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1.  Inferring human population size and separation history from multiple genome sequences 
Nature genetics  2014;46(8):919-925.
The availability of complete human genome sequences from populations across the world has given rise to new population genetic inference methods that explicitly model their ancestral relationship under recombination and mutation. So far, application of these methods to evolutionary history more recent than 20-30 thousand years ago and to population separations has been limited. Here we present a new method that overcomes these shortcomings. The Multiple Sequentially Markovian Coalescent (MSMC) analyses the observed pattern of mutations in multiple individuals, focusing on the first coalescence between any two individuals. Results from applying MSMC to genome sequences from nine populations across the world suggest that the genetic separation of non-African ancestors from African Yoruban ancestors started long before 50,000 years ago, and give information about human population history as recently as 2,000 years ago, including the bottleneck in the peopling of the Americas, and separations within Africa, East Asia and Europe.
PMCID: PMC4116295  PMID: 24952747
2.  Extending reference assembly models 
Genome Biology  2015;16(1):13.
The human genome reference assembly is crucial for aligning and analyzing sequence data, and for genome annotation, among other roles. However, the models and analysis assumptions that underlie the current assembly need revising to fully represent human sequence diversity. Improved analysis tools and updated data reporting formats are also required.
PMCID: PMC4305238  PMID: 25651527
3.  Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association 
PLoS Genetics  2014;10(11):e1004798.
Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to identify quantitative trait loci (QTLs) that influence the binding of a transcription factor in humans, we measured binding of the multifunctional transcription and chromatin factor CTCF in 51 HapMap cell lines. We identified thousands of QTLs in which genotype differences were associated with differences in CTCF binding strength, hundreds of them confirmed by directly observable allele-specific binding bias. The majority of QTLs were either within 1 kb of the CTCF binding motif, or in linkage disequilibrium with a variant within 1 kb of the motif. On the X chromosome we observed three classes of binding sites: a minority class bound only to the active copy of the X chromosome, the majority class bound to both the active and inactive X, and a small set of female-specific CTCF sites associated with two non-coding RNA genes. In sum, our data reveal extensive genetic effects on CTCF binding, both direct and indirect, and identify a diversity of patterns of CTCF binding on the X chromosome.
Author Summary
We have systematically measured the effect of normal genetic variation present in a human population on the binding of a specific chromatin protein (CTCF) to DNA by measuring its binding in 51 human cell lines. We observed a large number of changes in protein binding that we can confidently attribute to genetic effects. The corresponding genetic changes are often clustered around the binding motif for CTCF, but only a minority are actually within the motif. Unexpectedly, we also find that at most binding sites on the X chromosome, CTCF binding occurs equally on both the X chromosomes in females at the same level as on the single X chromosome in males. This finding suggests that in general, CTCF binding is not subject to global dosage compensation, the process which equalizes gene expression levels from the two female X chromosomes and the single male X.
PMCID: PMC4238955  PMID: 25411781
4.  Estimation of Epistatic Variance Components and Heritability in Founder Populations and Crosses 
Genetics  2014;198(4):1405-1416.
Genetic association studies have explained only a small proportion of the estimated heritability of complex traits, leaving the remaining heritability “missing.” Genetic interactions have been proposed as an explanation for this, because they lead to overestimates of the heritability and are hard to detect. Whether this explanation is true depends on the proportion of variance attributable to genetic interactions, which is difficult to measure in outbred populations. Founder populations exhibit a greater range of kinship than outbred populations, which helps in fitting the epistatic variance. We extend classic theory to founder populations, giving the covariance between individuals due to epistasis of any order. We recover the classic theory as a limit, and we derive a recently proposed estimator of the narrow sense heritability as a corollary. We extend the variance decomposition to include dominance. We show in simulations that it would be possible to estimate the variance from pairwise interactions with samples of a few thousand from strongly bottlenecked human founder populations, and we provide an analytical approximation of the standard error. Applying these methods to 46 traits measured in a yeast (Saccharomyces cerevisiae) cross, we estimate that pairwise interactions explain 10% of the phenotypic variance on average and that third- and higher-order interactions explain 14% of the phenotypic variance on average. We search for third-order interactions, discovering an interaction that is shared between two traits. Our methods will be relevant to future studies of epistatic variance in founder populations and crosses.
PMCID: PMC4256760  PMID: 25326236
cross; epistasis; founder; heritability; interaction
6.  Managing clinically significant findings in research: the UK10K example 
European Journal of Human Genetics  2014;22(9):1100-1104.
Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs.
PMCID: PMC4026295  PMID: 24424120
incidental findings; ethics; sequencing; research; consortia; management pathway
7.  Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population 
PLoS Genetics  2014;10(7):e1004494.
Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5–5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10−8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10−117). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10−4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
Author Summary
We explored the coding regions of 3,000 Finnish individuals with 3,000 non-Finnish Europeans (NFEs) using whole-exome sequence data, in order to understand how an individual from a bottlenecked population might differ from an individual from an out-bred population. We provide empirical evidence that there are more rare and low-frequency deleterious alleles in Finns compared to NFEs, such that an average Finn has almost twice as many low-frequency complete knockouts of a gene. As such, we hypothesized that some of these low-frequency loss-of-function variants might have important medical consequences in humans and genotyped 83 of these variants in 36,000 Finns. In doing so, we discovered that completely knocking out the TSFM gene might result in inviability or a very severe phenotype in humans and that knocking out the LPA gene might confer protection against coronary heart diseases, suggesting that LPA is likely to be a good potential therapeutic target.
PMCID: PMC4117444  PMID: 25078778
8.  Genetic interactions affecting human gene expression identified by variance association mapping 
eLife  2014;3:e01381.
Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ∼70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.
eLife digest
Every person has two copies of each gene: one is inherited from their mother and the other from their father. These two copies are often not identical because there can be many different variants of the same gene in the human population. Traits (such as height, body mass and risk of disease) vary from one person to the next—and for many traits this variation depends in part on the different gene variants that each person has inherited. Studies seeking to find the differences in DNA that can predict this variation have often assumed that the changes in DNA act on traits independently of the effect of environment and of other genetic variants.
In contrast, studies with animals have shown that some genetic variants can interact to produce a bigger (or smaller) effect than would be expected from simply ‘adding together’ their individual effects—a phenomenon called epistasis. But how much does epistasis contribute to variation in human traits, if at all? This question has been much disputed, and is difficult to test, not least because of the sheer number of interactions to assess: tens of millions of changes in DNA have been observed in the human genome, and so there are many more than billions of possible combinations of these changes to investigate.
Here, Brown et al. have examined the sequences of all the genes that were expressed in cells taken from a cohort of twins and searched for genetic variants that show these epistatic interactions. By studying gene expression, which can be greatly affected by small changes in the DNA code, Brown et al. were able to identify 508 variants that had a bigger than expected effect on the level of gene expression. This may be a sign that these variants act in combinations: if within one genome a variant increased expression and in another it decreased expression, then this would cause greater variation in gene expression. Further investigation of these 508 variants led to the discovery of 256 examples of epistasis, and 57 of these were replicated in samples from another cohort. Brown et al. calculated that these epistatic interactions explained up to 16% of the variation in gene expression. Furthermore, as well as being involved in epistatic interactions, about 70% of the genetic variants that had an effect on the variation in gene expression were also involved in interactions between genes and the environment.
In addition to showing that epistasis contributes to variation in human traits, the work of Brown et al. could help to uncover interactions behind complex traits—beyond the expression level of a gene—that could not previously be investigated.
PMCID: PMC4017648  PMID: 24771767
gene expression; epistasis; gene-environment interactions; human
9.  Estimating telomere length from whole genome sequence data 
Nucleic Acids Research  2014;42(9):e75.
Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs.
PMCID: PMC4027178  PMID: 24609383
10.  A High-Definition View of Functional Genetic Variation from Natural Yeast Genomes 
Molecular Biology and Evolution  2014;31(4):872-888.
The question of how genetic variation in a population influences phenotypic variation and evolution is of major importance in modern biology. Yet much is still unknown about the relative functional importance of different forms of genome variation and how they are shaped by evolutionary processes. Here we address these questions by population level sequencing of 42 strains from the budding yeast Saccharomyces cerevisiae and its closest relative S. paradoxus. We find that genome content variation, in the form of presence or absence as well as copy number of genetic material, is higher within S. cerevisiae than within S. paradoxus, despite genetic distances as measured in single-nucleotide polymorphisms being vastly smaller within the former species. This genome content variation, as well as loss-of-function variation in the form of premature stop codons and frameshifting indels, is heavily enriched in the subtelomeres, strongly reinforcing the relevance of these regions to functional evolution. Genes affected by these likely functional forms of variation are enriched for functions mediating interaction with the external environment (sugar transport and metabolism, flocculation, metal transport, and metabolism). Our results and analyses provide a comprehensive view of genomic diversity in budding yeast and expose surprising and pronounced differences between the variation within S. cerevisiae and that within S. paradoxus. We also believe that the sequence data and de novo assemblies will constitute a useful resource for further evolutionary and population genomics studies.
PMCID: PMC3969562  PMID: 24425782
population genomics; functional variation; genome evolution; yeast; subtelomeres; loss-of-function variants
11.  Efficient haplotype matching and storage using the positional Burrows–Wheeler transform (PBWT) 
Bioinformatics  2014;30(9):1266-1272.
Motivation: Over the last few years, methods based on suffix arrays using the Burrows–Wheeler Transform have been widely used for DNA sequence read matching and assembly. These provide very fast search algorithms, linear in the search pattern size, on a highly compressible representation of the dataset being searched. Meanwhile, algorithmic development for genotype data has concentrated on statistical methods for phasing and imputation, based on probabilistic matching to hidden Markov model representations of the reference data, which while powerful are much less computationally efficient. Here a theory of haplotype matching using suffix array ideas is developed, which should scale too much larger datasets than those currently handled by genotype algorithms.
Results: Given M sequences with N bi-allelic variable sites, an O(NM) algorithm to derive a representation of the data based on positional prefix arrays is given, which is termed the positional Burrows–Wheeler transform (PBWT). On large datasets this compresses with run-length encoding by more than a factor of a hundred smaller than using gzip on the raw data. Using this representation a method is given to find all maximal haplotype matches within the set in O(NM) time rather than O(NM2) as expected from naive pairwise comparison, and also a fast algorithm, empirically independent of M given sufficient memory for indexes, to find maximal matches between a new sequence and the set. The discussion includes some proposals about how these approaches could be used for imputation and phasing.
PMCID: PMC3998136  PMID: 24413527
12.  Mapping cis- and trans-regulatory effects across multiple tissues in twins 
Nature genetics  2012;44(10):1084-1089.
Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many eQTL studies typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis-effect on expression cannot be accounted for by common cis-variants, a finding which exposes the contribution of low frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene and identify several replicating trans-variants which act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
PMCID: PMC3784328  PMID: 22941192
13.  Gene expression changes with age in skin, adipose tissue, blood and brain 
Genome Biology  2013;14(7):R75.
Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.
Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.
Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.
PMCID: PMC4054017  PMID: 23889843
Aging; gene expression; skin; adipose; brain; microarrays
14.  Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species 
Bradnam, Keith R | Fass, Joseph N | Alexandrov, Anton | Baranay, Paul | Bechner, Michael | Birol, Inanç | Boisvert, Sébastien | Chapman, Jarrod A | Chapuis, Guillaume | Chikhi, Rayan | Chitsaz, Hamidreza | Chou, Wen-Chi | Corbeil, Jacques | Del Fabbro, Cristian | Docking, T Roderick | Durbin, Richard | Earl, Dent | Emrich, Scott | Fedotov, Pavel | Fonseca, Nuno A | Ganapathy, Ganeshkumar | Gibbs, Richard A | Gnerre, Sante | Godzaridis, Élénie | Goldstein, Steve | Haimel, Matthias | Hall, Giles | Haussler, David | Hiatt, Joseph B | Ho, Isaac Y | Howard, Jason | Hunt, Martin | Jackman, Shaun D | Jaffe, David B | Jarvis, Erich D | Jiang, Huaiyang | Kazakov, Sergey | Kersey, Paul J | Kitzman, Jacob O | Knight, James R | Koren, Sergey | Lam, Tak-Wah | Lavenier, Dominique | Laviolette, François | Li, Yingrui | Li, Zhenyu | Liu, Binghang | Liu, Yue | Luo, Ruibang | MacCallum, Iain | MacManes, Matthew D | Maillet, Nicolas | Melnikov, Sergey | Naquin, Delphine | Ning, Zemin | Otto, Thomas D | Paten, Benedict | Paulo, Octávio S | Phillippy, Adam M | Pina-Martins, Francisco | Place, Michael | Przybylski, Dariusz | Qin, Xiang | Qu, Carson | Ribeiro, Filipe J | Richards, Stephen | Rokhsar, Daniel S | Ruby, J Graham | Scalabrin, Simone | Schatz, Michael C | Schwartz, David C | Sergushichev, Alexey | Sharpe, Ted | Shaw, Timothy I | Shendure, Jay | Shi, Yujian | Simpson, Jared T | Song, Henry | Tsarev, Fedor | Vezzi, Francesco | Vicedomini, Riccardo | Vieira, Bruno M | Wang, Jun | Worley, Kim C | Yin, Shuangye | Yiu, Siu-Ming | Yuan, Jianying | Zhang, Guojie | Zhang, Hao | Zhou, Shiguo | Korf, Ian F
GigaScience  2013;2:10.
The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly.
In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies.
Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another.
PMCID: PMC3844414  PMID: 23870653
Genome assembly; N50; Scaffolds; Assessment; Heterozygosity; COMPASS
15.  A Genome-Wide Survey of Genetic Variation in Gorillas Using Reduced Representation Sequencing 
PLoS ONE  2013;8(6):e65066.
All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations.
PMCID: PMC3672199  PMID: 23750230
16.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry 
Bentley, David R. | Balasubramanian, Shankar | Swerdlow, Harold P. | Smith, Geoffrey P. | Milton, John | Brown, Clive G. | Hall, Kevin P. | Evers, Dirk J. | Barnes, Colin L. | Bignell, Helen R. | Boutell, Jonathan M. | Bryant, Jason | Carter, Richard J. | Cheetham, R. Keira | Cox, Anthony J. | Ellis, Darren J. | Flatbush, Michael R. | Gormley, Niall A. | Humphray, Sean J. | Irving, Leslie J. | Karbelashvili, Mirian S. | Kirk, Scott M. | Li, Heng | Liu, Xiaohai | Maisinger, Klaus S. | Murray, Lisa J. | Obradovic, Bojan | Ost, Tobias | Parkinson, Michael L. | Pratt, Mark R. | Rasolonjatovo, Isabelle M. J. | Reed, Mark T. | Rigatti, Roberto | Rodighiero, Chiara | Ross, Mark T. | Sabot, Andrea | Sankar, Subramanian V. | Scally, Aylwyn | Schroth, Gary P. | Smith, Mark E. | Smith, Vincent P. | Spiridou, Anastassia | Torrance, Peta E. | Tzonev, Svilen S. | Vermaas, Eric H. | Walter, Klaudia | Wu, Xiaolin | Zhang, Lu | Alam, Mohammed D. | Anastasi, Carole | Aniebo, Ify C. | Bailey, David M. D. | Bancarz, Iain R. | Banerjee, Saibal | Barbour, Selena G. | Baybayan, Primo A. | Benoit, Vincent A. | Benson, Kevin F. | Bevis, Claire | Black, Phillip J. | Boodhun, Asha | Brennan, Joe S. | Bridgham, John A. | Brown, Rob C. | Brown, Andrew A. | Buermann, Dale H. | Bundu, Abass A. | Burrows, James C. | Carter, Nigel P. | Castillo, Nestor | Catenazzi, Maria Chiara E. | Chang, Simon | Cooley, R. Neil | Crake, Natasha R. | Dada, Olubunmi O. | Diakoumakos, Konstantinos D. | Dominguez-Fernandez, Belen | Earnshaw, David J. | Egbujor, Ugonna C. | Elmore, David W. | Etchin, Sergey S. | Ewan, Mark R. | Fedurco, Milan | Fraser, Louise J. | Fajardo, Karin V. Fuentes | Furey, W. Scott | George, David | Gietzen, Kimberley J. | Goddard, Colin P. | Golda, George S. | Granieri, Philip A. | Green, David E. | Gustafson, David L. | Hansen, Nancy F. | Harnish, Kevin | Haudenschild, Christian D. | Heyer, Narinder I. | Hims, Matthew M. | Ho, Johnny T. | Horgan, Adrian M. | Hoschler, Katya | Hurwitz, Steve | Ivanov, Denis V. | Johnson, Maria Q. | James, Terena | Jones, T. A. Huw | Kang, Gyoung-Dong | Kerelska, Tzvetana H. | Kersey, Alan D. | Khrebtukova, Irina | Kindwall, Alex P. | Kingsbury, Zoya | Kokko-Gonzales, Paula I. | Kumar, Anil | Laurent, Marc A. | Lawley, Cynthia T. | Lee, Sarah E. | Lee, Xavier | Liao, Arnold K. | Loch, Jennifer A. | Lok, Mitch | Luo, Shujun | Mammen, Radhika M. | Martin, John W. | McCauley, Patrick G. | McNitt, Paul | Mehta, Parul | Moon, Keith W. | Mullens, Joe W. | Newington, Taksina | Ning, Zemin | Ng, Bee Ling | Novo, Sonia M. | O'Neill, Michael J. | Osborne, Mark A. | Osnowski, Andrew | Ostadan, Omead | Paraschos, Lambros L. | Pickering, Lea | Pike, Andrew C. | Pike, Alger C. | Pinkard, D. Chris | Pliskin, Daniel P. | Podhasky, Joe | Quijano, Victor J. | Raczy, Come | Rae, Vicki H. | Rawlings, Stephen R. | Rodriguez, Ana Chiva | Roe, Phyllida M. | Rogers, John | Rogert Bacigalupo, Maria C. | Romanov, Nikolai | Romieu, Anthony | Roth, Rithy K. | Rourke, Natalie J. | Ruediger, Silke T. | Rusman, Eli | Sanches-Kuiper, Raquel M. | Schenker, Martin R. | Seoane, Josefina M. | Shaw, Richard J. | Shiver, Mitch K. | Short, Steven W. | Sizto, Ning L. | Sluis, Johannes P. | Smith, Melanie A. | Sohna, Jean Ernest Sohna | Spence, Eric J. | Stevens, Kim | Sutton, Neil | Szajkowski, Lukasz | Tregidgo, Carolyn L. | Turcatti, Gerardo | vandeVondele, Stephanie | Verhovsky, Yuli | Virk, Selene M. | Wakelin, Suzanne | Walcott, Gregory C. | Wang, Jingwen | Worsley, Graham J. | Yan, Juying | Yau, Ling | Zuerlein, Mike | Rogers, Jane | Mullikin, James C. | Hurles, Matthew E. | McCooke, Nick J. | West, John S. | Oaks, Frank L. | Lundberg, Peter L. | Klenerman, David | Durbin, Richard | Smith, Anthony J.
Nature  2008;456(7218):53-59.
PMCID: PMC2581791  PMID: 18987734
17.  Insights into hominid evolution from the gorilla genome sequence 
Nature  2012;483(7388):169-175.
Gorillas are humans’ closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago (Mya). In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.
PMCID: PMC3303130  PMID: 22398555
18.  Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses 
Nature protocols  2012;7(3):500-507.
We present PEER (probabilistic estimation of expression residuals), a software package implementing statistical models that improve the sensitivity and interpretability of genetic associations in population-scale expression data. This approach builds on factor analysis methods that infer broad variance components in the measurements. PEER takes as input transcript profiles and covariates from a set of individuals, and then outputs hidden factors that explain much of the expression variability. Optionally, these factors can be interpreted as pathway or transcription factor activations by providing prior information about which genes are involved in the pathway or targeted by the factor. The inferred factors are used in genetic association analyses. First, they are treated as additional covariates, and are included in the model to increase detection power for mapping expression traits. Second, they are analyzed as phenotypes themselves to understand the causes of global expression variability. PEER extends previous related surrogate variable models and can be implemented within hours on a desktop computer.
PMCID: PMC3398141  PMID: 22343431
19.  Identity-by-Descent-Based Phasing and Imputation in Founder Populations Using Graphical Models 
Genetic epidemiology  2011;35(8):853-860.
Accurate knowledge of haplotypes, the combination of alleles co-residing on a single copy of a chromosome, enables powerful gene mapping and sequence imputation methods. Since humans are diploid, haplotypes must be derived from genotypes by a phasing process. In this study, we present a new computational model for haplotype phasing based on pairwise sharing of haplotypes inferred to be Identical-By-Descent (IBD). We apply the Bayesian network based model in a new phasing algorithm, called systematic long-range phasing (SLRP), that can capitalize on the close genetic relationships in isolated founder populations, and show with simulated and real genome-wide genotype data that SLRP substantially reduces the rate of phasing errors compared to previous phasing algorithms. Furthermore, the method accurately identifies regions of IBD, enabling linkage-like studies without pedigrees, and can be used to impute most genotypes with very low error rate.
PMCID: PMC3368215  PMID: 22006673
haplotype; population isolate; long-range phasing; Bayesian network
20.  Extent, Causes, and Consequences of Small RNA Expression Variation in Human Adipose Tissue 
PLoS Genetics  2012;8(5):e1002704.
Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.
Author Summary
Genetic information is transmitted to the cell only through RNA molecules. A special class of RNAs is comprised of the small (up to 30 nucleotide) ones, known to be potent regulators of various cellular processes. At the same time, they have not been as widely studied as messenger RNAs—we do not know how much variation in their sequence and expression level occurs naturally in human populations or how this variability influences other traits. We measured small RNA levels and genetic variability in fat tissue from 131 individuals by high-throughput sequencing. We could associate the expression levels with genetic background of the individuals, as well as changes in metabolic traits. Surprisingly, we found no large scale influence of small RNA variation on mRNA levels, their main regulatory target. Overall, our study is the first to give a quantitative picture of the naturally occurring variation in these important regulatory molecules in human fat tissue.
PMCID: PMC3349731  PMID: 22589741
21.  High levels of RNA-editing site conservation amongst 15 laboratory mouse strains 
Genome Biology  2012;13(4):r26.
Adenosine-to-inosine (A-to-I) editing is a site-selective post-transcriptional alteration of double-stranded RNA by ADAR deaminases that is crucial for homeostasis and development. Recently the Mouse Genomes Project generated genome sequences for 17 laboratory mouse strains and rich catalogues of variants. We also generated RNA-seq data from whole brain RNA from 15 of the sequenced strains.
Here we present a computational approach that takes an initial set of transcriptome/genome mismatch sites and filters these calls taking into account systematic biases in alignment, single nucleotide variant calling, and sequencing depth to identify RNA editing sites with high accuracy. We applied this approach to our panel of mouse strain transcriptomes identifying 7,389 editing sites with an estimated false-discovery rate of between 2.9 and 10.5%. The overwhelming majority of these edits were of the A-to-I type, with less than 2.4% not of this class, and only three of these edits could not be explained as alignment artifacts. We validated 24 novel RNA editing sites in coding sequence, including two non-synonymous edits in the Cacna1d gene that fell into the IQ domain portion of the Cav1.2 voltage-gated calcium channel, indicating a potential role for editing in the generation of transcript diversity.
We show that despite over two million years of evolutionary divergence, the sites edited and the level of editing at each site is remarkably consistent across the 15 strains. In the Cds2 gene we find evidence for RNA editing acting to preserve the ancestral transcript sequence despite genomic sequence divergence.
PMCID: PMC3446300  PMID: 22524474
22.  Patterns of Cis Regulatory Variation in Diverse Human Populations 
PLoS Genetics  2012;8(4):e1002639.
The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.
Author Summary
Variation among individuals in the degree to which genes are expressed (i.e. turned on or off) is a characteristic exhibited by all species, and studies have identified regions of the genome harboring genetic variation affecting gene expression levels. To assess the degree of human inter-population variability in regulatory variation, we describe mapping of regions of the genome that have functional effects on gene expression levels. We analyzed genome-wide gene expression in human cell lines derived from 726 unrelated individuals representing 8 global populations that have been genetically well-characterized by the International HapMap Project. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We identify ∼5,700 genes whose expression levels are associated with genetic variation located physically close to the gene, and we observe significant sharing of associations that is partially dependent on population genetic relatedness, among Asians, European-admixed, and African subpopulations. We identify biological functions affected by regulatory variation and describe common and unique characteristics of population-specific and population-shared associations. These results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation.
PMCID: PMC3330104  PMID: 22532805
23.  Mouse genomic variation and its effect on phenotypes and gene regulation 
Nature  2011;477(7364):289-294.
We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.
PMCID: PMC3276836  PMID: 21921910
24.  Inference of Human Population History From Whole Genome Sequence of A Single Individual 
Nature  2011;475(7357):493-496.
The history of human population size is important to understanding human evolution. Various studies1-5 have found evidence for a founder event (bottleneck) in East Asian and European populations associated with the human dispersal out-of-Africa event around 60 thousand years ago (kya) before present. However, these studies have to assume simplified demographic models with few parameters and do not precisely date the start and stop times of the bottleneck. Here, with fewer assumptions on population size changes, we present a more detailed history of human population sizes between approximately ten thousand to a million years ago, using the pairwise sequentially Markovian coalescent (PSMC) model applied to the complete diploid genome sequences of a Chinese male (YH)6, a Korean male (SJK)7, three European individuals (Venter8, NA12891 and NA128789) and two Yoruba males (NA1850710 and NA19239). We infer that European and Chinese populations had very similar population size histories before 10–20kya. Both populations experienced a severe bottleneck between 10–60kya while African populations experienced a milder bottleneck from which they recovered earlier. All three populations have an elevated effective population size between 60–250kya, possibly due to a population structure11. We also infer that the differentiation of genetically modern humans may have started as early as 100–120kya12, but considerable genetic exchanges may still have occurred until 20–40kya.
PMCID: PMC3154645  PMID: 21753753
25.  WormBase 
Worm  2012;1(1):15-21.
WormBase ( has been serving the scientific community for over 11 years as the central repository for genomic and genetic information for the soil nematode Caenorhabditis elegans. The resource has evolved from its beginnings as a database housing the genomic sequence and genetic and physical maps of a single species, and now represents the breadth and diversity of nematode research, currently serving genome sequence and annotation for around 20 nematodes. In this article, we focus on WormBase’s role of genome sequence annotation, describing how we annotate and integrate data from a growing collection of nematode species and strains. We also review our approaches to sequence curation, and discuss the impact on annotation quality of large functional genomics projects such as modENCODE.
PMCID: PMC3670165  PMID: 24058818
Caenorhabditis elegans; annotation; community resource; genome; model organism database; nematode; parasitic nematode; sequence curation

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