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We present a genome assembly from an individual female Philereme vetulata (the Brown Scallop; Arthropoda; Insecta; Lepidoptera; Geometridae). The genome sequence is 771 megabases in span. Most of the assembly is scaffolded into 68 chromosomal pseudomolecules, including the assembled Z sex chromosome. The mitochondrial genome has also been assembled and is 16.3 kilobases in length. Gene annotation of this assembly on Ensembl has identified 18,096 protein coding genes.

A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ~80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P=0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P=3.4x10-6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of grey matter in males (P=0.00094), and smaller volumes of grey (P=0.00021) and white (P=0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behaviour or cognition, but it might have been the driving force underlying the positive selection in humans.

Additional file 3 Supplementary Text. Information about additional examples of shared and population-specific signals of positive selection.

Additional file 2 Supplementary Table 1. The 99.99th and 99.90th percentile thresholds of SFselect and iHS calculated after the neutral simulations. Supplementary Table 2. SFselect positive selection signals found in the five populations of study. Supplementary Table 3. SFselect positive selection signals found in the five populations of study. Supplementary Table 4. iHS positive selection signals found in the five populations of study. Supplementary Table 5. iHS positive selection signals shared among the five populations of study.

Additional file 1 Supplementary Fig. 1. Location of the five sampled populations. Supplementary Fig. 2. Genome-wide Manhattan plots of SFselect scores of the five populations of study. Supplementary Fig. 3. Density plots of SFselect and iHS scores of neutral and real data. Supplementary Fig. 4. Principal component analysis of the five East African populations. Supplementary Fig. 5. ADMIXTURE analysis of the Ethiopian samples and a set of worldwide populations. Supplementary Fig. 6. Genome-wide Manhattan plots of the –log10(p-value) of iHS of the five populations of study. Supplementary Fig. 7. PCA of the masked East African samples with a set of Europeans and Africans. Supplementary Fig. 8. Schematic representation of the demographic model used to simulate neutral sequences. Supplementary Fig. 9. Relative site frequency spectrum of Afroasiatic and Gumuz populations.

Figures S1, S2, and S3Table S1Table S2. Split-time estimates using the ρ statistic

Additional file 2: Supplementary notes for breakpoint identification. (PDF 4747 kb)

Additional file 1: Figure S1. Tandem duplication in HG01097. Figure S2. Tandem duplication in HG04131. Figure S3. Tandem duplication in NA18953. Figure S4. Fiber-FISH results for HG00707, HG01031 and HG00982. (PDF 689 kb)

Additional file 4: Review history. (DOCX 19 kb)

Description of meta-analysis, enrichment analyses, and novel candidates found in this study. (DOCX 182 kb)

Supplementary text explaining the archeological details of ancient samples; isolation of ancient DNA, genotyping, statistical analyses and peopling of South Asia and Parsi chapters. 12 figures and 10 tables are also incorporated in this file. (PDF 13264 kb)

Low-coverage short-read resequencing experiments have the potential to expand our understanding of Y chromosome haplogroups. However, the uncertainty associated with these experiments mean that haplogroups must be assigned probabilistically to avoid false inferences. We propose an efficient dynamic programming algorithm that can assign haplogroups by maximum likelihood, and represent the uncertainty in assignment. We apply this to both genotype and low-coverage sequencing data, and show that it can assign haplogroups accurately and with high resolution. The method is implemented as the program YFitter, which can be downloaded from http://sourceforge.net/projects/yfitter/

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.

Supplementary figures [130, 131]. (PDF 16467 kb)

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

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. 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.

INTRODUCTION: Large-scale human genome sequencing studies to date have been limited to large, metropolitan populations or to small numbers of genomes from each group. Much remains to be understood about the extent and structure of genetic variation in our species and how it was shaped by past population separations, admixture, adaptation, size changes, and gene flow from archaic human groups. Larger numbers of genome sequences from more diverse populations are needed to illuminate these questions. RATIONALE: We sequence 929 genomes from 54 geographically, linguistically and culturally diverse human populations to an average of 35x coverage, and analyze the variation among them. We also physically resolve the haplotype phase of 26 of these genomes using linked-read sequencing. RESULTS: We identify 67.3 million single-nucleotide polymorphisms (SNPs), 8.8 million small insertions or deletions (indels) and 40,736 copy number variants (CNVs). This includes hundreds of thousands of variants that had not been discovered by previous sequencing efforts but which are common in one or more population. We demonstrate benefits to the study of population relationships of genome sequences over ascertained array genotypes, particularly when involving African populations. Populations in central and southern Africa, the Americas and Oceania each harbour tens to hundreds of thousands of private, common genetic variants. The majority of these variants arose as novel mutations rather than through archaic introgression, except in Oceanian populations where many private variants derive from Denisovan admixture. While some reach high frequencies, no variants are fixed between major geographical regions. We estimate that the genetic separation between present-day human populations occurred mostly within the last 250,000 years. However, these early separations were gradual in nature and shaped by protracted gene flow. All populations thus still had some genetic contact more recently than this, but there is also evidence that a small fraction of present-day structure might be hundreds of thousands of years older. Most populations expanded in size over the last 10,000 years, but hunter-gatherer groups did not. The low diversity among the Neanderthal haplotypes segregating in present-day populations indicates that, while more than one Neanderthal individual must have contributed genetic material to modern humans, there was likely only one major episode of admixture. In contrast, Denisovan haplotype diversity reflects a more complex history involving more than one episode of admixture. We find small amounts of Neanderthal ancestry in West African genomes, most likely reflecting Eurasian admixture. Despite their very low levels or absence of archaic ancestry, African populations share many Neanderthal and Denisovan variants that are absent from Eurasia, reflecting how a larger proportion of the ancestral human variation has been maintained in Africa. CONCLUSION: The discovery of substantial amounts of common genetic variation that was previously undocumented, and is geographically restricted, highlights the continued value of anthropologically informed study designs for understanding human diversity. The genome sequences presented here are a freely available resource with relevance to population history, medical genetics, anthropology and linguistics. [Figure: see text]

The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans., This work was supported by Wellcome Trust grant 098051.

The predominantly African origin of all modern human populations is well established, but the route taken out of Africa is still unclear. Two alternative routes, via Egypt and Sinai or across the Bab el Mandeb strait into Arabia, have traditionally been proposed as feasible gateways in light of geographic, paleoclimatic, archaeological, and genetic evidence. Distinguishing among these alternatives has been difficult. We generated 225 whole-genome sequences (225 at 8× depth, of which 8 were increased to 30×; Illumina HiSeq 2000) from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 individuals). West Eurasian components were masked out, and the remaining African haplotypes were compared with a panel of sub-Saharan African and non-African genomes. We showed that masked Northeast African haplotypes overall were more similar to non-African haplotypes and more frequently present outside Africa than were any sets of haplotypes derived from a West African population. Furthermore, the masked Egyptian haplotypes showed these properties more markedly than the masked Ethiopian haplotypes, pointing to Egypt as the more likely gateway in the exodus to the rest of the world. Using five Ethiopian and three Egyptian high-coverage masked genomes and the multiple sequentially Markovian coalescent (MSMC) approach, we estimated the genetic split times of Egyptians and Ethiopians from non-African populations at 55,000 and 65,000 years ago, respectively, whereas that of West Africans was estimated to be 75,000 years ago. Both the haplotype and MSMC analyses thus suggest a predominant northern route out of Africa via Egypt.

Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations., Humans and chimps diverged about 5 million years ago. This study seeks to find the genes that have undergone positive selection during the evolution of both lineages since that time.