Gleis Week 11

GO Terms

Metacyclic: produced in an intermediate host, and infective for the definitive host; said of the infective stages of trypanosomes. http://medical-dictionary.thefreedictionary.com/metacyclic

Promastigote:The flagellate stage of a trypanosomatid protozoan, as that of any of the Leishmania parasites http://medical-dictionary.thefreedictionary.com/promastigote

Phagolysosome:a cytoplasmic body formed by the fusion of a phagosome, or ingested particle, with a lysosome containing hydrolytic enzymes. The enzymes digest most of the material within the phagosome http://medical-dictionary.thefreedictionary.com/phagolysosome

Tripartite:having three corresponding parts or copies http://www.merriam-webster.com/dictionary/tripartite

"Repeated-repeat": repeated tandem repeats, Copies of DNA sequences which lie adjacent to each other in the same orientation (direct tandem repeats) or in the opposite direction to each other http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Tandem+Repeat

bacterial clade:Related organisms descended from a common ancestor. For example, isolate M of HIV-1 (the human immunodeficiency virus) consists of at least ten clades. Imported from the Greek, klados, branch in 1911 in reference to the Tree of Life. http://www.medterms.com/script/main/art.asp?articlekey=22233

filarial:related to or infested with or transmitting parasitic worms especially filaria http://wordnetweb.princeton.edu/perl/webwn?s=filarial

trypanosomatid:common name for a member of the family Trypanosomatidae http://medical-dictionary.thefreedictionary.com/trypanosomatid

chromodomain:Chromodomains are highly conserved sequence motifs that have been identified in a variety of animal and plant species. A chromodomain harbours a methylated lysine residue. http://www.springerreference.com/docs/html/chapterdbid/34668.html

bromodomain:Protein containing at least one bromodomain. The bromodomain is a conserved region, approximately 70 amino acids, characteristic for a class of regulatory proteins. It mediates interactions with proteins that are necessary for transcriptional activation. http://www.uniprot.org/keywords/KW-0103

Reference Article Outline

I. Abstract

• Leishmania major causes leishmaniasis, a dreadful human disease found throughout the world.
• Many genes currently studied involved the pathogenic nature of Leishmania major
• The lack of certain genes in the genome of Leishmania suggest novel expression and regulation systems

II. Introduction

• Leishmania parasites are transmitted by sand flies
• Once Leishmania have infected the host, the parasite subsequently proliferates and spreads throughout the host.
• Different Leishmania species exhibit differences in genome composition and structure
• This article presents the structure and content of the Leishmania major genome
• Special emphasis is given to fundamental molecular processes and pathogen-speicific functions

III. Genome structure and content

• Shotgun sequencing was used to sequence the genome chromosome by chromosome
• Table 1 is a summary of genome information for Leishmania. It includes size and gene information
• Table 2 includes information regarding families of genes in the Leishmania genome
• Several algorithms were used to predict the number of genes of each type in the genome
• Many genes in Leishmania major resemble genes other Leishmania species
• Some genes appear to be Leishmania major specific
• The Leishmania genome contains genes for MIFs which are likely responsible for the promotion of parasite survival in the host.

IV. RNA genes

• RNA participate in many important cellular processes
• RNA genes are similar between Leishmania species but their organization in the genome varies
• The genomes of Leishmania species demonstrate similarity in RNA composition and function

V. Chromatin remodeling

• Chromatin remodeling genes are distributed throughout the genome in L. major as opposed to clustering in other species
• The L. major genome contains several genes responsible for various histone modifications as well as chromatin modifications
• The modifications include acetylation and methylation

VI. Transcription

• The Leishmania major genome demonstrates unique gene clustering
• Transcription initiation in L. major is not fully understood but transcription appears to begin bidirectionally in strand-switch regions
• The genomes of Leishmania species lack components of genes encoding for RNA polymerase
• The genes for RNA polymerase vary greatly from other species
• Few homologs were found for RNA polymerase transcription factors
• Figure 1 provides a graphical image of Leishmania RNA polymerase subunits and transcription factors
• The genes located in the genome suggest post transcriptional control mechanisms as the primary determinants of gene expression
• Figure 2 provides information on the association of protein domains and gene expression regulation
• The bar graph demonstrates individual genome sequence similarity for protein domains

VII. RNA Processing

• mRNA processing is unique trypanasomatids
• However, many spliceosome proteins were identified in the genome
• Advanced splicing regulatory protein networks were identified suggesting early evolutionary development
• Two distinct, dissimilar poly(A) polymerases were identified
• The absence of certain polymerase domains reflects the polycistronic transcription of the organism
• Genes playing a role in mRNA degradation have been identified and appear similar to mammalian genes
• Leishmania lacks regulation and specificity of these mRNA degrading proteins
• A high number of RNA recognition motifs furthers suggest polycistronic transcription
• A novel domain was identified in these RNA binding proteins

VIII. Translation and post translational modification

• Genes encoding translation machinery are similar to that of other lower Eukaryotes
• Relatively high number of translation factors suggests high degree of specialization
• The genome encodes for typical protein modification processes
• A particularly high number of genes encode for enzymes that produce certain protein modifications
• These enzymes could be potential drug targets

IX. Surface Molecules

• Surface molecules are particularly important for Leishmania due to infectious processes requiring these molecules
• Many genes encoding for these surface molecules appear to be novel and have not been completely identified
• Some of these molecules are assembled in the lumen of the golgi due to a need for sugar assembly
• L. major specific genes have been identified for these processes
• Some of these genes are clustered together on the genome
• The primary sphingolipid in Leishmania is IPC
• This is not produced in mammals and is therefore and excellent drug target
• The major insect stage surface protein of Leishmania is GP63 which is a zinc metallopeptidase
• Surface proteins appear to be expressed variably with development
• L. major shares surface molecule similarity to other related species

X. Proteolysis

• Peptidases are very diverse and are characterized by evolutionary similarity
• L. major lacks certain peptidases common to other parasites but share similarities to other Leishmania species
• Exhibit nonlysosomal protein degradation through ubiquitin
• Cell death through caspase independent mechanism
• No trypsin/chymotripsin
• Other serene peptidases present as well as other metallopeptidases other than GP63
• Lack certain peptidase inhibitors but exhibit inhibitors not present in mammals
• Produce inhibitors of peptidases to aid in infection of host

XI. Conclusion

• Leishmania genomes share many similarities but genomic differences express important factors that enable specific functioning of the organism
• Genomic data provides important insight to drug targets for Leishmanaiasis

Model Organism Database

http://tritrypdb.org/tritrypdb/

1. Sequence information, functional data and annotations are included in the database; meta-database, curated manually in a community setting
2. EuPathDB maintains the site. A special committee of Leishmania experts from a variety of universities oversees the curation of the TriTrypDB site
3. Funding is provided by The Bill and Melinda Gates Foundation, Wellcome Trust, and NIAID
4. Data is provided freely for public use. No restrictions.
5. Last updated 25 September 2013
6. There are links to GeneDB as well as EuPathDB. THe website also provides links to a variety of tools contained in other databases.
7. Files are available to download in many formats such as .ppt .pdf .docx .tiff .jpg .txt .gff
8. The website is fairly easy to follow although the site navigation is not the most intuitive. There is a help section with a variety of video tutorials. The results make sense as long as the desired result is specific.
9. LmjF.##.####

Powerpoint Presentation

Leishmania major Genome Reference Article Presentation

Gleis (talk) 22:08, 11 November 2013 (PST)