Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence.
Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.
Bioinformatics Unit, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
Lavinia
L
Gordon
Jihoon E
JE
Joo
Joseph E
JE
Powell
Miina
M
Ollikainen
Boris
B
Novakovic
Xin
X
Li
Roberta
R
Andronikos
Mark N
MN
Cruickshank
Karen N
KN
Conneely
Alicia K
AK
Smith
Reid S
RS
Alisch
Ruth
R
Morley
Peter M
PM
Visscher
Jeffrey M
JM
Craig
Richard
R
Saffery
D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000235:genetics; D040961:Genetic Drift; D015894:Genome, Human; D005865:Gestational Age; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D040582:Inheritance Patterns; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D010641:Phenotype; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D012044:Regression Analysis; D013269:Stochastic Processes; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*