Understanding human DNA sequence variation

Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different populations and the species as a whole, among other studies. With the advent of DNA-based markers in the last quarter century, these studies have accelerated. One of the challenges for the next century is to understand that variation. One component of that understanding will be population genetics. We present here examples of many of the ways these new data can be analyzed from a population perspective using results from our laboratory on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support an "out of Africa" hypothesis for human dispersal around the world and begin to refine the understanding of population structures and genetic relationships. We are also developing baseline information against which we can compare findings at different loci to aid in the identification of loci subject, now and in the past, to selection (directional or balancing). We do not yet have a comprehensive understanding of the extensive variation in the human genome, but some of that understanding is coming from population genetics.     

Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome

Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic H_R^(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.     

Natural selection in the water: freshwater invasion and adaptation by water colour in the Amazonian pufferfish

Natural selection and ecological adaptation are ultimately responsible for much of the origin of biodiversity. Yet, the identification of divergent natural selection has been hindered by the spatial complexity of natural systems, the difficulty in identifying genes under selection and their relationship to environment, and the confounding genomic effects of time. Here, we employed genome scans, population genetics and sequence-based phylogeographic methods to identify divergent natural selection on population boundaries in a freshwater invader, the Amazonian pufferfish, Colomesus asellus. We sampled extensively across markedly different hydrochemical settings in the Amazon Basin and use 'water colour' to test for ecological isolation. We distinguish the relative contribution of natural selection across hydrochemical gradients from biogeographic history in the origin and maintenance of population boundaries within a single species and across a complex ecosystem. We show that spatially distinct population structure generated by multiple forces (i.e. water colour and vicariant biogeographic history) can be identified if the confounding effects of genetic drift have not accumulated between selective populations. Our findings have repercussions for studies aimed at identifying engines of biodiversity and assessing their temporal progression in understudied and ecologically complex tropical ecosystems.     

Positive selection for elevated gene expression noise in yeast

It is well known that the expression noise is lessened by natural selection for genes that are important for cell growth or are sensitive to dosage. In theory, expression noise can also be elevated by natural selection when noisy gene expression is advantageous. Here we analyze yeast genome‐wide gene expression noise data and show that plasma‐membrane transporters show significantly elevated expression noise after controlling all confounding factors. We propose a model that explains why and under what conditions elevated expression noise may be beneficial and subject to positive selection. Our model predicts and the simulation confirms that, under certain conditions, expression noise also increases the evolvability of gene expression by promoting the fixation of favorable expression level‐altering mutations. Indeed, yeast genes with higher noise show greater between‐strain and between‐species divergences in expression, even when all confounding factors are excluded. Together, our theoretical model and empirical results suggest that, for yeast genes such as plasma‐membrane transporters, elevated expression noise is advantageous, is subject to positive selection, and is a facilitator of adaptive gene expression evolution.     

Natural Selection and Functional Potentials of Human Noncoding Elements Revealed by Analysis of Next Generation Sequencing Data

Noncoding DNA sequences (NCS) have attracted much attention recently due to their functional potentials. Here we attempted to reveal the functional roles of noncoding sequences from the point of view of natural selection that typically indicates the functional potentials of certain genomic elements. We analyzed nearly 37 million single nucleotide polymorphisms (SNPs) of Phase I data of the 1000 Genomes Project. We estimated a series of key parameters of population genetics and molecular evolution to characterize sequence variations of the noncoding genome within and between populations, and identified the natural selection footprints in NCS in worldwide human populations. Our results showed that purifying selection is prevalent and there is substantial constraint of variations in NCS, while positive selectionis more likely to be specific to some particular genomic regions and regional populations. Intriguingly, we observed larger fraction of non-conserved NCS variants with lower derived allele frequency in the genome, indicating possible functional gain of non-conserved NCS. Notably, NCS elements are enriched for potentially functional markers such as eQTLs, TF motif, and DNase I footprints in the genome. More interestingly, some NCS variants associated with diseases such as Alzheimer''s disease, Type 1 diabetes, and immune-related bowel disorder (IBD) showed signatures of positive selection, although the majority of NCS variants, reported as risk alleles by genome-wide association studies, showed signatures of negative selection. Our analyses provided compelling evidence of natural selection forces on noncoding sequences in the human genome and advanced our understanding of their functional potentials that play important roles in disease etiology and human evolution.     

Phylogenetic Dependency Networks: Inferring Patterns of CTL Escape and Codon Covariation in HIV-1 Gag

HIV avoids elimination by cytotoxic T-lymphocytes (CTLs) through the evolution of escape mutations. Although there is mounting evidence that these escape pathways are broadly consistent among individuals with similar human leukocyte antigen (HLA) class I alleles, previous population-based studies have been limited by the inability to simultaneously account for HIV codon covariation, linkage disequilibrium among HLA alleles, and the confounding effects of HIV phylogeny when attempting to identify HLA-associated viral evolution. We have developed a statistical model of evolution, called a phylogenetic dependency network, that accounts for these three sources of confounding and identifies the primary sources of selection pressure acting on each HIV codon. Using synthetic data, we demonstrate the utility of this approach for identifying sites of HLA-mediated selection pressure and codon evolution as well as the deleterious effects of failing to account for all three sources of confounding. We then apply our approach to a large, clinically-derived dataset of Gag p17 and p24 sequences from a multicenter cohort of 1144 HIV-infected individuals from British Columbia, Canada (predominantly HIV-1 clade B) and Durban, South Africa (predominantly HIV-1 clade C). The resulting phylogenetic dependency network is dense, containing 149 associations between HLA alleles and HIV codons and 1386 associations among HIV codons. These associations include the complete reconstruction of several recently defined escape and compensatory mutation pathways and agree with emerging data on patterns of epitope targeting. The phylogenetic dependency network adds to the growing body of literature suggesting that sites of escape, order of escape, and compensatory mutations are largely consistent even across different clades, although we also identify several differences between clades. As recent case studies have demonstrated, understanding both the complexity and the consistency of immune escape has important implications for CTL-based vaccine design. Phylogenetic dependency networks represent a major step toward systematically expanding our understanding of CTL escape to diverse populations and whole viral genes.     

Current relaxation of selection on the human genome: Tolerance of deleterious mutations on olfactory receptors

Knowledge and understanding about the selective pressures that have shaped present human genetic diversity have dramatically increased in the last few years in parallel with the availability of large genomic datasets. The release of large datasets composed of millions of SNPs across hundreds of genomes by HAPMAP, the Human Genome Diversity Panel, and other projects has led to considerable effort to detect selection signals across the nuclear genome (Coop et al., 2009, Lopez Herraez et al., 2009, Sabeti et al., 2006, Sabeti et al., 2007, Voight et al., 2006). Most of the research has focused on positive selection forces although other selective forces, such as negative selection, may have played a substantive role on the shape of our genome. Here we studied the selective strengths acting presently on the genome by making computational predictions of the pathogenicity of nonsynonymous protein mutations and interpreting the distribution of scores in terms of selection. We could show that the genetic diversity for all the major pathways is still constrained by negative selection in all 11 human populations studied. In a single exception, we observed a relaxation of negative selection acting on olfactory receptors. Since a decreased number of functioning olfactory receptors in human compared with other primates had already been shown, this suggests that the role of olfactory receptors for survival and reproductive success has decreased during human evolution. By showing that negative selection is still relaxed, the present results imply that no plateau of minimal function has yet been reached in modern humans and therefore that olfactory capability might still be decreasing. This is a first clue to present human evolution.     

虱目裂化线粒体基因组研究进展

虱目是哺乳类和鸟类体表的专性寄生虫。在虱科、阴虱科、长角鸟虱科和兽羽虱科的某些寄生虱种中发现了线粒体基因组裂化现象, 其线粒体基因组裂化成了多个环状的线粒体染色体, 如体虱(Pediculus humanus)、头虱(pediculus capitis)和阴虱(Pthirus pubis)的线粒体基因组分别裂化形成20个、20个和14个微环染色体。微环染色体可能是基因删除和同源重组的结果, 关于线粒体基因组裂化的具体原因和机制, 目前并不清楚, 推测可能是进化选择或随机遗传漂变的结果或与线粒体单链DNA结合蛋白的缺失有关。鉴于线粒体基因组裂化研究对于深入理解线粒体的起源和进化方面具有重要意义, 文章以虱目裂化线粒体基因组为主线, 列举了动物裂化线粒体基因组和裂化特征, 阐述了虱目裂化线粒体基因组的研究现状, 分析了虱目线粒体基因组裂化的类型、原因和机制, 并对该领域未来的研究方向进行了展望。     

Evidence for widespread selection in shaping the genomic landscape during speciation of Populus

Increasing our understanding of how evolutionary processes drive the genomic landscape of variation is fundamental to a better understanding of the genomic consequences of speciation. However, genome‐wide patterns of within‐ and between‐ species variation have not been fully investigated in most forest tree species despite their global ecological and economic importance. Here, we use whole‐genome resequencing data from four Populus species spanning the speciation continuum to reconstruct their demographic histories and investigate patterns of diversity and divergence within and between species. Using Populus trichocarpa as an outgroup species, we further infer the genealogical relationships and estimate the extent of ancient introgression among the three aspen species (Populus tremula, Populus davidiana and Populus tremuloides) throughout the genome. Our results show substantial variation in these patterns along the genomes with this variation being strongly predicted by local recombination rates and the density of functional elements. This implies that the interaction between recurrent selection and intrinsic genomic features has dramatically sculpted the genomic landscape over long periods of time. In addition, our findings provide evidence that, apart from background selection, recent positive selection and long‐term balancing selection have also been crucial components in shaping patterns of genome‐wide variation during the speciation process.     

Evolutionary genomics of animal personality

Research on animal personality can be approached from both a phenotypic and a genetic perspective. While using a phenotypic approach one can measure present selection on personality traits and their combinations. However, this approach cannot reconstruct the historical trajectory that was taken by evolution. Therefore, it is essential for our understanding of the causes and consequences of personality diversity to link phenotypic variation in personality traits with polymorphisms in genomic regions that code for this trait variation. Identifying genes or genome regions that underlie personality traits will open exciting possibilities to study natural selection at the molecular level, gene-gene and gene-environment interactions, pleiotropic effects and how gene expression shapes personality phenotypes. In this paper, we will discuss how genome information revealed by already established approaches and some more recent techniques such as high-throughput sequencing of genomic regions in a large number of individuals can be used to infer micro-evolutionary processes, historical selection and finally the maintenance of personality trait variation. We will do this by reviewing recent advances in molecular genetics of animal personality, but will also use advanced human personality studies as case studies of how molecular information may be used in animal personality research in the near future.     

Creation of the whole human genome microarray

Several companies have recently announced the availability of products that enable a scientist to probe gene expression from the entire human genome on a single DNA microarray. This review will focus on the underlying technological trends that have made this achievement possible, the particular methodologies which are employed to create such microarrays and the implications of the whole human genome microarray for future biological studies. The single genome array represents an important milestone on the path to unraveling the complexity of the cellular networks that control living processes. The microarrays being designed today may, however, become distant ancestors to the whole human genome arrays of the future as our understanding of the functioning of the human genome increases.     

Genomic variation in neurons

Neurons born during the fetal period have extreme longevity and survive until the death of the individual because the human brain has highly limited tissue regeneration. The brain is comprised of an enormous variety of neurons each exhibiting different morphological and physiological characteristics and recent studies have further reported variations in their genome including chromosomal abnormalities, copy number variations, and single nucleotide mutations. During the early stages of brain development, the increasing number of neurons generated at high speeds has been proposed to lead to chromosomal instability. Additionally, mutations in the neuronal genome can occur in the mature brain. This observed genomic mosaicism in the brain can be produced by multiple endogenous and environmental factors and careful analyses of these observed variations in the neuronal genome remain central for our understanding of the genetic basis of neurological disorders.     

Creation of the whole human genome microarray

Several companies have recently announced the availability of products that enable a scientist to probe gene expression from the entire human genome on a single DNA microarray. This review will focus on the underlying technological trends that have made this achievement possible, the particular methodologies which are employed to create such microarrays and the implications of the whole human genome microarray for future biological studies. The single genome array represents an important milestone on the path to unraveling the complexity of the cellular networks that control living processes. The microarrays being designed today may, however, become distant ancestors to the whole human genome arrays of the future as our understanding of the functioning of the human genome increases.     

多基因遗传病基因研究的策略和方法

基因在决定个体表型方面起着决定性的作用。虽然单基因疾病的致病基因的克隆工作取得了显著的进展,但对于多基因疾病来说,仍然存在许多问题,同时也是巨大的挑战。本文综述了多基因疾病的遗传特点和多基因疾病易感基因识别、分离和克隆的一般步骤和存在的问题,介绍了人类基因组计划在此过程中的作用和单核苷酸多态性的应用前景,提出 了最有可能克隆出多基因疾病易感基因的策略和方法。     

The genomics of speciation-with-gene-flow

The emerging field of speciation genomics is advancing our understanding of the evolution of reproductive isolation from the individual gene to a whole-genome perspective. In this new view it is important to understand the conditions under which 'divergence hitchhiking' associated with the physical linkage of gene regions, versus 'genome hitchhiking' associated with reductions in genome-wide rates of gene flow caused by selection, can enhance speciation-with-gene-flow. We describe here a theory predicting four phases of speciation, defined by changes in the relative effectiveness of divergence and genome hitchhiking, and review empirical data in light of the theory. We outline future directions, emphasizing the need to couple next-generation sequencing with selection, transplant, functional genomics, and mapping studies. This will permit a natural history of speciation genomics that will help to elucidate the factors responsible for population divergence and the roles that genome structure and different forms of hitchhiking play in facilitating the genesis of new biodiversity.     

Facial attractiveness,developmental stability,and fluctuating asymmetry

Despite robust cross-cultural reliability of human facial attractiveness ratings, research on facial attractiveness has only superficially addressed the connection between facial attractiveness and the history of sexual selection in Homo sapiens. There are reasons to believe that developmental stability and phenotypic quality are related. Recent studies of nonhuman animals indicate that developmental stability, measured as fluctuating asymmetry in generally bilateral symmetrical traits, is predictive of performance in sexual selection: Relatively symmetrical males are advantaged under sexual selection. This pattern is suggested by our study of facial attractiveness and fluctuating asymmetry in seven bilateral body traits in a student population. Overall, facial attractiveness negatively correlated with fluctuating asymmetry; the relation for men, but not for women, was statistically reliable. Possible confounding factors were controlled for in the analysis.     

Evolutionary impact of human Alu repetitive elements

Early studies of human Alu retrotransposons focused on their origin, evolution and biological properties, but current focus is shifting toward the effect of Alu elements on evolution of the human genome. Recent analyses indicate that numerous factors have affected the chromosomal distribution of Alu elements over time, including male-driven insertions, deletions and rapid CpG mutations after their retrotransposition. Unequal crossing over between Alu elements can lead to local mutations or to large segmental duplications responsible for genetic diseases and long-term evolutionary changes. Alu elements can also affect human (primate) evolution by introducing alternative splice sites in existing genes. Studying the Alu family in a human genomic context is likely to have general significance for our understanding of the evolutionary impact of other repetitive elements in diverse eukaryotic genomes.     

The search for the genetic contribution to autoimmune thyroid disease: the never ending story?

Unlocking the genetic contribution to autoimmune thyroid disease (AITD) will hold one of the keys to understanding disease pathogenesis and developing improved treatments. Significant increases in our understanding of the human genome combined with methodological advances in our ability to search for genetic variation have transformed the way in which we screen the genome for susceptibility loci. From early linkage analysis through to candidate gene studies and most recently genome-wide association screening, each methodology has revealed important insights into not just the heritability of AITD but also the best way of identifying disease causing DNA variants. This review will examine each of the different genome screening techniques, highlighting the successes and failures of each methodology and the lessons learnt which have helped inform the next phase of the disease-gene identification process. We will also look to see where we should be focusing our research efforts in the future.