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[
Trends Genet,
2003]
The advent of whole-genome sequencing and genome-wide transcriptional profiling has opened up new approaches to the resolution of questions that only a few years ago seemed unanswerable. At the same time they have revealed new and sometimes unexpected patterns of gene conservation and functional compensation, chromosomal clustering of transcriptionally related genes, relocation of genes to depopulate or overpopulate the X chromosome with certain functional classes of genes, and gene duplication and functional divergence. What makes molecular evolutionary genomics different from previous approaches is the generality of the results. Choice of genes, and the uncertainties of extrapolating from a sample of genes to the entire genome, is supplanted by direct genome-wide observations. In this article we examine some key recent experiments in RNA interference that illustrate some of the strengths and limitations of evolutionary genomic analysis.
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[
Genome Res,
2004]
The relationship between protein and regulatory sequence evolution is a central question in molecular evolution. It is currently not known to what extent changes in gene expression are coupled with the evolution of protein coding sequences, or whether these changes differ among orthologs (species homologs) and paralogs (duplicate genes). Here, we develop a method to measure the extent of functionally relevant cis-regulatory sequence change in homologous genes, and validate it using microarray data and experimentally verified regulatory elements in different eukaryotic species. By comparing the genomes of Caenorhabditis elegans and C. briggsae, we found that protein and regulatory evolution is weakly coupled in orthologs but not paralogs, suggesting that selective pressure on gene expression and protein evolution is quite similar and persists for a significant amount of time following speciation but not gene duplication. Additionally, duplicates of both species exhibit a dramatic acceleration of both regulatory and protein evolution compared to orthologs, suggesting increased directional selection and/or relaxed selection on both gene expression patterns and protein function in duplicate genes.
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[
Mol Biol Evol,
2002]
It has been hypothesized that evolutionary changes will be more frequent in later ontogeny than early ontogeny because of developmental constraint. To test this hypothesis, a genomewide examination of molecular evolution through ontogeny was carried out using comparative genomic data in Caenorhabditis elegans and Caenorhabditis briggsae. We found that the mean rate of amino acid replacement is not significantly different between genes expressed during and after embryogenesis. However, synonymous substitution rates differed significantly between these two classes. A genomewide survey of correlation between codon bias and expression level found codon bias to be significantly correlated with mRNA expression (r(s) = -0.30 and P < 10-(131)) but does not alone explain difference, in dS between classes. Surprisingly. it was found that genes expressed after embryogenesis have a significantly greater number of duplicates in both the C. elegans and C briggsae genomes (P < 10(-20) and P < 10(-13)) when compared with early-expressed and nonmodulated genes. A similarity in the distribution of duplicates of nonmodulated and early-expressed genes, as well as a disproportionately higher number of early pseudogenes, lend support to the hypothesis that this difference in duplicate number is caused by selection against gene duplicates of early-expressed genes. reflecting developmental constraint. Developmental constraint at the level of gene duplication may have important implications for macroevolutionary change.
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[
Nat Genet,
2002]
Transcription is a slow and expensive process: in eukaryotes, approximately 20 nucleotides can be transcribed per second(1,2) at the expense of at least two ATP molecules per nucleotide(3). Thus, at least for highly expressed genes, transcription of long introns, which are particularly common in mammals, is costly. Using data on the expression of genes that encode proteins in Caenorhabditis elegans and Homo sapiens, we show that introns in highly expressed genes are substantially shorter than those in genes that are expressed at low levels. This difference is greater in humans, such that introns are, on average, 14 times shorter in highly expressed genes than in genes with low expression, whereas in C. elegans the difference in intron length is only twofold. In contrast, the density of introns in a gene does not strongly depend on the level of gene expression. Thus, natural selection appears to favor short introns in highly expressed genes to minimize the cost of transcription and other molecular
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[
Genome Res,
2004]
We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage.
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[
Genetics,
2024]
Transposable elements (TEs) are DNA sequences capable of moving within genomes and significantly influence genomic evolution. The nematode Caenorhabditis inopinata exhibits a much higher TE copy number than its sister species, C. elegans. In this study, we identified a novel autonomous TE belonging to the hAT superfamily from a spontaneous TE-insertion mutant in C. inopinata and named this transposon Ci-hAT1. Further bioinformatic analyses uncovered three additional autonomous hAT elements-Ci-hAT2, Ci-hAT3, and Ci-hAT4-along with over 1,000 copies of two non-autonomous miniature inverted-repeat transposable elements (MITEs), mCi-hAT1 and mCi-hAT4, likely derived from Ci-hAT1 and Ci-hAT4 through internal deletion. We tracked at least three sequential transpositions of Ci-hAT1 over several years. However, the transposition rates of the other three autonomous hAT elements were lower, suggesting varying activity levels. Notably, the distribution patterns of the two MITE families differed significantly: mCi-hAT1 was primarily located in the chromosome arms, a pattern observed in the TEs of other Caenorhabditis species, whereas mCi-hAT4 was more evenly distributed across chromosomes. Additionally, interspecific transcriptome analysis indicated that C. inopinata genes with upstream or intronic these MITE insertions tend to be more highly expressed than their orthologous genes in C. elegans. These findings highlight the significant role of de-silenced TEs in driving the evolution of genomes and transcriptomes, leading to species-specific genetic diversity.
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[
Nucleic Acids Res,
2006]
Gene expression over time is, biologically, a continuous process and can thus be represented by a continuous function, i.e. a curve. Individual genes often share similar expression patterns (functional forms). However, the shape of each function, the number of such functions, and the genes that share similar functional forms are typically unknown. Here we introduce an approach that allows direct discovery of related patterns of gene expression and their underlying functions (curves) from data without a priori specification of either cluster number or functional form. Smoothing spline clustering (SSC) models natural properties of gene expression over time, taking into account natural differences in gene expression within a cluster of similarly expressed genes, the effects of experimental measurement error, and missing data. Furthermore, SSC provides a visual summary of each cluster''s gene expression function and goodness-of-fit by way of a ''mean curve'' construct and its associated confidence bands. We apply this method to gene expression data over the life-cycle of Drosophila melanogaster and Caenorhabditis elegans to discover 17 and 16 unique patterns of gene expression in each species, respectively. New and previously described expression patterns in both species are discovered, the majority of which are biologically meaningful and exhibit statistically significant gene function enrichment. Software and source code implementing the algorithm, SSClust, is freely available
(http://genemerge.bioteam.net/SSClust.html). -
[
Am J Physiol,
1998]
We isolated and characterized the cDNAs far the human, pig, and Caenorhabditis elegans K-CI cotransporters. The pig and human homologs are 94% identical and contain 1,085 and 1,086 amino acids, respectively. The deduced protein of the C. elegans K-CI cotransporter clone (CE-KCC1) contains 1,003 amino acids. The mammalian K-CI cotransporters share similar to 45% similarity with CE-KCC1. Hydropathy analyses of the three clones indicate typical KCC topology patterns with 12 transmembrane segments, large extracellular loops between transmembrane domains 5 and 6 (unique to KCC), and large COOH-terminal domains. Human KCC1 is widely expressed among various tissues. This KCC1 gene spans 23 kb and is organized in 24 exons, whereas the CE-KCC1 gene spans 3.5 kb and contains ID exons. Transiently and stably transfected human embryonic kidney cells (HEK-293) expressing the human, pig, and C. elegans K-Cl cotransporter fulfilled two (pig) or five (human and C. elegans) criteria for increased expression of the K-Cl cotransporter. The criteria employed were basal K-CI cotransport; stimulation of cotransport by swelling, N-ethylmaleimide, staurosporine, and reduced cell Mg concentration; and secondary stimulation of Na-K-CI cotransport.
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[
PLoS One,
2013]
BACKGROUND: Aging is a biological process strongly determined by genetics. However, only a few single nucleotide polymorphisms (SNPs) have been reported to be consistently associated with aging. While investigating whether copy number variations (CNVs) could fill this gap, we focused on CNVs that have not been studied in previous SNP-based searches via tagging SNPs. METHODS: TaqMan qPCR assays were developed to quantify 20 common CNVs in 222 senior American Caucasians in order to reveal possible association with longevity. The replication study was comprised of 1283 community-dwelling senior European Caucasians. Replicated CNVs were further investigated for association with healthy aging and aging-related diseases, while association with longevity was additionally tested in Caenorhabditis elegans. RESULTS: In the discovery study of 80 vs.<80 years old seniors, a homozygous intronic CNV deletion in the CNTNAP4 gene was inversely associated with survival to the age of 80 (OR=0.51, 95%CI 0.29-0.87, p=0.015 before correction for multiple testing). After stratification by sex, association remained significant in females (OR=0.41, 95%CI 0.21-0.77, p=0.007), but not in males (OR=0.97, 95%CI 0.33-2.79, p=1). The finding was validated in a replication study (OR=0.66, 95%CI 0.48-0.90, p=0.011 for females). CNTNAP4 association with longevity was supported by a marked 25% lifespan change in C. elegans after knocking down the ortholog gene. An inverse association of the CNV del/del variant with female healthy aging was observed (OR=0.39, 95%CI 0.19-0.76, p=0.006). A corresponding positive association with aging-related diseases was revealed for cognitive impairment (OR=2.17, 95%CI 1.11-4.22, p=0.024) and, in independent studies, for Alzheimer's (OR=4.07, 95%CI 1.17-14.14, p=0.036) and Parkinson's (OR=1.59, 95%CI 1.03-2.42, p=0.041) diseases. CONCLUSION: This is the first demonstration for association of the CNTNAP4 gene and one of its intronic CNV polymorphisms with aging. Association with particular aging-related diseases awaits replication and independent validation.
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Dominguez A, Castro J, Sauerbrey M, Catu E, Lindblade KA, Unnasch TR, Richards FO, Arana B, Punkosdy GA, Cruz-Ortiz N, Rizzo N, Zea-Flores G, Richards J, Oliva O, Porter CH
[
Am J Trop Med Hyg,
2007]
To eliminate transmission of Onchocerca volvulus, semiannual mass treatment with ivermectin (Mectizan; donated by Merck & Co) has been underway in Guatemala since 2000. We applied the 2001 World Health Organization (WHO) elimination criteria in the Santa Rosa focus of onchocerciasis transmission in Guatemala (10,923 persons at risk). No evidence of parasite DNA was found in 2,221 Simulium ochraceum vectors (one-sided 95% confidence interval [CI], 0-0.086%), and no IgG4 antibody positives to recombinant antigen OV16 were found in a sample of 3,232 school children (95% CI, 0-0.009%). We also found no evidence of microfilariae in the anterior segment of the eye in 363 area residents (95% CI, 0-0.08%). Our interpretation of these data, together with historical information, suggest that transmission of O. volvulus is permanently interrupted in Santa Rosa and that ivermectin treatments there can be halted.