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The genetic architecture of gene expression levels in wild baboons.

Tung J, Zhou X, Alberts SC, Stephens M, Gilad Y - Elife (2015)

Bottom Line: Primate evolution has been argued to result, in part, from changes in how genes are regulated.We performed complementary expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses, discovering substantial evidence for, and surprising power to detect, genetic effects on gene expression levels in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes; interestingly, genes with eQTL significantly overlapped between baboons and a comparable human eQTL data set.Our results suggest that genes vary in their tolerance of genetic perturbation, and that this property may be conserved across species.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, United States.

ABSTRACT
Primate evolution has been argued to result, in part, from changes in how genes are regulated. However, we still know little about gene regulation in natural primate populations. We conducted an RNA sequencing (RNA-seq)-based study of baboons from an intensively studied wild population. We performed complementary expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses, discovering substantial evidence for, and surprising power to detect, genetic effects on gene expression levels in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes; interestingly, genes with eQTL significantly overlapped between baboons and a comparable human eQTL data set. Our results suggest that genes vary in their tolerance of genetic perturbation, and that this property may be conserved across species. Further, they establish the feasibility of eQTL mapping using RNA-seq data alone, and represent an important step towards understanding the genetic architecture of gene expression in primates.

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Coverage by genotype call.Mean coverage by genotype class for (A) all SNPs tested inthe baboon eQTL analysis (n = 64,432), and (B) SNPsidentified as eQTL (n = 1693). QQ plot of mean coverage inhomozygotes for the reference allele vs homozygotes for the alternateallele for (C) all SNPs and (D) SNPs identifiedas eQTL. The magnitude of increased coverage in reference allelehomozygotes indicates the degree of systematic reference allele mappingbias (dashed line shows the expectation for no mapping bias). Referenceallele homozygotes tend to have higher coverage, on average, thanalternate allele homozygotes (K-S test: p < 2.2 ×10−16 for all SNPs; p = 3.9 ×10−5 for eQTL SNPs), suggesting some degree ofmapping bias; however the effect is actually smaller for eQTL SNPs thanfor all SNPs (K-S D = 0.167 for all SNPs; K-S D = 0.084 foreQTL SNPs).DOI:http://dx.doi.org/10.7554/eLife.04729.016
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fig1s13: Coverage by genotype call.Mean coverage by genotype class for (A) all SNPs tested inthe baboon eQTL analysis (n = 64,432), and (B) SNPsidentified as eQTL (n = 1693). QQ plot of mean coverage inhomozygotes for the reference allele vs homozygotes for the alternateallele for (C) all SNPs and (D) SNPs identifiedas eQTL. The magnitude of increased coverage in reference allelehomozygotes indicates the degree of systematic reference allele mappingbias (dashed line shows the expectation for no mapping bias). Referenceallele homozygotes tend to have higher coverage, on average, thanalternate allele homozygotes (K-S test: p < 2.2 ×10−16 for all SNPs; p = 3.9 ×10−5 for eQTL SNPs), suggesting some degree ofmapping bias; however the effect is actually smaller for eQTL SNPs thanfor all SNPs (K-S D = 0.167 for all SNPs; K-S D = 0.084 foreQTL SNPs).DOI:http://dx.doi.org/10.7554/eLife.04729.016

Mentions: Second, SNP calling might be biased towards the reference allele. If so, more readswould be required to support a genotype call of homozygote alternate than a genotypecall of homozygote reference. This bias would result in higher apparent expressionlevels for alternate allele homozygotes and lower expression levels for referenceallele homozygotes, which could create false positive eQTLs. However, we observe noevidence for this scenario in our data set. For all tested SNPs (n = 64,432)and for eQTL SNPs only (n = 1693), alternate allele homozygotes tend to haveslightly lower coverage than reference allele homozygotes, and heterozygotes tend tohave the highest coverage (because more reads are required to support inference ofheterozygosity) (Figure 1—figure supplement13). Thus, coverage and genotype do not covary additively, and thispotential confound is unlikely to produce false positive eQTLs.


The genetic architecture of gene expression levels in wild baboons.

Tung J, Zhou X, Alberts SC, Stephens M, Gilad Y - Elife (2015)

Coverage by genotype call.Mean coverage by genotype class for (A) all SNPs tested inthe baboon eQTL analysis (n = 64,432), and (B) SNPsidentified as eQTL (n = 1693). QQ plot of mean coverage inhomozygotes for the reference allele vs homozygotes for the alternateallele for (C) all SNPs and (D) SNPs identifiedas eQTL. The magnitude of increased coverage in reference allelehomozygotes indicates the degree of systematic reference allele mappingbias (dashed line shows the expectation for no mapping bias). Referenceallele homozygotes tend to have higher coverage, on average, thanalternate allele homozygotes (K-S test: p < 2.2 ×10−16 for all SNPs; p = 3.9 ×10−5 for eQTL SNPs), suggesting some degree ofmapping bias; however the effect is actually smaller for eQTL SNPs thanfor all SNPs (K-S D = 0.167 for all SNPs; K-S D = 0.084 foreQTL SNPs).DOI:http://dx.doi.org/10.7554/eLife.04729.016
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383332&req=5

fig1s13: Coverage by genotype call.Mean coverage by genotype class for (A) all SNPs tested inthe baboon eQTL analysis (n = 64,432), and (B) SNPsidentified as eQTL (n = 1693). QQ plot of mean coverage inhomozygotes for the reference allele vs homozygotes for the alternateallele for (C) all SNPs and (D) SNPs identifiedas eQTL. The magnitude of increased coverage in reference allelehomozygotes indicates the degree of systematic reference allele mappingbias (dashed line shows the expectation for no mapping bias). Referenceallele homozygotes tend to have higher coverage, on average, thanalternate allele homozygotes (K-S test: p < 2.2 ×10−16 for all SNPs; p = 3.9 ×10−5 for eQTL SNPs), suggesting some degree ofmapping bias; however the effect is actually smaller for eQTL SNPs thanfor all SNPs (K-S D = 0.167 for all SNPs; K-S D = 0.084 foreQTL SNPs).DOI:http://dx.doi.org/10.7554/eLife.04729.016
Mentions: Second, SNP calling might be biased towards the reference allele. If so, more readswould be required to support a genotype call of homozygote alternate than a genotypecall of homozygote reference. This bias would result in higher apparent expressionlevels for alternate allele homozygotes and lower expression levels for referenceallele homozygotes, which could create false positive eQTLs. However, we observe noevidence for this scenario in our data set. For all tested SNPs (n = 64,432)and for eQTL SNPs only (n = 1693), alternate allele homozygotes tend to haveslightly lower coverage than reference allele homozygotes, and heterozygotes tend tohave the highest coverage (because more reads are required to support inference ofheterozygosity) (Figure 1—figure supplement13). Thus, coverage and genotype do not covary additively, and thispotential confound is unlikely to produce false positive eQTLs.

Bottom Line: Primate evolution has been argued to result, in part, from changes in how genes are regulated.We performed complementary expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses, discovering substantial evidence for, and surprising power to detect, genetic effects on gene expression levels in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes; interestingly, genes with eQTL significantly overlapped between baboons and a comparable human eQTL data set.Our results suggest that genes vary in their tolerance of genetic perturbation, and that this property may be conserved across species.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago, Chicago, United States.

ABSTRACT
Primate evolution has been argued to result, in part, from changes in how genes are regulated. However, we still know little about gene regulation in natural primate populations. We conducted an RNA sequencing (RNA-seq)-based study of baboons from an intensively studied wild population. We performed complementary expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses, discovering substantial evidence for, and surprising power to detect, genetic effects on gene expression levels in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes; interestingly, genes with eQTL significantly overlapped between baboons and a comparable human eQTL data set. Our results suggest that genes vary in their tolerance of genetic perturbation, and that this property may be conserved across species. Further, they establish the feasibility of eQTL mapping using RNA-seq data alone, and represent an important step towards understanding the genetic architecture of gene expression in primates.

Show MeSH