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PubMed1999

Comparative genomics and evolutionary dynamics of Saccharomyces cerevisiae Ty elements.

The availability of the complete genome sequence of Saccharomyces cerevisiae provides the unique opportunity to study an entire genomic complement of retrotransposons from an evolutionary perspective. There are five families of yeast retrotransposons, Ty1-Ty5. We have conducted a series of comparative sequence analyses within and among S. cerevisiae Ty families in an effort to document the evolutionary forces that have shaped element variation. Our results indicate that within families Ty elements vary little in terms of both size and sequence. Furthermore, intra-element 5'-3' long terminal repeat (LTR) sequence comparisons indicate that almost all Ty elements in the genome have recently transposed. For each family, solo LTR sequences generated by intra-element recombination far outnumber full length insertions. Taken together, these results suggest a rapid genomic turnover of S. cerevisiae Ty elements. The closely related Ty1 and Ty2 are the most numerous elements in the genome. Phylogenetic analysis of full length insertions reveals that reverse transcriptase mediated recombination between Ty1 and Ty2 elements has generated a number of hybrid Ty1/2 elements. These hybrid Ty1/2 elements have similar genomic structures with chimeric LTRs and chimeric TYB (pol) genes. Analysis of the levels of nonsynonymous (Ka) and synonymous (Ks) nucleotide variation indicates that Ty1 and Ty2 coding regions have been subject to strong negative (purifying) selection. Distribution of Ka and Ks on Ty1, Ty2 and Ty1/2 phylogenies reveals evidence of negative selection on both internal and external branches. This pattern of variation suggests that the majority of full length Ty1, Ty2 and Ty1/2 insertions represent active or recently active element lineages and is consistent with a high level of genomic turnover. The evolutionary dynamics of S. cerevisae Ty elements uncovered by our analyses are discussed with respect to selection among elements and the interaction between the elements and their host genome.

Amino Acid Sequence↗
PubMed2005

Investigation of malaria susceptibility determinants in the IFNG/IL26/IL22 genomic region.

Interferon-gamma, encoded by IFNG, is a key immunological mediator that is believed to play both a protective and a pathological role in malaria. Here, we investigate the relationship between IFNG variation and susceptibility to malaria. We began by analysing West African and European haplotype structure and patterns of linkage disequilibrium across a 100 kb genomic region encompassing IFNG and its immediate neighbours IL22 and IL26. A large case-control study of severe malaria in a West Africa population identified several weak associations with individual single-nucleotide polymorphisms in the IFNG and IL22 genes, and defined two IL22 haplotypes that are, respectively, associated with resistance and susceptibility. These data provide a starting point for functional and genetic analysis of the IFNG genomic region in malaria and other infectious and inflammatory conditions affecting African populations.

Black People↗
PubMed2002

Sequence variations in the public human genome data reflect a bottlenecked population history.

Single-nucleotide polymorphisms (SNPs) constitute the great majority of variations in the human genome, and as heritable variable landmarks they are useful markers for disease mapping and resolving population structure. Redundant coverage in overlaps of large-insert genomic clones, sequenced as part of the Human Genome Project, comprises a quarter of the genome, and it is representative in terms of base compositional and functional sequence features. We mined these regions to produce 500,000 high-confidence SNP candidates as a uniform resource for describing nucleotide diversity and its regional variation within the genome. Distributions of marker density observed at different overlap length scales under a model of recombination and population size change show that the history of the population represented by the public genome sequence is one of collapse followed by a recent phase of mild size recovery. The inferred times of collapse and recovery are Upper Paleolithic, in agreement with archaeological evidence of the initial modern human colonization of Europe.

Databases, Nucleic Acid↗
PubMed2025

Mapping Cerebellar Morphology in 15q11.2 CNV Carriers Using Normative Modeling.

Copy number variations (CNVs) at the 15q11.2 locus of the human genome have been associated with altered brain structure and increased risk for neurodevelopmental and neuropsychiatric disorders. The cerebellum is increasingly seen as a crucial brain region for neurodevelopmental conditions, yet the effects of 15q11.2 CNVs on cerebellar morphology remain largely unclear. Importantly, 15q11.2 CNVs shows reduced or incomplete penetrance (meaning that not all CNV carriers are affected) and variable expressivity (meaning that symptoms may differ between individuals with the same genetic alteration). Thus, there is a need to not only assess group differences, but also to quantify anatomical variability at the individual level. Here, we address these issues using normative models of brain anatomy trained on large datasets (n > 52k, age range: 3-85) to assess both group and individual-level deviations in cerebellar anatomy in carriers of 15q11.2 deletions (n = 120, mean [SD] age= 64.95 [7.58]) and duplications (n = 149, mean [SD] age=64.31 [7.21]), compared to non-carriers (n = 19,028, mean [SD] age=64.31 [7.58]). Group-level case-control analyses revealed significantly smaller total and regional cerebellar volumes in both deletion and duplication carriers, though with small effect sizes. Individual-level deviation analyses, capturing pronounced alterations in specific individuals, revealed a heterogeneous pattern among carriers. Overall, our findings suggest that CNVs at the 15q11.2 locus exert modest and highly individualized effects on cerebellar morphology.

15q11.2↗
PubMed1982

Cloning and sequence analysis reveal structural variation among related zein genes in maize.

We have isolated a gene encoding one of the 19,000 dalton zein proteins from a maize genomic library constructed in Charon 4A. This gene occurs on a 7.7 kb Eco RI fragment, and based on Southern hybridization analysis, represents one of several homologous sequences present in the maize genome. The nucleotide sequence of the gene predicts a protein composed of 235 amino acids, including a signal peptide of 21 amino acids. There are no intervening sequences in the gene. By comparing the nucleotide sequence of this gene with that of a homologous cDNA clone, we have identified a basis for microheterogeneity within the gene family. The 5' nucleotide sequences of the genomic and cDNA clones are identical, but they differ in the center of the protein, where repeated amino acid sequences occur. A nucleotide sequence encoding a conserved peptide of 20 amino acids is repeated nine times in the center of both of these clones.

Base Sequence↗
PubMed1980

Genetic structure and genetic variation of influenza viruses.

The following contribution summarizes our most recent results concerning analysis of the influenza A, B and C virus genomes. In addition, we present data on the extent of genetic variation of H1N1 influenza viruses isolated during the months following the 1977 outbreak of H1N1 influenza in China and Russia. A detailed description of these results is published elsewhere.

Base Sequence↗
PubMed2006

Colour variation in red grapevines (Vitis vinifera L.): genomic organisation, expression of flavonoid 3'-hydroxylase, flavonoid 3',5'-hydroxylase genes and related metabolite profiling of red cyanidin-/blue delphinidin-based anthocyanins in berry skin.

BACKGROUND: Structural genes of the phenyl-propanoid pathway which encode flavonoid 3'- and 3',5'-hydroxylases (F3'H and F3'5'H) have long been invoked to explain the biosynthesis of cyanidin- and delphinidin-based anthocyanin pigments in the so-called red cultivars of grapevine. The relative proportion of the two types of anthocyanins is largely under genetic control and determines the colour variation among red/purple/blue berry grape varieties and their corresponding wines. RESULTS: Gene fragments of VvF3'H and VvF3'5'H, that were isolated from Vitis vinifera 'Cabernet Sauvignon' using degenerate primers designed on plant homologous genes, translated into 313 and 239 amino acid protein fragments, respectively, with up to 76% and 82% identity to plant CYP75 cytochrome P450 monooxygenases. Putative function was assigned on the basis of sequence homology, expression profiling and its correlation with metabolite accumulation at ten different ripening stages. At the onset of colour transition, transcriptional induction of VvF3'H and VvF3'5'H was temporally coordinated with the beginning of anthocyanin biosynthesis, the expression being 2-fold and 50-fold higher, respectively, in red berries versus green berries. The peak of VvF3'5'H expression was observed two weeks later concomitantly with the increase of the ratio of delphinidin-/cyanidin-derivatives. The analysis of structural genomics revealed that two copies of VvF3'H are physically linked on linkage group no. 17 and several copies of VvF3'5'H are tightly clustered and embedded into a segmental duplication on linkage group no. 6, unveiling a high complexity when compared to other plant flavonoid hydroxylase genes known so far, mostly in ornamentals. CONCLUSION: We have shown that genes encoding flavonoid 3'- and 3',5'-hydroxylases are expressed in any tissues of the grape plant that accumulate flavonoids and, particularly, in skin of ripening red berries that synthesise mostly anthocyanins. The correlation between transcript profiles and the kinetics of accumulation of red/cyanidin- and blue/delphinidin-based anthocyanins indicated that VvF3'H and VvF3'5'H expression is consistent with the chromatic evolution of ripening bunches. Local physical maps constructed around the VvF3'H and VvF3'5'H loci should help facilitate the identification of the regulatory elements of each isoform and the future manipulation of grapevine and wine colour through agronomical, environmental and biotechnological tools.

Anthocyanins↗
PubMed1995

Molecular evolution of aphthoviruses.

Aphthoviruses are an important group of animal pathogens. A combination of genetic and structural studies has revealed one of the main principles governing their evolution: severe limitations to variation imposed by functional and structural constraints, in conjunction with high mutation and recombination rates operating during genome replication. Evolution occurs by positive selection and random drift acting on complex quasispecies distributions. The mutant composition of a quasi-species (or mutant spectrum) is largely dictated by tolerance to nucleotide and amino acid substitutions in viral RNAs and proteins, which must remain functionally competent. We review recent evidence to support this proposal, and we suggest that similar concepts may apply to other RNA viruses as well.

Adaptation, Physiological↗
PubMed1995

Human genome organization.

Recent advances have been made in addressing three intriguing aspects of human genome organization: the organization of protein-coding sequences within chromosomes, the structural basis of the metaphase chromosomal banding pattern, and the function of non protein coding DNA. At the cytogenetic level, R band heterogeneity has been examined by fluorescence in situ hybridization using complex fractions of genomic DNA as probes. DNA fractionated according to GC content and CpG is island density both generated patterns related G and R bands and directly demonstrated regional variations in gene densities. A structural basis for metaphase bands has been proposed that is based on the differential size and packing of DNA loops and matrix attachment sites in G versus R bands. The model presents interesting opportunities for structure/function and organization investigations. At the molecular level, the human genome initiative has resulted in extensive genomic clone coverage for many large chromosomal regions, permitting detailed documentation of CpG islands, base composition and repeat sequence context, as well as fueling comprehensive gene searches. Sequence and functional characteristics are being examined at the kilobase level and are prompting new suggestions of roles for 'junk' DNA. Because of these developments, opportunities are now emerging for direct assessment of the molecular characteristics of individual metaphase bands.

Chromosome Banding↗
PubMed1995

Genetic variation on chromosome 1 associated with variation in body fat distribution in men.

BACKGROUND: Interindividual variation in fat deposition in swine is determined by loci on porcine chromosome 4, which are contained in a region that is syntenic with part of the long arm of human chromosome 1. We hypothesized that genomic variation of chromosome 1q would be associated with variation in the ratio of waist-to-hip circumference in male North American Hutterites, a genetic isolate characterized by significant relatedness and sharing of environmental factors. METHODS AND RESULTS: In 316 male Hutterites, we tested for phenotype-genotype association of two DNA polymorphisms on chromosome 1q and the ratio of waist-to-hip circumference. We included control loci on 10 other chromosomes in the multivariate model. We observed that DNA variation on chromosome 1q was significantly associated with variation in the ratio of waist-to-hip circumference in men (P = .0029). CONCLUSIONS: The association of DNA variation chromosome 1q with the ratio of waist-to-hip circumference in male Hutterites suggests that there are important structural elements in this genomic region that have a functional impact on body fat distribution.

Adipose Tissue↗
PubMed2006

Geographic patterns of microsatellite variation in Boechera stricta, a close relative of Arabidopsis.

The genus Boechera is a widespread North American group with great potential for studies of ecology and evolution: Boechera is closely related to Arabidopsis and exhibits different ecological and reproductive strategies. Boechera stricta (previously Arabis drummondii) is a morphologically and genetically well-defined, perennial crucifer species. Fifteen natural populations of diploid individuals from the Rocky Mountains were analysed using 21 microsatellite loci. In accordance with our expectation for this predominately inbreeding species, a high F IS value (0.89) was observed. Furthermore, populations of B. stricta were highly differentiated, as indicated by F ST = 0.56. Three clusters were identified using structure- the majority of populations belonged to either the Northern or Southern cluster. Together, the north-south partitioning and evenness of genetic variation across the two clusters suggested multiple refugia for this perennial herb in the Rocky Mountains. Pleistocene glaciation, together with the topographically and climatologically heterogeneous cordillera, has profoundly influenced the genetic architecture of B. stricta. Genetic population structure was also influenced by relatively recent genome admixture at two levels: within species (involving individuals from the Northern and Southern clusters) and between species (with the hybridization of B. stricta and Boechera holboellii). This complexity of population structure at presumably neutral microsatellite loci located throughout the genome in B. stricta provides a baseline against which to test whether functional genetic variation is undergoing local adaptive evolution throughout the natural species range.

Brassicaceae↗
PubMed2003

Words in DNA sequences: some case studies based on their frequency statistics.

One of the critical requirements of data analysis involving large DNA sequences is an effective statistical summarization of those sequences. In this article DNA sequences have been analyzed based on word frequencies. Our analysis focuses on the detection of structural signature of a genome reflected in word frequencies and identification of phylogenetic relationships among different species reflected in the variation of word distributions in their DNA sequences. We have carried out a statistical study of the complete genome of baker's yeast, of various ribosomal RNA sequences from different prokaryotic and eukaryotic organisms and of the full genomes of some bacteriophages. Our exploratory analysis amply demonstrates the usefulness of DNA word frequencies in reducing the dimensionality of large sequences while retaining some of the structural information there that can have biological significance. Some conceptual issues that arise in course of our investigation have been addressed. A few interesting problems related to the statistics of DNA words have been pointed out with some indication of their possible solutions. The work has been partially motivated by the fact that sequence alignment and homology techniques that are quite popular for comparing and analyzing relatively smaller DNA sequences of nearly equal sizes are not applicable to data consisting of large sequences with widely varying sizes, which may contain segments with unknown or no biological functions, and consequently their comparison through functional homology is either impossible or extremely difficult.

Bacteriophages↗
PubMed1988

[Molecular-genetic mechanisms of antigenic variability of pathogenic bacteria].

The literature on the molecular genetic mechanisms for antigenic variability of pathogenic bacteria is reviewed. Ability to antigenic variability in any case discussed is considered to be a pathogenicity factor permitting efficient struggle against the immune system of the host-organism. The molecular basis for such variability is instability of the genome structure, coding for highly immunogenic bacterial proteins.

Antigenic Variation↗
PubMed2004

Comparative genomic structure of prokaryotes.

Recent advances in DNA-sequencing technologies have made available an enormous resource of data for the study of bacterial genomes. The broad sample of complete genomes currently available allows us to look at variation in the gross features and characteristics of genomes while the detail of the sequences reveal some of the mechanisms by which these genomes evolve. This review aims to describe bacterial genome structures according to current knowledge and proposed hypotheses. We also describe examples where mechanisms of genome evolution have acted in the adaptation of bacterial species to particular niches.

Bacteria↗
PubMed1996

Wheat retrotransposon families identified by reverse transcriptase domain analysis.

Variations in the reverse transcriptase domain were analyzed to clarify the family structure of retrotransposons in the wheat genome. Seven families were identified on the basis of the nucleotide sequence similarities of the domain. These families are common to the genomes of ancestral diploid species of wheat, evidence that they were established prior to diploid speciation, and their presence in barley and rice was suggested. Recent activity of some of the families was inferred in wheat on the basis of data that included synonymous and nonsynonymous nucleotide substitution rates in the reverse transcriptase domain.

Cloning, Molecular↗
PubMed2006

A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications.

Compared with other sequenced animal genomes, human segmental duplications appear larger, more interspersed, and disproportionately represented as high-sequence identity alignments. Global sequence divergence estimates of human duplications have suggested an expansion relatively recently during hominoid evolution. Based on primate comparative sequence analysis of 37 unique duplication-transition regions, we establish a molecular clock for their divergence that shows a significant increase in their effective substitution rate when compared with unique genomic sequence. Fluorescent in situ hybridization (FISH) analyses from 1053 random nonhuman primate BACs indicate that great-ape species have been enriched for interspersed segmental duplications compared with representative Old World and New World monkeys. These findings support computational analyses that show a 12-fold excess of recent (>98%) intrachromosomal duplications when compared with duplications between nonhomologous chromosomes. These architectural shifts in genomic structure and elevated substitution rates have important implications for the emergence of new genes, gene-expression differences, and structural variation among humans and great apes.

Animals↗
PubMed2003

MutDB: annotating human variation with functionally relevant data.

SUMMARY: We have developed a resource, MutDB (http://mutdb.org/), to aid in determining which single nucleotide polymorphisms (SNPs) are likely to alter the function of their associated protein product. MutDB contains protein structure annotations and comparative genomic annotations for 8000 disease-associated mutations and SNPs found in the UCSC Annotated Genome and the human RefSeq gene set. MutDB provides interactive mutation maps at the gene and protein levels, and allows for ranking of their predicted functional consequences based on conservation in multiple sequence alignments. AVAILABILITY: http://mutdb.org/ SUPPLEMENTARY INFORMATION: http://mutdb.org/about/about.html

Database Management Systems↗
PubMed1994

Mitochondrial DNA control region polymorphisms: genetic markers for ecological studies of marine turtles.

We describe a rapid and sensitive method for the detection of population-specific genetic markers in mitochondrial DNA (mtDNA) and the use of such markers to analyse population structure of marine turtles. A series of oligonucleotide primers specific for the amplification of the mtDNA control region in Cheloniid turtles were designed from preliminary sequence data. Using two of these primers, a 384-385-bp sequence was amplified from the 5' portion of the mtDNA control region of 15 green turtles Chelonia mydas from 12 different Indo-Pacific rookeries. Fourteen of the 15 individuals, including some with identical whole-genome restriction fragment patterns, had sequences that differed by one or more base substitutions. Analysis of sequence variation among individuals identified a total of 41 nucleotide substitutions and a 1-bp insertion/deletion. Comparison with evidence from whole-genome restriction enzyme analysis of the same individuals indicated that this portion of the control region is evolving approximately eight times faster than the average rate and that the sequence analysis detected approximately one fifth of the total variation present in the genome. Restriction enzyme analysis of amplified products from an additional 256 individuals revealed significant geographic structuring in the distribution of mtDNA genotypes among five of the 10 rookeries surveyed extensively. Additional geographic structuring of genotypes was identified through denaturing gradient gel electrophoresis (DGGE) of amplified products. Only two of the 10 rookeries surveyed could not be differentiated, indicating that the Indo-Pacific C. mydas include a number of genetically differentiated populations, with minimal female-mediated gene flow among them. Important applications for genetic markers in the conservation and management of marine turtles include the identification of appropriate demographic units for research and management (i.e. genetically discrete populations) and assessment of the composition of feeding and harvested populations.

Animals↗