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Autozygosity

Mapping analysis software Dr Ian Carr PhD. MCSD. Leeds Institute of Molecular Medicine St James’s University Hospital. Autozygosity. LA = local (common) ancestor LI = local inheritance. But!. Autozygosity. You only know part of the picture And

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Autozygosity

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  1. Mapping analysis softwareDr Ian Carr PhD. MCSD.Leeds Institute of Molecular MedicineSt James’s University Hospital

  2. Autozygosity LA = local (common) ancestor LI = local inheritance But!

  3. Autozygosity You only know part of the picture And What you don’t know can be more important than what you do know DA = distant (common) ancestor DI = distant inheritance

  4. Analysis • Old way • Spend 1.5 years mapping a family with highly informative microsatellites • Analyse data as you go • Hope you find something! • New way • Send DNA off with £300 per sample • Wait three weeks • Stare at a million uninformative SNPs worth of data and wonder what to do with it!

  5. AutoSNPa • What is it: • It’s one big database which draws pretty pictures • There is no maths, because there is no complete knowledge of the system • Assumptions • All affecteds are consanguineous and have the same mutation and hence a common haplotype

  6. AutoSNPA: Pedigree one • First family • Results • 135Mb region on chromosome 4 • Out come • To many genes: Move on. 135Mb

  7. AutoSNPA: Pedigree two • Two families • New Results • 45Mb Region on chromosome 4 • Out come • Still to many genes: Move on 45Mb

  8. AutoSNPA: Pedigree three • Three families • New new Results • 4.5Mb region on chromosome 4 • Out come • 8 genes, one good candidate: Sequenced it and published. 4.5Mb

  9. The problem with AutoSNPa • It requires a large family with multiple affected people who will give a DNA sample or a number of families with the same founder mutation. • In reality large families are rare as hens teeth and a each family tends to have its own mutation.

  10. IBDFinder • What is it: • It’s another big database which draws pretty pictures • Again no maths • Assumptions • The affecteds are consanguineous and most have mutations in the same gene.

  11. Molar pregnancies and IBDFinder Number of patients homozygous for the region 19p-tel 19q-tel • Disease has social stigma, so no pedigree data • Most unrelated to each other. • 2 have mutations in a different gene. • 2 have an IBD region of one SNP in the data set

  12. Milk drinkers and IBDfinder • The ability for adults to drink milk is relatively new and there are only a few genotypes that have the phenotype. Therefore most of us are homozygous for the LCT gene on chromosome 2

  13. Problems with IBDfinder • DNA from affecteds is not always easy to come by.

  14. “SAMPLE” Shadow Autozygosity MaPping by Linkage Exclusion • What is it: • A program that finds disease genes without the DNA of an affected patient, only DNA from the parents and siblings of affecteds. • Assumptions: • An inbreed family is 3 times more likely to have an unaffected kid than an affected one, none of whom will be homozygous for the disease causing allele.

  15. Meckel-Gruber Syndrome (MKS3) • DNA available from individuals with yellow symbols. No data from affected individuals

  16. SAMPLE test data SAMPLE excludes most of the genome (~98%) and the remaining regions can be checked using microsatellites.

  17. Problems with SAMPLE • All the pedigree have to have a mutation in the same gene. • It works at the level of individual SNPs and does not consider extended haplotypes.

  18. Phaser • What is it • A program that uses logic to determine the phase of the genotypes of the SNPs on each chromosome. • It can then calculate how autozygous each person is, how related a pedigree is to another and to find common haplotypes in affecteds. • Requirements • It needs SNP data for parents and at less two children and ideally a number of pedigrees.

  19. Meckel-Gruber Syndrome (MKS3) • Phaser identifies segments of chromosomes present individuals allowing the user to analysis dominant and recessive diseases.

  20. Degree of relatedness

  21. Degree of relatedness • By knowing how related two pedigrees are, it is possible to judge how likely they are to have a common haplotype

  22. The problem with Phaser • It has not been tested exhaustively and so may not work!

  23. Sequence analysis • Sanger sequencing mutation detection • Next generation clonal sequencing mutation detection

  24. Genescreen • Rapid detection and annotation of sequence variants

  25. Annotation of simple mutations • Single base mutations are automatically annotated with genomic, cDNA and protein information.

  26. Annotation of complex mutations • Heterozygous indels are deconvoluted and annotated. This window also annotates indels and homozygous insertions and deletions

  27. Exporting data • Plain text, LOVD import file or a web page. • The webpage is updatable and so acts a data display and data base.

  28. Clonal sequencing • Nothing lasts for ever so the current sequencing project is to create a program that analysers Illumina sequence data. • At the moment the base program analyses data at a rate of 3.6 billion bases an hour or 320Mb of data a minute.

  29. Underlying data for a heterozygous base change

  30. Underlying data for a heterozygous base pair insertion

  31. All released programs can be obtained from: www.Autozygosity.com

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