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(12) Patent Application Publication (10) Pub. No.: US 2011/0098193 A1 Kingsmore Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0098193 A1 Kingsmore Et Al US 2011 0098193A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0098193 A1 Kingsmore et al. (43) Pub. Date: Apr. 28, 2011 (54) METHODS AND SYSTEMS FOR MEDICAL type (such as a disease symptom) of the trait, wherein the SEQUENCING ANALYSIS association of the relevant element with the relevant compo nent phenotype identifies the relevant element as an element (76) Inventors: Stephen F. Kingsmore, St. associated with the trait, wherein the relevant component Augustine, FL (US); Callum J. phenotype is a component phenotype having a threshold Bell, Santa Fe, NM (US) value of severity, age of onset, specificity to the trait or dis ease, or a combination, wherein the relevant element is an (21) Appl. No.: 12/910,764 element having a threshold value of importance of the ele ment to homeostasis relevant to the trait, intensity of the (22) Filed: Oct. 22, 2010 perturbation of the element, duration of the effect of the element, or a combination. The disclosed methods are based Related U.S. Application Data on a model of how elements affect complex diseases. The disclosed model is based on the existence of significant (60) Provisional application No. 61/254,115, filed on Oct. genetic and environmental heterogeneity in complex dis 22, 2009. eases. Thus, the specific combinations of genetic and envi ronmental elements that cause disease vary widely among the Publication Classification affected individuals in a cohort. The disclosed model is an (51) Int. Cl. effective, general experimental design and analysis approach C4OB 30/04 (2006.01) for the identification of causal variants in common, complex C4DB 60/2 (2006.01) diseases by medical sequencing. Also disclosed herein are methods of identifying an inherited trait in a subject. The (52) U.S. Cl. ............................................... 506/9; 506/39 disclosed methods compare a reference sequence from a Sub ject to a library of sequences that contain each mutation. For (57) ABSTRACT a given mutation, a normal sequence read aligns best to the Disclosed are methods of identifying elements associated normal library sequence. A read having the mutation aligns with a trait, such as a disease. The methods can comprise, for best to the mutant library sequence. The disclosed model and example, identifying the association of a relevant element the disclosed methods based on the model can be used to (such as a genetic variant) with a relevant component pheno generate valuable and useful information. O Select a set of samples 102 Extract nucleic acids from samples 1 Perform DNA sequencing 04 Align sequence reads to a reference database 1 05 Identify potential variants for each sample (for example, SNPs) 106 Apply a first subset of rules to the candidate variants 1 Of Apply a second subset of rules to the candidate variants 1 08 Walidate nominated genes 109 Examine association of validated gene variants with component phenotypes Patent Application Publication Apr. 28, 2011 Sheet 1 of 40 US 2011/0098193A1 FIG. 1 FIG. 2 101 201 Select a set of samples Select a set of samples 102 Extract nucleic acids from Extract nucleic acids from samples samples 103 203 Perform DNA sequencing Perform DNA sequencing 104 204 Align Sequence reads to a Align Sequence reads to a reference database reference database 105 205 ldentify potential variants for ldentify potential variants for each sample (for example, each Sample (for example, SNPs) indels) 106 Apply a first subset of rules to Apply a first subset of rules to the candidate variants the Candidate variants 107 Apply a second subset of rules Apply a second subset of rules to the Candidate variants to the Candidate variants 108 208 Validate nominated genes Validate nominated genes 109 209 Examine association of validated Examine association of validated gene variants with component gene variants with component phenotypes phenotypes Patent Application Publication Apr. 28, 2011 Sheet 2 of 40 US 2011/00981.93 A1 FIG. 3 301 Identify an association of a relevant element With a relevant component phenotype of the trait Wherein the association of the relevant element With the relevant component phenotype identifies the relevant element as an element associated with the trait Wherein the relevant component phenotype is a component phenotype having a threshold value of severity, age of Onset, specificity to the trait or disease, Or a Combination Wherein the relevant element is an element having a threshold value of importance of the element to homeostasis relevant to the trait, intensity of the perturbation of the element, duration of the effect of the element, or a Combination Patent Application Publication Apr. 28, 2011 Sheet 3 of 40 US 2011/00981.93 A1 9717 Patent Application Publication Apr. 28, 2011 Sheet 4 of 40 US 2011/00981.93 A1 G09 9ouembæS Spee»- ?seO M??AuÐAO Patent Application Publication Apr. 28, 2011 Sheet 5 of 40 US 2011/00981.93 A1 Patent Application Publication Apr. 28, 2011 Sheet 6 of 40 US 2011/00981.93 A1 transcript: NM 080426.1 cose: SD1437 Help variant filter A. Restrict where ot least reods Co variont DSNP OnSSNP Oin/del B. Restrict where ot least reads cover position Voront in Coding region C. Restrict where between 2, and % of reads call variant DVOriont Couses premature stop NOTE: A/B=C. UPDATE CLEAR Overview o SNP nSSNP in/del closeup Obp ----Y - -a -a -a -a -a -a -a --a - - a 4- - A 4-- - a 4- 4 - - a 4- - a 4 a 4- 4- -a -- 4----- 4- 4- -- 4 4- - a -a - a 4- 4- -a 4- -A FG.7A Patent Application Publication Apr. 28, 2011 Sheet 7 of 40 US 2011/00981.93 A1 transcript: NM_080426. COSe: SD1437 Help variant filter A. Restrict where ot least 4 reads cat YOriont SNP InsSNP in/del B. Restrict where at least reods COver position Variant in Coding region C. Restrict where between 50 % and % of reads coil variont VOriont Couses premature stop NOTE: A/B=C% UPDATE CLEAR Overview o SNP asSNP in/del closeup Obp 1551bp -a a -ara a4- -- - 4--a 4 --a 4-4-4--as-a-- A 4 - - A - A - A - A - 4 - A a - a 4- - a - a 4- -a - a 4- 4 - 4 - - a 4 -la-la all 4l la la 4-l. 4 l 4-l la 4-l la a sea a a sa sea a -a a -a a - a 4- - a -a - a -a - a 4- - A 4 - - A 4- 4- -a -a - a 4- 4- 4 - -a -a -a 4 4- 4 - -A 4 - - a 4- -a - A 4- - A 4 - - a 4- - a 4 + 4- - a 4- - a -a - a 4- - a 4 -a 4- 4 - -A 4- -A 4-4- 4--a 4- -A as a 4-a- 4a aa a -a 4- a -a a 4-a- sa 4s sa sa sy sla as a as sla 4-s - a 4- - a 4- - a -a - a -a - a 4- - a as a 4s as a sa as sea a 4s as sla - a 4- 4- 4 - - a 4- -a - a 4- -a - a 4 -a -a. -a -a -a -a -a -a -a - a 4 4- 4l -la -la 4-l. 4-l la la la la sa sa as as sea as a sla sa sla - a 4- - a 4- - a 4- 4 - - a 4- - a 4 -A - a 4- a 4- -a -a -a -a 4 area rea 4-e 4-e are sea e A v. A 4-see sea ala 4- a - a 4a a ma ma 4- 4- -a -a -a - a -A 4- 4- -a -a 4 sea area 4e are 4- 4 - - a 4 4- - a -a - a 4- -a -la 4 - a 4- 4- 4 - 4- 4 - a 4- -a -a - a 4 4l 4-l -la. 4l la sea as as a ra as - a 4- - a m a 4m ma 4m. FIG.7B Patent Application Publication Apr. 28, 2011 Sheet 8 of 40 US 2011/00981.93 A1 FG. 8 30 SID1437 25 o .. SD1438 2O X ...) SD1439 t 15 & 10 & S S S S S is is & S S is is 303 f 8. :::: Number of aligned teads per RefSeq transcript, run Patent Application Publication Apr. 28, 2011 Sheet 9 of 40 US 2011/00981.93 A1 A01A/040 0 Patent Application Publication Apr. 28, 2011 Sheet 10 of 40 US 2011/00981.93 A1 0??V\/\/\/\/010LOLVOLLOLLO\/\/910L\/\/9LVVOOLV?©(VVO 669][99VVVVV?LÐLOLVOLLOLLOVVOLS)LVVOLVVOOLV?©?VVOLO |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||| Patent Application Publication Apr. 28, 2011 Sheet 12 of 40 US 2011/00981.93 A1 O FIG. 3 Patent Application Publication Apr. 28, 2011 Sheet 13 of 40 US 2011/00981.93 A1 y Patent Application Publication Apr. 28, 2011 Sheet 14 of 40 US 2011/00981.93 A1 Patent Application Publication Apr. 28, 2011 Sheet 15 of 40 US 2011/00981.93 A1 Process Overview Enter Sample Rock the Samples in to MS -8) Bood Rock the Extract DNA DNA sample QC by NSureSelect Samples in from blood in hand nanodrop fridge Roin)drce 7 SPR Corcotenate QC by RainDOnce QC by Sonicote purification- Prep Bibrary Sonicote bioanalyzer errichmenttarget bioanalyzer 3 kb Pool braries QC enriched Poolbroies 8. QC by E.--DNA conse--(PSR-Agent yard Bioanalyzer & SPR, Prep library - St. Sequencing & nonodrop) DNA enrichment nanodrop purification 150 bp Disambiguate Export MP Pogle Run illuminC multiplexed Sequence Quality Scores Run Alpheus Run COverage plot and VC pipeline Indexes dota as files report pipeline Script chart reports 1st Cycle % of redds Run mutation % contro 8 ot binned detection genotypes colled Final report Scripts correctly FG 16 Patent Application Publication Apr. 28, 2011 Sheet 16 of 40 US 2011/00981.93 A1 F.G.
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