Bo S et al. (2019) J Theor Biol "Potential relations between post-spliced introns and mature mRNAs in the Caenorhabditis elegans genome."

Zhao X, Li H, Bao T, Zhang Q, Lu Z, Bo S

[J Theor Biol, 2019]

There are potential interactions between introns and their corresponding coding sequences (CDSs) in ribosomal protein genes that have been proposed by our group and the interactions are achieved by sequence matches between the two kinds of sequences. Here, the optimal matching relations between mature mRNAs and their corresponding introns in Caenorhabditis elegans (C.elegans) were investigated by improved Smith-Waterman local alignment software. Our results showed that the remarkably matched regions appear in the untranslated regions (UTRs) of mRNAs, especially in the 3' UTR. The optimal matched segments (OMSs) are highly organized segments. In addition, the optimal matching relations were analysed between mature mRNAs and other introns. The matching strengths in the UTRs are clearly lower than those in their corresponding introns. Our studies indicate that there are potential interactions between mature mRNAs and their corresponding introns and the post-spliced introns should have other novel functions in the gene expression process.

Cohn DH et al. (2003) Am J Hum Genet "Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel, evolutionarily conserved gene."

Ehtesham N, Shanske A, Cohn DH, Krakow D, Powell BR, Rimoin DL, Unger S, Reinker K

[Am J Hum Genet, 2003]

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.

Boateng R et al. (2018) Genetics "New Role for an Old Protein: An Educational Primer for Use with "The Identification of a Novel Mutant Allele of topoisomerase II in Caenorhabditis elegans Reveals a Unique Role in Chromosome Segregation During Spermatogenesis"."

Allen AK, Boateng R

[Genetics, 2018]

Modern experimental techniques, such as whole-genome sequencing and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 endogenous genome editing, are enabling researchers to identify and further characterize the roles of proteins that were previously thought of as well defined. In the December 2016 issue of GENETICS, an article by Jaramillo-Lambert et al. identified a new role for the enzyme topoisomerase II in Caenorhabditis elegans male meiosis. This Primer article is designed to provide essential background information on C. elegans spermatogenesis and the relevant scientific techniques that will assist students and instructors in their understanding and discussion of the related article.Related article in GENETICS: Jaramillo-Lambert, A., A. S. Fabritius A. S., T. J. Hansen T. J., H. E. Smith H. E., and A. Golden A., 2016The identification of a novel mutant allele of topoisomerase II in Caenorhabditis elegans reveals a unique role in chromosome segregation during spermatogenesis. Genetics204: 1407-1422.

Ehtesham N et al. (2002) Am J Hum Genet "Evidence that Smith-McCort dysplasia and Dyggve-Melchior-Clausen dysplasia are allelic disorders that result from mutations in a gene on chromosome 18q12."

Cohn DH, Shanske A, King LM, Unger S, Ehtesham N, Powell BR, Cantor RM, Rimoin DL, Reinker K

[Am J Hum Genet, 2002]

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.

Robins H et al. (2005) Proc Natl Acad Sci U S A. "Incorporating structure to predict microRNA targets."

Li Y, Robins H, Padgett RW

[Proc Natl Acad Sci U S A., 2005]

MicroRNAs (miRNAs) are a recently discovered set of regulatory genes that constitute up to an estimated 1% of the total number of genes in animal genomes, including Caenorhabditis elegans, Drosophila, mouse, and humans [Lagos-Quintana, M., Rauhut, R., Lendeckel, W. M Tuschl, T. (2001) Science 294, 853-858; Lai, E. C., Tomancak, P., Williams, R. W. M Rubin, G.M. (2003) Genome Biol. 4, R42; Lau, N. C., Lim, L. P., Weinstein, E. G. M Bartel, D. P. (2001) Science 294, 858-862; Lee, R. C. M Ambros, V. (2001) Science 294, 862-8644; and Lee, R. C., Feinbaum, R. L. M Ambros, V. (1993) Cell 115, 787-798]. In animals, miRNAs regulate genes by attenuating protein translation through imperfect base pair binding to 3' UTR sequences of target genes. A major challenge in understanding the regulatory role of miRNAs is to accurately predict regulated targets. We have developed an algorithm for predicting targets that does not rely on evolutionary conservation. As one of the features of this algorithm, we incorporate the folded structure of mRNA. By using Drosophila miRNAs as a test case, we have validated our predictions in 10 of 15 genes tested. One of these validated genes is mad as a target for bantam. Furthermore, our computational and experimental data suggest that miRNAs have fewer targets than previously reported.

Tabish M et al. (1999) Biochem J "Organization and alternative splicing of the Caenorhabditis elegans cAMP-dependent protein kinase catalytic-subunit gene (kin-1)."

Tabish M, Clegg RA, Rees HH, Fisher MJ

[Biochem J, 1999]

The cAMP-dependent protein kinase (protein kinase A, PK-A) is multifunctional in nature, with key roles in the control of diverse aspects of eukaryotic cellular activity. In the case of the free-living nematode, Caenorhabditis elegans, a gene encoding the PK-A catalytic subunit has been identified and two isoforms of this subunit, arising from a C-terminal alternative-splicing event, have been characterized [Gross, Bagchi, Lu and Rubin (1990) J. Biol. Chem. 265, 6896-6907]. Here we report the occurrence of N-terminal alternative-splicing events that, in addition to generating a multiplicity of non-myristoylatable isoforms, also generate the myristoylated variant(s) of the catalytic subunit that we have recently characterized [Aspbury, Fisher, Rees and Clegg (1997) Biochem. Biophys. Res. Commun. 238, 523-527]. The gene spans more than 36 kb and is divided into a total of 13 exons. Each of the mature transcripts contains only 7 exons. In addition to the already characterized exon 1, the 5'-untranslated region and first intron actually contain 5 other exons, any one of which may be alternatively spliced on to exon 2 at the 5' end of the pre-mRNA. This N-terminal alternative splicing occurs in combination with either of the already characterized C-terminal alternative exons. Thus, C. elegans expresses at least 12 different isoforms of the catalytic subunit of PK-A. The significance of this unprecedented structural diversity in the family of PK-A catalytic subunits is discussed.

Shaham S (2009) PLoS One "galign: a tool for rapid genome polymorphism discovery."

Shaham S

[PLoS One, 2009]

BACKGROUND: Highly parallel sequencing technologies have become important tools in the analysis of sequence polymorphisms on a genomic scale. However, the development of customized software to analyze data produced by these methods has lagged behind. METHODS/PRINCIPAL FINDINGS: Here I describe a tool, 'galign', designed to identify polymorphisms between sequence reads obtained using Illumina/Solexa technology and a reference genome. The 'galign' alignment tool does not use Smith-Waterman matrices for sequence comparisons. Instead, a simple algorithm comparing parsed sequence reads to parsed reference genome sequences is used. 'galign' output is geared towards immediate user application, displaying polymorphism locations, nucleotide changes, and relevant predicted amino-acid changes for ease of information processing. To do so, 'galign' requires several accessory files easily derived from an annotated reference genome. Direct sequencing as well as in silico studies demonstrate that 'galign' provides lesion predictions comparable in accuracy to available prediction programs, accompanied by greater processing speed and more user-friendly output. We demonstrate the use of 'galign' to identify mutations leading to phenotypic consequences in C. elegans. CONCLUSION/SIGNIFICANCE: Our studies suggest that 'galign' is a useful tool for polymorphism discovery, and is of immediate utility for sequence mining in C. elegans.

Evan Johnson W et al. (2011) Biometrics "Dynamic linear model for the identification of miRNAs in next-generation sequencing data."

Evan Johnson W, Bass BL, Welker NC

[Biometrics, 2011]

Next-generation sequencing technologies are poised to revolutionize the field of biomedical research. The increased resolution of these data promise to provide a greater understanding of the molecular processes that control the morphology and behavior of a cell. However, the increased amounts of data require innovative statistical procedures that are powerful while still being computationally feasible. In this article, we present a method for identifying small RNA molecules, called miRNAs, which regulate genes by targeting their mRNAs for degradation or translational repression. In the first step of our modeling procedure, we apply an innovative dynamic linear model that identifies candidate miRNA genes in high-throughput sequencing data. The model is flexible and can accurately identify interesting biological features while accounting for both the read count, read spacing, and sequencing depth. Additionally, miRNA candidates are also processed using a modified Smith-Waterman sequence alignment that scores the regions for potential RNA hairpins, one of the defining features of miRNAs. We illustrate our method on simulated datasets as well as on a small RNACaenorhabditis elegansdataset from the Illumina sequencing platform. These examples show that our method is highly sensitive for identifying known and novel miRNA genes.

Zhang Q et al. (2015) J Theor Biol "Distribution bias of the sequence matching between exons and introns in exon joint and EJC binding region in C. elegans."

Zhou D, Zheng Y, Zhang Q, Li H, Zhao X

[J Theor Biol, 2015]

We propose a mechanism that there are matching relations between mRNA sequences and corresponding post-spliced introns, and introns play a significant role in the process of gene expression. In order to reveal the sequence matching features, Smith-Waterman local alignment method is used on C. elegans mRNA sequences to obtain optimal matched segments between exon-exon sequences and their corresponding introns. Distribution characters of matching frequency on exon-exon sequences and sequence characters of optimal matched segments are studied. Results show that distributions of matching frequency on exon-exon junction region have obvious differences, and the exon boundary is revealed. Distributions of the length and matching rate of optimal matched segments are consistent with sequence features of siRNA and miRNA. The optimal matched segments have special sequence characters compared with their host sequences. As for the first introns and long introns, matching frequency values of optimal matched segments with high GC content, rich CG dinucleotides and high CG values show the minimum distribution in exon junction complex (EJC) binding region. High CG values in optimal matched segments are main characters in distinguishing EJC binding region. Results indicate that EJC and introns have competitive and cooperative relations in the process of combining on protein coding sequences. Also intron sequences and protein coding sequences do have concerted evolution relations.

Calero M et al. (2001) J Biol Chem "Yop1p, the yeast homolog of the polyposis locus protein 1, interacts with Yip1p and negatively regulates cell growth."

Calero M, Collins RN, Whittaker GR

[J Biol Chem, 2001]

Rab proteins are small GTPases that are essential elements of the protein transport machinery of eukaryotic cells. Each round of membrane transport requires a cycle of Rab protein nucleotide binding and hydrolysis. We have recently characterized a protein, Yip1p, which appears to play a role in Rab-mediated membrane transport in Saccharomyces cerevisiae. In this study, we report the identification of a Yip1p-associated protein, Yop1p. Yop1p is a membrane protein with a hydrophilic region at its N terminus through which it interacts specifically with the cytosolic domain of Yip1p. Yop1p could also be coprecipitated with Rab proteins from total cellular lysates. The TB2 gene is the human homolog of Yop1p (Kinzler, K. W., Nilbert, M. C., Su, L.-K., Vogelstein, B., Bryan, T. M., Levey, D. B., Smith, K. J., Preisinger, A. C., Hedge, P., McKechnie, D., Finniear, R., Markham, A., Groffen, J., Boguski, M. S., Altschul, S. F., Horii, A., Ando, H. M., Y., Miki, Y., Nishisho, I., and Nakamura, Y. (1991) Science 253, 661-665). Our data demonstrate that Yop1p negatively regulates cell growth. Disruption of YOP1 has no apparent effect on cell viability, while overexpression results in cell death, accumulation of internal cell membranes, and a block in membrane traffic. These results suggest that Yop1p acts in conjunction with Yip1p to mediate a common step in membrane traffic.