Snps mutations haplotypes
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SNPs Mutations Haplotypes. Sequence variations. http://www.ebi.ac.uk/mutations/. How much variation in human genome?. 3000 Mb; a SNP every 1kb = 3 milj. Underestimate? Rare ones might be the most interesting 40 000 genes x 100 variants = 4 milj. slow build-up

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Sequence variations

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Snps mutations haplotypes

SNPs

Mutations

Haplotypes

Sequence variations

http://www.ebi.ac.uk/mutations/


How much variation in human genome

How much variation in human genome?

  • 3000 Mb; a SNP every 1kb = 3 milj.

    • Underestimate?

    • Rare ones might be the most interesting

  • 40 000 genes x 100 variants = 4 milj.

    • slow build-up

  • Bottlenecks in human population history!


Variations

Variations

  • SNPs (Single Nucleotide Polymorphisms)

  • Indels, dinucleotide mutations

  • Mutations, polymorphisms

  • Chromosomal rearrangements

    • inversions

    • translocations

    • indels


Levels of biological data

Mutations

Levels of biological data

DNA

RNA

Polypeptide

Protein structure

Protein function

Protein interection pathways

Cellular dynamics

Tissue interactions

Organism (phenotype)

Population dynamics


Uses of sequence variations

Gene

structure &

function

Diagnosis of

inherited

disorders

Evolution &

ecology

Trans-

plantation

Genetic

mapping

Tissue

typing

Forensics

Epidemi-

ology

Insurance

evaluation

?

Association

studies

Carrier

screening

Pharmaco-

genetics

Scientists

Biomed

students

Healthcare

professionals

"General

public"

Uses of sequence variations


Data sources

Nucleotide sequences

Amino acid sequences

EMBL/GenBank/DDBJ

Non-redundant human sequence

SWISS-PROT

SNPs

Data sources

Central variation databases

Sequence alignments

Population studies

Direct submissions

Literature / Publishers

Single Locus Databases

Blood Cells, Molecules

and Diseases

HGVS


Dna mutation checker v 2

DNA Mutation Checker v.2

Bio::LiveSeq

Bio::Variation

http://bio.perl.org/


Sequence variations

SNPs

  • dbSNP

    • main repository

  • HGVbase

    • clean subset

  • TSC

    • verified SNPs

    • allele frequency project

  • National SNP projects

    • Japan, China, ...


  • Sequence variations

    SNPs

    • dbSNP #29

      • 2,673,925 (414,853 masked)

  • HGVbase #13

    • 1,451,426

  • TSC #10

    • 1,389,655

    • 1,062,212 mapped


  • Hgvbase

    HGVbase

    • Human Genome Variation database http://hgvbase.cgb.ki.se/

    • ex. HGBASE

    • Three part collaboration betweenTony Brookes (KI), Heikki Lehvaslaiho (EBI) and Peer Bork (EMBL).

      • text and homology searches

      • Distributions: SQL dump, XML, flat file, FASTA


    Snp synchronization

    SNP synchronization

    Ensembl

    dbSNP

    HGVbase


    Hgbase update

    HGBASE update

    • Assays

    • Flanking sequence retrieval

    • Effects on predicted genes

    • Chromosomal locations

    • Similarity scoring

    • Haplotypes

    • WOW extensions

    http://hgbase.cgb.ki.se/


    Mutation distribution

    Mutation distribution


    Mutation numbering options

    Mutation numbering options

    Reference

    Sequence

    Numbering

    Schema

    -1 +1

    Coding region

    cDNA

    DB entry

    Coding region

    gDNA

    DB entry

    Genomic gene seq


    Sequence variations

    HGVS

    • Human Genome Variation Society

      • http://www.hgvs.org/

      • ex. HUGO MDI

      • Society Journal: Human Mutation

    • “The Society aims to foster discovery and characterization

    • of genomic variations including population distribution and

    • phenotypic associations.

    • We will promote collection, documentation and free distribution of

    • genomic variation information and associated clinical variations and

    • endeavor to foster the development of the necessary

    • methodology and informatics.”


    A human sequence variation database emphasizing data quality and a broad spectrum of data sources

    A human sequence variation database emphasizing data quality and a broad spectrum of data sources

    WaystationOfficeWarehouse

    WOW

    Jamie Cutticia

    Dick Cotton

    Heikki Lehväslaiho

    Tony Brookes


    Wo warehouse plans

    WOWarehouse plans

    • Expansion of the HGBASE design

    • Use of the Ensembl framework

    • Data flow from WayStation

      • Novel mutations

  • Direct parsing

    • Existing resources (SRS)

    • Need to get the the data in quickly

  • Haplotype & Genotype descriptions

  • Phenotype desciption


  • Wow structure

    Other

    sources

    LSDB

    LSDB

    LSDB

    LSDB

    ID

    WayStation

    Submitter

    Warehouse

    Updates

    Downloads

    PubMed

    Human Mutation

    Interfaces

    LSDB

    LSDB

    LSDB

    Editor

    WOW structure

    Correction requests

    Downloads

    Updates

    Submission

    Peer review


    Reference sequence

    Reference Sequence

    • Strive to use genomic coordinates

    • Use Ensembl to visualise all variants in genomic context

    • Ensembl is now using NCBI genome builds => only one, up-to-date reference sequence

    • Easy way to transform gene coordinates into genomic coordinates


    Haplotype representation

    Haplotype representation

    • Haplotype = list of Marker/AlleleIDs & HaplotypeIDs.

    • No ordering of IDs in Haplotype definition – taken care of by Marker definition.

    • No reference haplotypes

    • Genotype: >2 Haplotypes


    Haplotypes

    Haplotypes

    • Chr21, 6 chromoses

      • David Cox (Patil et al, Science)

      • whole human genome coming

    • Chr22, >200 individuals

      • Ian Dunham, in preparation

    • Haplotype Blocks!

    • HapMap (Eric Lander, NIH)


    Phenotype

    Phenotype

    • Pragmatic approach!

    • Ideas:

      • Based on extended GO terminogy developed at Jackson Laboratory

        • Phenotype = modifier + traits

      • OMIM compatible

      • US NML anatomy vocabulary subset?


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