Showing papers by "Xiang Zhou published in 2014"

Efficient multivariate linear mixed model algorithms for genome-wide association studies

Abstract: Multivariate linear mixed models (mvLMMs) are powerful tools for testing associations between single-nucleotide polymorphisms and multiple correlated phenotypes while controlling for population stratification in genome-wide association studies. We present efficient algorithms in the genome-wide efficient mixed model association (GEMMA) software for fitting mvLMMs and computing likelihood ratio tests. These algorithms offer improved computation speed, power and P-value calibration over existing methods, and can deal with more than two phenotypes.

Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers

Abstract: The evolutionary history of the human pygmy phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (east central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses, we computed the haplotypebased integrated haplotype score (iHS) statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each genomic SNP. Both jiHSj and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (west central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated jiHSj or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.

Epigenetic modifications are associated with inter-species gene expression variation in primates

Abstract: Background: Changes in gene regulation have long been thought to play an important role in evolution and speciation, especially in primates. Over the past decade, comparative genomic studies have revealed extensive inter-species differences in gene expression levels, yet we know much less about the extent to which regulatory mechanisms differ between species. Results: To begin addressing this gap, we perform a comparative epigenetic study in primate lymphoblastoid cell lines, to query the contribution of RNA polymerase II and four histone modifications, H3K4me1, H3K4me3, H3K27ac, and H3K27me3, to inter-species variation in gene expression levels. We find that inter-species differences in mark enrichment near transcription start sites are significantly more often associated with inter-species differences in the corresponding gene expression level than expected by chance alone. Interestingly, we also find that first-order interactions among the five marks, as well as chromatin states, do not markedly contribute to the degree of association between the marks and inter-species variation in gene expression levels, suggesting that the marginal effects of the five marks dominate this contribution. Conclusions: Our observations suggest that epigenetic modifications are substantially associated with changes in gene expression levels among primates and may represent important molecular mechanisms in primate evolution.

Epigenetic Modifications are Associated with Inter-species Gene Expression Variation in Primates

Abstract: Changes in gene regulation level have long been thought to play an important role in evolution and speciation, especially in primates. Over the past decade, comparative genomic studies have revealed extensive inter-species differences in gene expression levels yet we know much less about the extent to which regulatory mechanisms differ between species. To begin addressing this gap, we performed a comparative epigenetic study in primate lymphoblastoid cell lines (LCLs), to query the contribution of RNA polymerase II (Pol II) and four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me3) to inter-species variation in gene expression levels. We found that inter-species differences in mark enrichment near transcription start sites are significantly more often associated with inter-species differences in the corresponding gene expression level than expected by chance alone. Interestingly, we also found that first-order interactions among the histone marks and Pol II do not markedly contribute to the degree of association between the marks and inter-species variation in gene expression levels, suggesting that the marginal effects of the five marks dominate this contribution.

The Genetic Architecture of Gene Expression Levels in Wild Baboons

Abstract: Gene expression variation is well documented in human populations and its genetic architecture has been extensively explored. However, we still know little about the genetic architecture of gene expression variation in other species, particularly our closest living relatives, the nonhuman primates. To address this gap, we performed an RNA sequencing (RNA-seq)-based study of 63 wild baboons, members of the intensively studied Amboseli baboon population in Kenya. Our study design allowed us to measure gene expression levels and identify genetic variants using the same data set, enabling us to perform complementary mapping of putative cis-acting expression quantitative trait loci (eQTL) and measurements of allele-specific expression (ASE) levels. We discovered substantial evidence for genetic effects on gene expression levels in this population. Surprisingly, we found more power to detect individual eQTL in the baboons relative to a HapMap human data set of comparable size, probably as a result of greater genetic variation, enrichment of SNPs with high minor allele frequencies, and longer-range linkage disequilibrium in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes. Interestingly, genes with eQTL significantly overlapped between the baboon and human data sets, suggesting that some genes may tolerate more genetic perturbation than others, and that this property may be conserved across species. Finally, we used a Bayesian sparse linear mixed model to partition genetic, demographic, and early environmental contributions to variation in gene expression levels. We found a strong genetic contribution to gene expression levels for almost all genes, while individual demographic and environmental effects tended to be more modest. Together, our results establish the feasibility of eQTL mapping using RNA-seq data alone, and act as an important first step towards understanding the genetic architecture of gene expression variation in nonhuman primates.