Example of Function Prediction

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1 Find similar genes

2 Example of Function Prediction Suggesting functions of newly identified genes It was known that mutations of NF1 are associated with inherited disease neurofibromatosis 1; but little is known about the molecular basis of the disease Sequence search found that NF1 is homologous to a yeast protein called Ira, which is a GAP type protein and known to regulate the function of a second type of protein called Ras Hypothesis: NF1 regulates Ras in human cell; follow on experiments verified this.

3 orthology vs. paralogy Orthologous gene = two genes found in different species that trace back to a common ancestral gene at the time of the last common ancestor Species A Gene A Ancestral Species Gene A Species B Gene A Paralogous genes = genes duplicated within a species Species A Gene A Gene A Ancestral Species Gene A Species B Paralogous genes Gene A

4 Detection of orthologous genes One simple approach: genes A and B of two genomes are predicted to be orthologous genes if A is the best hit of B in A s genome and vice versa this may not always work when two genomes are only remotely related An enhanced method: genes A, B, C from three genomes are considered to orthologous if A and B, B and C and C and A are all best hits for pairwise comparisons an implementation of this strategy is called COG (clusters of orthologous genes)

5 Detection of orthologous genes

6 MGI: mouse genome informatics

7 Inparanoid and orthomcl bin/e.cgi bin/orthomclweb.cgi

8 What is InParanoid? Homologs that originate from a speciation event are called orthologs. homologs that originate from a gene duplication event are called paralogs. If a duplication event predates the speciation event the parlogs are called outparalogs, and they can be present in different species. If instead an ortholog undegoes one or several duplication events, the resulting paralogs are called inparalogs, and they are co orthologs to one or more orthologs in another species. Since an outparalog pair ought to have a more diversified function than inparalogs, it is useful to distinguish between the two. Furthermore, clustering inparalogs together allows proper identification of both one to one and many tomany orthology case.

9 How does InParanoid detect orthologs? The InParanoid program uses the pairwise similarity scores, calculated by NCBI Blast, between two complete proteomes for constructing orthology groups. An orthology group is initially composed of two so called seed orthologs that are found by two way best hits between two proteomes. More sequences are added to the group if there are sequences in the two proteomes that are closer to the correpsonding seed ortholog than to any sequence in the other proteome. These members of an orthology group are called inparalogs.

10 ENSEMBL

11 ENSEMBL orthologous genes Stat1, oct4, NM_199153

12 Pfam Protein domain often tell us some function of the genes and proteins.

13 Structural similarity Orthologs are based on sequence similarity, we can also infer gene function based on structural similarity or domain content similarity.

14 Gene Sorter bin/hgnear The UCSC Gene Sorter is an excellent resource for exploring gene families and the relationships among genes. This tool displays a table of genes within a selected genome that are related to one another. Several different relationships may be explored: protein level homology, similarity of gene expression profiles, or genomic proximity.

15 Gene expression clustering Select a dataset and cluster and then use the GO analysis

16 Notes Slides 2 5 are copied from Ying Xu s class materials. Ortholog, paralog Orthologous genes and expression patterns can tell you new gene functions.

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