title: Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
abstract: Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94143, USA. sebaran@cgl.ucsf.edu
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Joann
authors.initials: J
authors.lastname: Mudge
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: van Velkinburgh
authors.forename: Pouya
authors.initials: P
authors.lastname: Khankhanian
authors.forename: Irina
authors.initials: I
authors.lastname: Khrebtukova
authors.forename: Neil A
authors.initials: NA
authors.lastname: Miller
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Farmer
authors.forename: Callum J
authors.initials: CJ
authors.lastname: Bell
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Kim
authors.forename: Gregory D
authors.initials: GD
authors.lastname: May
authors.forename: Jimmy E
authors.initials: JE
authors.lastname: Woodward
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McElroy
authors.forename: Refujia
authors.initials: R
authors.lastname: Gomez
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Pando
authors.forename: Leonda E
authors.initials: LE
authors.lastname: Clendenen
authors.forename: Elena E
authors.initials: EE
authors.lastname: Ganusova
authors.forename: Faye D
authors.initials: FD
authors.lastname: Schilkey
authors.forename: Thiruvarangan
authors.initials: T
authors.lastname: Ramaraj
authors.forename: Omar A
authors.initials: OA
authors.lastname: Khan
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Huntley
authors.forename: Shujun
authors.initials: S
authors.lastname: Luo
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
mesh_terms: D000293:Adolescent; D000328:Adult; D022981:Allelic Imbalance / Q000235:genetics; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: D012333:RNA, Messenger