Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain
A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We present a set of integrated experiments that investigate the effects of common genetic variability on DNA methylation and mRNA expression in four human brain regions each from 150 individuals (600 samples total). We find an abundance of genetic cis regulation of mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation across the genome. We show peak enrichment for cis expression QTLs to be approximately 68,000 bp away from individual transcription start sites; however, the peak enrichment for cis CpG methylation QTLs is located much closer, only 45 bp from the CpG site in question. We observe that the largest magnitude quantitative trait loci occur across distinct brain tissues. Our analyses reveal that CpG methylation quantitative trait loci are more likely to occur for CpG sites outside of islands. Lastly, we show that while we can observe individual QTLs that appear to affect both the level of a transcript and a physically close CpG methylation site, these are quite rare. We believe these data, which we have made publicly available, will provide a critical step toward understanding the biological effects of genetic variation.
Vyšlo v časopise:
Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain. PLoS Genet 6(5): e32767. doi:10.1371/journal.pgen.1000952
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000952
Souhrn
A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We present a set of integrated experiments that investigate the effects of common genetic variability on DNA methylation and mRNA expression in four human brain regions each from 150 individuals (600 samples total). We find an abundance of genetic cis regulation of mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation across the genome. We show peak enrichment for cis expression QTLs to be approximately 68,000 bp away from individual transcription start sites; however, the peak enrichment for cis CpG methylation QTLs is located much closer, only 45 bp from the CpG site in question. We observe that the largest magnitude quantitative trait loci occur across distinct brain tissues. Our analyses reveal that CpG methylation quantitative trait loci are more likely to occur for CpG sites outside of islands. Lastly, we show that while we can observe individual QTLs that appear to affect both the level of a transcript and a physically close CpG methylation site, these are quite rare. We believe these data, which we have made publicly available, will provide a critical step toward understanding the biological effects of genetic variation.
Zdroje
1. MelzerD
PerryJR
HernandezD
CorsiAM
StevensK
2008 A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4 e1000072 doi:10.1371/journal.pgen.1000072
2. MyersAJ
GibbsJR
WebsterJA
RohrerK
ZhaoA
2007 A survey of genetic human cortical gene expression. Nat Genet 39 1494 1499
3. SchadtEE
MolonyC
ChudinE
HaoK
YangX
2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107
4. StrangerBE
NicaAC
ForrestMS
DimasA
BirdCP
2007 Population genomics of human gene expression. Nat Genet 39 1217 1224
5. VeyrierasJB
KudaravalliS
KimSY
DermitzakisET
GiladY
2008 High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4 e1000214 doi:10.1371/journal.pgen.1000214
6. CooksonW
LiangL
AbecasisG
MoffattM
LathropM
2009 Mapping complex disease traits with global gene expression. Nat Rev Genet 10 184 194
7. GiladY
RifkinSA
PritchardJK
2008 Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet 24 408 415
8. EggerG
LiangG
AparicioA
JonesPA
2004 Epigenetics in human disease and prospects for epigenetic therapy. Nature 429 457 463
9. EisenMB
SpellmanPT
BrownPO
BotsteinD
1998 Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95 14863 14868
10. KhaitovichP
MuetzelB
SheX
LachmannM
HellmannI
2004 Regional patterns of gene expression in human and chimpanzee brains. Genome Res 14 1462 1473
11. Ladd-AcostaC
PevsnerJ
SabunciyanS
YolkenRH
WebsterMJ
2007 DNA methylation signatures within the human brain. Am J Hum Genet 81 1304 1315
12. ZhangY
RohdeC
TierlingS
JurkowskiTP
BockC
2009 DNA methylation analysis of chromosome 21 gene promoters at single base pair and single allele resolution. PLoS Genet 5 e1000438 doi:10.1371/journal.pgen.1000438
13. MeissnerA
MikkelsenTS
GuH
WernigM
HannaJ
2008 Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454 766 770
14. Gardiner-GardenM
FrommerM
1987 CpG islands in vertebrate genomes. J Mol Biol 196 261 282
15. BockC
WalterJ
PaulsenM
LengauerT
2007 CpG island mapping by epigenome prediction. PLoS Comput Biol 3 e110 doi:10.1371/journal.pcbi.0030110
16. LiY
DingJ
AbecasisGR
2006 Mach 1.0: Rapid haplotype reconstruction and missing genotype inference. American Journal of Human Genetics 79 S2290
17. PurcellS
NealeB
Todd-BrownK
ThomasL
FerreiraMA
2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
18. ChurchillGA
DoergeRW
1994 Empirical threshold values for quantitative trait mapping. Genetics 138 963 971
19. KwanT
BenovoyD
DiasC
GurdS
ProvencherC
2008 Genome-wide analysis of transcript isoform variation in humans. Nat Genet 40 225 231
20. BarrettT
EdgarR
2006 Mining microarray data at NCBI's Gene Expression Omnibus (GEO)*. Methods Mol Biol 338 175 190
21. EdgarR
DomrachevM
LashAE
2002 Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30 207 210
22. MailmanMD
FeoloM
JinY
KimuraM
TrykaK
2007 The NCBI dbGaP database of genotypes and phenotypes. Nat Genet 39 1181 1186
23. HeinzenEL
GeD
CroninKD
MaiaJM
ShiannaKV
2008 Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol 6 e1 doi:10.1371/journal.pbio.1000001
24. KwanT
GrundbergE
KokaV
GeB
LamKC
2009 Tissue effect on genetic control of transcript isoform variation. PLoS Genet 5 e1000608 doi:10.1371/journal.pgen.1000608
25. DimasAS
DeutschS
StrangerBE
MontgomerySB
BorelC
2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250
26. JakobssonM
ScholzSW
ScheetP
GibbsJR
VanLiereJM
2008 Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451 998 1003
27. van der BrugMP
BlackintonJ
ChandranJ
HaoLY
LalA
2008 RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc Natl Acad Sci U S A 105 10244 10249
28. 2005 A haplotype map of the human genome. Nature 437 1299 1320
29. WorkmanC
JensenLJ
JarmerH
BerkaR
GautierL
2002 A new non-linear normalization method for reducing variability in DNA microarray experiments. Genome Biol 3 research0048
30. SchadtEE
LiC
EllisB
WongWH
2001 Feature extraction and normalization algorithms for high-density oligonucleotide gene expression array data. J Cell Biochem Suppl Suppl 37120 125
31. TsengGC
OhMK
RohlinL
LiaoJC
WongWH
2001 Issues in cDNA microarray analysis: quality filtering, channel normalization, models of variations and assessment of gene effects. Nucleic Acids Res 29 2549 2557
32. SaeedAI
SharovV
WhiteJ
LiJ
LiangW
2003 TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34 374 378
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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