Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
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.
Baranzini
Sergio E
SE
Department of Neurology, University of California at San Francisco, San Francisco, California 94143, USA. sebaran@cgl.ucsf.edu
Mudge
Joann
J
van Velkinburgh
Jennifer C
JC
Khankhanian
Pouya
P
Khrebtukova
Irina
I
Miller
Neil A
NA
Zhang
Lu
L
Farmer
Andrew D
AD
Bell
Callum J
CJ
Kim
Ryan W
RW
May
Gregory D
GD
Woodward
Jimmy E
JE
Caillier
Stacy J
SJ
McElroy
Joseph P
JP
Gomez
Refujia
R
Pando
Marcelo J
MJ
Clendenen
Leonda E
LE
Ganusova
Elena E
EE
Schilkey
Faye D
FD
Ramaraj
Thiruvarangan
T
Khan
Omar A
OA
Huntley
Jim J
JJ
Luo
Shujun
S
Kwok
Pui-Yan
PY
Wu
Thomas D
TD
Schroth
Gary P
GP
Oksenberg
Jorge R
JR
Hauser
Stephen L
SL
Kingsmore
Stephen F
SF
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*
D012333:RNA, Messenger