{"id":98,"date":"2015-10-29T11:03:56","date_gmt":"2015-10-29T18:03:56","guid":{"rendered":"https:\/\/www.enlis.com\/blog\/?p=98"},"modified":"2015-10-29T11:21:22","modified_gmt":"2015-10-29T18:21:22","slug":"reverse-engineering-23andmes-proprietary-insertions-and-deletions","status":"publish","type":"post","link":"https:\/\/www.enlis.com\/blog\/2015\/10\/29\/reverse-engineering-23andmes-proprietary-insertions-and-deletions\/","title":{"rendered":"Reverse engineering 23andMe’s proprietary insertions and deletions"},"content":{"rendered":"

Quick summary:<\/em><\/p>\n

23andMe raw data contains insertions and deletions with proprietary identifiers, most of which have never been analyzed.
\n<\/em><\/p>\n

Our software can now handle over 1,000 of these “indels”, and nearly all of them impact a human disease or trait!<\/em><\/p>\n<\/blockquote>\n

\n

 <\/p>\n

Background:<\/strong><\/span><\/p>\n

There are only a few thousand insertions and deletions (“indels”) in the 23andMe raw data.\u00c2\u00a0 That’s not many compared to the hundreds of thousands of SNPs.\u00c2\u00a0 But indels can be some of the most impactful types of genome alterations.\u00c2\u00a0 Many diseases and traits are caused by an insertion or deletion in a critical gene.<\/p>\n

 <\/p>\n

Analysis of the indels in 23andMe’s raw data is difficult, because many of the indels use 23andMe’s proprietary identifier (i.e. i5037354).\u00c2\u00a0 In addition, they do not provide enough information to determine the exact insertion or deletion that was designed to be tested.\u00c2\u00a0 We asked 23andMe if they would share this information, but they declined to do so.<\/p>\n

 <\/p>\n

In the latest 23andMe genotyping chip (v4) there are:<\/p>\n

4,093 total indels<\/p>\n

and 3,413 of these indels use a 23andMe proprietary identifier\u00c2\u00a0 (83.3%)<\/p>\n

 <\/p>\n

Even when a dbSNP (rs) identifier is used, the position of the indel can be shifted, such that it makes it difficult to compare to next-generation sequencing data.<\/p>\n

We knew there were likely to be many important indels among those in the 23andMe data, so we set out to reverse engineer as many as we could, and identify those that affect human disease and traits.<\/p>\n

 <\/p>\n

The Indel Analysis:<\/strong><\/span><\/p>\n

We started with over 1,500 23andMe raw data files from the Opensnp.org<\/a> database.\u00c2\u00a0 We compiled a list of every indel and the frequency with which we found a DD, DI, or II genotype.\u00c2\u00a0 Then, we cross-correlated this list with a list of nearby known indels from our own database – especially those with a disease or trait phenotype.\u00c2\u00a0 We expect that many of the indels in the 23andMe raw data were designed to test known clinically relevant genome variants.<\/p>\n

Finally, we went though a very labor intensive process to analyze each indel, the surrounding sequence, the nearby clinical variants, and the expected allele frequencies.\u00c2\u00a0 In the end, we were able to confidently identify over 1,000 indels, most of which have a known effect on a disease or trait.<\/p>\n

 <\/p>\n

An Example:<\/span><\/strong><\/p>\n

Let’s take a look at one:<\/p>\n

i5012559\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a08\u00c2\u00a0\u00c2\u00a0 \u00c2\u00a087656009\u00c2\u00a0\u00c2\u00a0\u00c2\u00a0 DI<\/p>\n

We have identified this as an autosomal recessive deletion that can lead to Achromatopsia – a condition where the individual cannot see any color – complete color blindness!\u00c2\u00a0 There are a few carriers of this deletion in the Opensnp database, but no homozygous individuals (2 copies and therefore affected).\u00c2\u00a0 The frequency of this deletion among the 1,500 23andMe users is consistent with the frequency of this deletion in next-generation sequencing data.<\/p>\n

 <\/p>\n

23andMe doesn’t tell you anything about this deletion (even if you have access to the health information).\u00c2\u00a0 In the old 23andMe health reports, 23andMe identifies only 20 total insertions and deletions.\u00c2\u00a0 Given that there is less total information in the new health reports, I expect this number to be even smaller in the newly announced 23andMe health reports.<\/p>\n

As of this publication, this deletion is not reported by other interpretation services, like SNPedia\/Promethease.\u00c2\u00a0 To examine further, I randomly selected 50 of the indels that we identified and looked for them in SNPedia.\u00c2\u00a0 SNPedia only had information on 2 out of the 50 indels tested.<\/p>\n

 <\/p>\n

Summary:<\/span><\/strong><\/p>\n

For the first time anywhere, we have been able to analyze over 1,000 of 23andMe’s proprietary indels.\u00c2\u00a0 To my knowledge, the Enlis software is the only solution for identifying and getting more information on the majority of these health-impacting variants.<\/p>\n

I will have a more complete analysis of the totality of health information in the 23andMe raw data in another blog post, but one interesting thing to leave you with — the 23andMe raw data contains information on hundreds<\/span> of indels that are related to hereditary cancer.\u00c2\u00a0 How many hereditary cancer variants does 23andMe report in their new system?\u00c2\u00a0 Zero.<\/p>\n

 <\/p>\n

Want to get your own 23andMe indels analyzed?\u00c2\u00a0 Click here to start our import process.<\/a><\/p>\n

 <\/p>\n

 <\/p>\n

Note:\u00c2\u00a0 23andMe recently revamped their online service, but the genotyping chip has not changed.\u00c2\u00a0 The v4 chip, launched in December\u00c2\u00a02013, is still being used.<\/em><\/p>\n

 <\/p>\n

Appendix:<\/p>\n

The indels that we analyze affect these diseases:<\/p>\n

Achondrogenesis, type IB
\nAchromatopsia 3
\nAlpha Thalassemia
\nAlpha-2-macroglobulin polymorphism
\nAlzheimer disease, susceptibility to
\nAmyotrophic lateral sclerosis type 2
\nAndermann syndrome
\nAspartylglycosaminuria
\nAtaxia with vitamin E deficiency
\nAtaxia, Friedreich-like, with isolated vitamin E deficiency
\nAtaxia-telangiectasia syndrome
\nAtypical Rett syndrome
\nBRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer
\nBecker muscular dystrophy
\nBenign scapuloperoneal muscular dystrophy with cardiomyopathy
\nBeta Thalassemia
\nBeta-plus-thalassemia
\nBeta-thalassemia dominant
\nBloom syndrome
\nBreast cancer, susceptibility to
\nBreast-ovarian cancer, familial 1
\nBreast-ovarian cancer, familial 2
\nBronchiectasis with or without elevated sweat chloride 1, modifier of
\nBrugada syndrome 1
\nCardiomyopathy
\nCarnitine palmitoyltransferase ii deficiency, late-onset
\nCeroid lipofuscinosis neuronal 5
\nCeroid lipofuscinosis, neuronal, 11
\nChoroideremia
\nColorectal cancer, hereditary, nonpolyposis, type 1
\nCone-rod dystrophy 3
\nCongenital myopathy with fiber type disproportion
\nCongestive heart failure and beta-blocker response, modifier of
\nCystic fibrosis
\nDeafness, autosomal recessive 1A
\nDeafness, digenic, GJB2\/GJB3
\nDeafness, digenic, GJB2\/GJB6
\nDebrisoquine, poor metabolism of
\nDelta-zero-thalassemia, knossos type
\nDermatitis, atopic, 2, susceptibility to
\nDiastrophic dysplasia
\nDilated cardiomyopathy 1A
\nDilated cardiomyopathy 3B
\nDuchenne muscular dystrophy
\nDystonia 1
\nDystonia 12
\nEarly infantile epileptic encephalopathy 2
\nEncephalopathy, neonatal severe, due to MECP2 mutations
\nEnlarged vestibular aqueduct syndrome
\nFamilial Mediterranean fever
\nFamilial cancer of breast
\nFamilial hypercholesterolemia
\nFamilial hypertrophic cardiomyopathy 2
\nFamilial hypertrophic cardiomyopathy 4
\nFamilial hypertrophic cardiomyopathy 7
\nFanconi anemia, complementation group C
\nFanconi anemia, complementation group D1
\nFrontotemporal dementia, ubiquitin-positive
\nFumarase deficiency
\nGaucher’s disease, type 1
\nGlucose-6-phosphate transport defect
\nGlycogen storage disease IIIa
\nGlycogen storage disease IIIb
\nGlycogen storage disease type 1A
\nGlycogen storage disease type III
\nHearing impairment
\nHeinz body hemolytic anemia
\nHemoglobinopathy
\nHereditary cancer-predisposing syndrome
\nHereditary factor VIII deficiency disease
\nHereditary fructosuria
\nHereditary leiomyomatosis and renal cell cancer
\nHereditary nonpolyposis colorectal cancer type 5
\nHereditary pancreatitis
\nHypertrophic cardiomyopathy
\nI cell disease
\nIchthyosis vulgaris
\nImmunodeficiency due to ficolin 3 deficiency
\nInfantile hypophosphatasia
\nInfantile-onset ascending hereditary spastic paralysis
\nInfertility associated with multi-tailed spermatozoa and excessive DNA
\nInflammatory bowel disease 1, susceptibility to
\nLeber congenital amaurosis 4
\nLeft ventricular noncompaction 6
\nLi-Fraumeni syndrome 1
\nLimb-girdle muscular dystrophy, type 2A
\nLimb-girdle muscular dystrophy, type 2G
\nLong QT syndrome 3
\nLynch syndrome
\nLynch syndrome I
\nLynch syndrome II
\nMacular dystrophy, vitelliform, adult-onset
\nMalignant tumor of prostate
\nMarfan’s syndrome
\nMaturity-onset diabetes of the young,\u00c2\u00a0 type 2
\nMeckel-Gruber syndrome
\nMental retardation, X-linked, syndromic 13
\nMicrocephaly, normal intelligence and immunodeficiency
\nMultiple epiphyseal dysplasia 4
\nMyopathy, distal, 1
\nNeurofibromatosis, familial spinal
\nNeurofibromatosis, type 1
\nNeurofibromatosis, type 2
\nNeurofibromatosis-Noonan syndrome
\nNiemann-Pick disease, type A
\nOsteogenesis imperfecta
\nOsteogenesis imperfecta type I
\nOsteogenesis imperfecta type III
\nPachydermoperiostosis syndrome
\nPachyonychia congenita type 2
\nPancreatic cancer 2
\nPancreatic cancer 4
\nPancreatic cancer, susceptibility to
\nParkinson disease 6, autosomal recessive early-onset
\nParkinson disease, late-onset
\nPendred’s syndrome
\nPersistent hyperinsulinemic hypoglycemia of infancy
\nPhenylketonuria
\nPhosphate transport defect
\nPolycystic kidney disease, infantile type
\nPrimary familial hypertrophic cardiomyopathy
\nPrimary hyperoxaluria, type II
\nPrimary progressive aphasia
\nPseudo-Hurler polydystrophy
\nPseudoxanthoma elasticum
\nRetinitis pigmentosa 19
\nRetinitis pigmentosa 7
\nRetinoblastoma
\nRett’s disorder
\nSchwannomatosis
\nSpastic ataxia Charlevoix-Saguenay type
\nStargardt disease 1
\nSupranuclear palsy, progressive, 1, atypical
\nSymmetrical dyschromatosis of extremities
\nTay-Sachs disease
\nTurcot syndrome
\nTyrosinase-negative oculocutaneous albinism
\nWerdnig-Hoffmann disease
\nWilson’s disease<\/p>\n","protected":false},"excerpt":{"rendered":"

Quick summary: 23andMe raw data contains insertions and deletions with proprietary identifiers, most of which have never been analyzed. Our software can now handle over 1,000 of these “indels”, and nearly all of them impact a human disease or trait!   Background: There are only a few thousand insertions and deletions (“indels”) in the 23andMe […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-98","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"_links":{"self":[{"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/posts\/98","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/comments?post=98"}],"version-history":[{"count":0,"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/posts\/98\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/media?parent=98"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/categories?post=98"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.enlis.com\/blog\/wp-json\/wp\/v2\/tags?post=98"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}