However, such analyses do not reveal anything about the evolutionary forces acting at these loci, or whether standing allelic variation contributes to phenotypic variance in natural populations. The Drosophila gene methuselah (mth) has been proposed as having major effects on organismal stress response and longevity phenotype. Here, we examine patterns of polymorphism and divergence at mth in population level samples of Drosophila melanogaster, D. simulans, and D. yakuba. Mth has experienced an unusually high level of adaptive amino acid divergence concentrated in the intra- and extracellular loop domains of the receptor protein, suggesting the historical action of positive selection on those regions of the molecule that modulate signal transduction. Further analysis of single nucleotide polymorphisms (SNPs) in D. melanogaster provided evidence for contemporary and spatially variable selection at the mth locus. In ten surveyed populations, the most common mth haplotype exhibited a 40% cline in frequency that coincided with population level differences in multiple life-history traits including lifespan. This clinal pattern was not associated with any particular SNP in the coding region, indicating that selection is operating at a closely linked site that may be involved in gene expression. Together, these consistently nonneutral patterns of inter- and intraspecific variation suggest adaptive evolution of a signal transduction pathway that may modulate lifespan in nature.

Adaptation, Biological↗
PubMed2006

Indirect exclusion of four candidate genes for generalized progressive retinal atrophy in several breeds of dogs.

BACKGROUND: Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina (ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs. RESULTS: Mutation screening was performed initially by PCR and single strand conformation polymorphism (SSCP) analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4, CX36, MERTK and RDH12 in 71 affected dogs of 29 breeds. Yet 30 new sequence variations were identified, both, in the coding regions and intronic sequences. Many of the sequence variations were in heterozygous state in affected dogs. CONCLUSION: Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK (for all 29 breeds) and RDH12 (for 9 breeds).

ATP-Binding Cassette Transporters↗
PubMed2005

Evolution and trans-species polymorphism of MHC class IIbeta genes in cyprinid fish.

The polymorphism of DAB genes encoding MHC IIbeta was investigated in 11 cyprinid species from central Europe. The species belonged to four subfamilies: Cyprininae, Tincinae, Gobioninae and Leuciscinae. Two paralogous groups of sequences, DAB1 and DAB3, were recognised according to the similarity of their nucleotide and amino-acid sequences and from phylogenetic analyses using either partial exon 2 or partial exon 3 sequences. A high allelic variability among species was found for exon 2, indicating extensive MHC polymorphism. Time divergence estimation supports the separation of DAB1 and DAB3 groups predating the separation into fish subfamilies, and a cyprinid origin of the DAB genes. Phylogenetic trees using exon 2 support the hypothesis of trans-species polymorphism, which appears to be limited to the subfamily level, i.e. the presence of sequences from different species in the same allelic group was more often recognised within subfamilies Cyprininae and Leuciscinae than between them. Phylogenetic trees using exon 3 reflect the phylogenetic patterns previously found for Cyprinidae systematics. Specific nucleotides and amino-acids in exon 3 that separate both subfamilies, as well as the species within the Cyprininae subfamily were observed. A lack of segregation in leuciscin species was recognised and the alleles of different leuciscin species tend to share similar motifs in exon 3. This could be explained by the ancient and complicated dispersion history of Cyprininae and the radiation of Leuciscinae. The effects of selective pressures were investigated: (1) within species, (2) among lineages, and (3) among sites. From intraspecific analyses, exon 2 sequences were identified as the targets of diversifying selection, whilst the evolution of exon 3 seems to be under the influence of purifying selection. The analyses among lineages indicate positive selection in many branches when using exon 2, therefore confirming trans-species polymorphism, whilst the DAB lineages of exon 3 are potentially submitted to purifying selection to some extent. Moreover, our results suggest the secondary acquisition of function of DAB1 group after duplication. The analyses among sites reveal that exon 2 exhibits sites under positive selection mostly corresponding to the putative PBR sites involved in the alpha-helix structure of the protein.

Animals↗
PubMed2002

Distinct patterns of chromosomal losses in clinically synchronous and asynchronous bilateral renal cell carcinoma.

PURPOSE: Bilateral renal cell carcinoma has been reported to occur in 1% to 4% of patients with renal cancer. However, whether bilateral renal cell carcinoma involves metastatic lesions of the contralateral kidney or develops as simultaneous primary tumors remains unclear to date. Thus, we investigated chromosomal losses and von Hippel-Lindau (VHL) gene abnormalities in bilateral tumors from patients with nonfamilial bilateral renal cell carcinoma. MATERIALS AND METHODS: Genomic DNA was exacted from 2 tumors in 8 patients each with nonfamilial bilateral renal cell carcinoma, including clinically asynchronous and synchronous disease in 5 and 3, respectively. The DNA was then subjected to microsatellite analysis on 13 chromosomal loci. In addition, polymerase chain reaction-single nucleotide specific conformation polymorphism analysis and direct sequencing of 3 exons of the VHL gene were performed. RESULTS: All 5 asynchronous cases showed loss of the same allele in bilateral tumors, indicating a common clonal origin. In contrast, 2 of the 3 synchronous cases showed different patterns of chromosomal loss in the right and left renal tumors, suggesting bilateral primary origins. The other synchronous case with loss of the same allele in each tumor involved right stage T3b and left stage T1a neoplasms. No VHL gene mutations were detected in any case. CONCLUSIONS: Except for a small number of cases synchronous and asynchronous bilateral renal cell carcinoma may represent the simultaneous appearance of separate primary tumors and metastatic progression from the contralateral kidney, respectively.

Adult↗
PubMed2002

Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease.

Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominantly in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.

Animals↗
PubMed1999

Mitochondrial genetic variation in Chinese pigs and wild boars.

The mitochondrial DNAs (mtDNAs) from 30 pig breeds (29 Chinese native breeds and 1 European breed) and wild boars were investigated for restriction fragment length polymorphisms (RFLPs) to determine the phylogenetic relationships and genetic diversity among pig breeds and wild boars. Of the 24 enzymes used, 8 (AvaI, BclI, BglII, EcoRI, EcoRV, ScaI, StuI, and XbaI) detected polymorphisms. By combining the cleavage patterns for each enzyme, 108 individuals were sorted into eight mtDNA mitotypes. There are two haplotype lineages in domestic pigs, i.e., Chinese and European lineages. The pairwise nucleotide sequence divergence was calculated to be 0.56% between Chinese pigs and European pigs, suggesting that they might have diverged from a common ancestor approximately 280,000 years ago. The wild boars showed more extensive genetic variation, four mitotypes were detected in six wild boars. In addition, one of the Zhejiang wild boars was found to share the same mitotype with Chinese native pigs. A UPGMA tree based on genetic distance among mitotypes indicated that mtDNAs of Chinese pigs and European pigs are clearly divided into two clusters, and Chinese wild boars are more closely related to the Chinese pigs. Our results provide molecular evidence to support the previous hypothesis that pigs may be derived from two maternal origins, Asian and European wild boars. Chinese native pig breeds may have a single origin.

Animals↗
PubMed2006

Testing for effects of recombination rate on nucleotide diversity in natural populations of Arabidopsis lyrata.

We investigated DNA sequence diversity for loci on chromosomes 1 and 2 in six natural populations of Arabidopsis lyrata and tested for the role of natural selection in structuring genomewide patterns of variability, specifically examining the effects of recombination rate on levels of silent polymorphism. In contrast with theoretical predictions from models of genetic hitchhiking, maximum-likelihood-based analyses of diversity and divergence do not suggest reduction of diversity in the region of suppressed recombination near the centromere of chromosome 1, except in a single population from Russia, in which the pericentromeric region may have undergone a local selective sweep or demographic process that reduced variability. We discuss various possibilities that might explain why nucleotide diversity in most A. lyrata populations is not related to recombination rate, including genic recombination hotspots, and low gene density in the low recombination rate region.

Arabidopsis↗
PubMed2003

[Coding single nucleotide polymorphism is an ideal marker for detecting gene imprinting by 5' nuclease assay].

OBJECTIVE: To establish a novel approach for quick and high throughput verification of human gene imprinting. METHODS: By use of a pair of dye-labeled probes, 5' nuclease assay was combined with reverse transcriptase-PCR(RT-PCR) to genotype a coding single nucleotide polymorphism (cSNP), rs705(C/T) of a known imprinted gene, small nuclear ribonucleotide protein N (SNRPN), on both genomic DNA and cDNA of human lymphoblast cell lines. RESULTS: Allele discrimination showed a clear monoallelic expression pattern of SNRPN, which was confirmed by RT-PCR based restriction fragment length polymorphisms. Pedigree analysis verified the paternal origin of expressed allele, which is in consistency with previous report. CONCLUSION: Coding SNP is an ideal marker for detecting gene imprinting by 5' nuclease assay. This approach has also a potentiality to discover differential allele expression of non-imprinted genes in order to find gene cis-acting functional polymorphism.

Alleles↗
PubMed2005

Role of selection in fixation of gene duplications.

New genes commonly appear through complete or partial duplications of pre-existing genes. Duplications of long DNA segments are constantly produced by rare mutations, may become fixed in a population by selection or random drift, and are subject to divergent evolution of the paralogous sequences after fixation, although gene conversion can impede this process. New data shed some light on each of these processes. Mutations which involve duplications can occur through at least two different mechanisms, backward strand slippage during DNA replication and unequal crossing-over. The background rate of duplication of a complete gene in humans is 10(-9)-10(-10) per generation, although many genes located within hot-spots of large-scale mutation are duplicated much more often. Many gene duplications affect fitness strongly, and are responsible, through gene dosage effects, for a number of genetic diseases. However, high levels of intrapopulation polymorphism caused by presence or absence of long, gene-containing DNA segments imply that some duplications are not under strong selection. The polymorphism to fixation ratios appear to be approximately the same for gene duplications and for presumably selectively neutral nucleotide substitutions, which, according to the McDonald-Kreitman test, is consistent with selective neutrality of duplications. However, this pattern can also be due to negative selection against most of segregating duplications and positive selection for at least some duplications which become fixed. Patterns in post-fixation evolution of duplicated genes do not easily reveal the causes of fixations. Many gene duplications which became fixed recently in a variety of organisms were positively selected because the increased expression of the corresponding genes was beneficial. The effects of gene dosage provide a unified framework for studying all phases of the life history of a gene duplication. Application of well-known methods of evolutionary genetics to accumulating data on new, polymorphic, and fixed duplication will enhance our understanding of the role of natural selection in the evolution by gene duplication.

Animals↗
PubMed2002

Characterization of IS999, an unstable genetic element in Mycobacterium avium.

An IS3-family insertion element, IS999, was identified in the opportunistic pathogen Mycobacterium avium. The 1347 bp element has 29 bp inverted repeats and two overlapping open reading frames coding for putative transposases. It was detected in the genomes of ten of 12 M. avium isolates examined. Copy numbers ranged from four to 16. IS999 is less stable than IS1245, the most commonly-used marker for typing M. avium isolates. Among 60 colonies picked from a single patient isolate, there were two distinct IS1245 restriction fragment length polymorphism banding patterns compared to eight distinct IS999 patterns (five in one IS1245 group and three in the other). In view of its instability, we asked whether transposition of IS999 might have phenotypic consequences. Nucleotide sequence analysis of insertion sites in four isolates revealed 16 putative structural genes that were variably disrupted by IS999. Insertions into hdhA, a gene that codes for a putative short chain alcohol dehydrogenase, were distributed non-randomly between colony type variants, consistent with phenotypic consequences that exert selective pressure. These observations illustrate the genetic heterogeneity that can exist within populations of M. avium that appear to be homogeneous by IS1245 analysis. IS999 may be a useful marker for tracking, at the sub-strain level, the rapid genetic drift that M. avium isolates undergo in nature and in the laboratory.

Binding Sites↗