A genome-wide map of diversity in Plasmodium falciparum

Genetic variation allows the malaria parasite Plasmodium falciparum to overcome chemotherapeutic agents, vaccines and vector control strategies and remain a leading cause of global morbidity and mortality. Here we describe an initial survey of genetic variation across the P. falciparum genome. We performed extensive sequencing of 16 geographically diverse parasites and identified 46,937 SNPs, demonstrating rich diversity among P. falciparum parasites (pi = 1.16 x 10(-3)) and strong correlation with gene function. We identified multiple regions with signatures of selective sweeps in drug-resistant parasites, including a previously unidentified 160-kb region with extremely low polymorphism in pyrimethamine-resistant parasites. We further characterized 54 worldwide isolates by genotyping SNPs across 20 genomic regions. These data begin to define population structure among African, Asian and American groups and illustrate the degree of linkage disequilibrium, which extends over relatively short distances in African parasites but over longer distances in Asian parasites. We provide an initial map of genetic diversity in P. falciparum and demonstrate its potential utility in identifying genes subject to recent natural selection and in understanding the population genetics of this parasite.     

Plasmodium cynomolgi genome sequences provide insight into Plasmodium vivax and the monkey malaria clade

P. cynomolgi, a malaria-causing parasite of Asian Old World monkeys, is the sister taxon of P. vivax, the most prevalent malaria-causing species in humans outside of Africa. Because P. cynomolgi shares many phenotypic, biological and genetic characteristics with P. vivax, we generated draft genome sequences for three P. cynomolgi strains and performed genomic analysis comparing them with the P. vivax genome, as well as with the genome of a third previously sequenced simian parasite, Plasmodium knowlesi. Here, we show that genomes of the monkey malaria clade can be characterized by copy-number variants (CNVs) in multigene families involved in evasion of the human immune system and invasion of host erythrocytes. We identify genome-wide SNPs, microsatellites and CNVs in the P. cynomolgi genome, providing a map of genetic variation that can be used to map parasite traits and study parasite populations. The sequencing of the P. cynomolgi genome is a critical step in developing a model system for P. vivax research and in counteracting the neglect of P. vivax.     

Detection of large-scale variation in the human genome

We identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals. Twenty-four variants are present in > 10% of the individuals that we examined. Half of these regions overlap with genes, and many coincide with segmental duplications or gaps in the human genome assembly. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure.     

Fine-scale structural variation of the human genome

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.     

Self-fertilization sweeps up variation in the worm genome

A new study reports a comprehensive survey of genetic diversity in natural populations of the nematode Caenorhabditis elegans. Their analyses suggest that recent chromosome-scale selective sweeps have reduced C. elegans genetic diversity worldwide and strongly structured genetic variation across its genome.     

Computational identification of promoters and first exons in the human genome.

The identification of promoters and first exons has been one of the most difficult problems in gene-finding. We present a set of discriminant functions that can recognize structural and compositional features such as CpG islands, promoter regions and first splice-donor sites. We explain the implementation of the discriminant functions into a decision tree that constitutes a new program called FirstEF. By using different models to predict CpG-related and non-CpG-related first exons, we showed by cross-validation that the program could predict 86% of the first exons with 17% false positives. We also demonstrated the prediction accuracy of FirstEF at the genome level by applying it to the finished sequences of human chromosomes 21 and 22 as well as by comparing the predictions with the locations of the experimentally verified first exons. Finally, we present the analysis of the predicted first exons for all of the 24 chromosomes of the human genome.     

Complex SNP-related sequence variation in segmental genome duplications

There is uncertainty about the true nature of predicted single-nucleotide polymorphisms (SNPs) in segmental duplications (duplicons) and whether these markers genuinely exist at increased density as indicated in public databases. We explored these issues by genotyping 157 predicted SNPs in duplicons and control regions in normal diploid genomes and fully homozygous complete hydatidiform moles. Our data identified many true SNPs in duplicon regions and few paralogous sequence variants. Twenty-eight percent of the polymorphic duplicon sequences we tested involved multisite variation, a new type of polymorphism representing the sum of the signals from many individual duplicon copies that vary in sequence content due to duplication, deletion or gene conversion. Multisite variations can masquerade as normal SNPs when genotyped. Given that duplicons comprise at least 5% of the genome and many are yet to be annotated in the genome draft, effective strategies to identify multisite variation must be established and deployed.     

Genome-wide patterns of genetic variation among elite maize inbred lines

We have resequenced a group of six elite maize inbred lines, including the parents of the most productive commercial hybrid in China. This effort uncovered more than 1,000,000 SNPs, 30,000 indel polymorphisms and 101 low-sequence-diversity chromosomal intervals in the maize genome. We also identified several hundred complete genes that show presence/absence variation among these resequenced lines. We discuss the potential roles of complementation of presence/absence variations and other deleterious mutations in contributing to heterosis. High-density SNP and indel polymorphism markers reported here are expected to be a valuable resource for future genetic studies and the molecular breeding of this important crop.     

A worldwide survey of haplotype variation and linkage disequilibrium in the human genome

Recent genomic surveys have produced high-resolution haplotype information, but only in a small number of human populations. We report haplotype structure across 12 Mb of DNA sequence in 927 individuals representing 52 populations. The geographic distribution of haplotypes reflects human history, with a loss of haplotype diversity as distance increases from Africa. Although the extent of linkage disequilibrium (LD) varies markedly across populations, considerable sharing of haplotype structure exists, and inferred recombination hotspot locations generally match across groups. The four samples in the International HapMap Project contain the majority of common haplotypes found in most populations: averaging across populations, 83% of common 20-kb haplotypes in a population are also common in the most similar HapMap sample. Consequently, although the portability of tag SNPs based on the HapMap is reduced in low-LD Africans, the HapMap will be helpful for the design of genome-wide association mapping studies in nearly all human populations.     

Predicting phenotypic variation in yeast from individual genome sequences

A central challenge in genetics is to predict phenotypic variation from individual genome sequences. Here we construct and evaluate phenotypic predictions for 19 strains of Saccharomyces cerevisiae. We use conservation-based methods to predict the impact of protein-coding variation within genes on protein function. We then rank strains using a prediction score that measures the total sum of function-altering changes in different sets of genes reported to influence over 100 phenotypes in genome-wide loss-of-function screens. We evaluate our predictions by comparing them with the observed growth rate and efficiency of 15 strains tested across 20 conditions in quantitative experiments. The median predictive performance, as measured by ROC AUC, was 0.76, and predictions were more accurate when the genes reported to influence a trait were highly connected in a functional gene network.     

Analyses of X-linked and autosomal genetic variation in population-scale whole genome sequencing

The ratio of genetic diversity on chromosome X to that on the autosomes is sensitive to both natural selection and demography. On the basis of whole-genome sequences of 69 females, we report that whereas this ratio increases with genetic distance from genes across populations, it is lower in Europeans than in West Africans independent of proximity to genes. This relative reduction is most parsimoniously explained by differences in demographic history without the need to invoke natural selection.     

Evidence for substantial fine-scale variation in recombination rates across the human genome

Characterizing fine-scale variation in human recombination rates is important, both to deepen understanding of the recombination process and to aid the design of disease association studies. Current genetic maps show that rates vary on a megabase scale, but studying finer-scale variation using pedigrees is difficult. Sperm-typing experiments have characterized regions where crossovers cluster into 1-2-kb hot spots, but technical difficulties limit the number of studies. An alternative is to use population variation to infer fine-scale characteristics of the recombination process. Several surveys reported 'block-like' patterns of diversity, which may reflect fine-scale recombination rate variation, but limitations of available methods made this impossible to assess. Here, we applied a new statistical method, which overcomes these limitations, to infer patterns of fine-scale recombination rate variation in 74 genes. We found extensive rate variation both within and among genes. In particular, recombination hot spots are a common feature of the human genome: 47% (35 of 74) of genes showed substantive evidence for a hot spot, and many more showed evidence for some rate variation. No primary sequence characteristics are consistently associated with precise hot-spot location, although G+C content and nucleotide diversity are correlated with local recombination rate.     

Human genome sequence variation and the influence of gene history,mutation and recombination

Variation in the human genome sequence is key to understanding susceptibility to disease in modern populations and the history of ancestral populations. Unlocking this information requires knowledge of the patterns and underlying causes of human sequence diversity. By applying a new population-genetic framework to two genome-wide polymorphism surveys, we find that the human genome contains sizeable regions (stretching over tens of thousands of base pairs) that have intrinsically high and low rates of sequence variation. We show that the primary determinant of these patterns is shared genealogical history. Only a fraction of the variation (at most 25%) is due to the local mutation rate. By measuring the average distance over which genealogical histories are typically preserved, these data provide the first genome-wide estimate of the average extent of correlation among variants (linkage disequilibrium). The results are best explained by extreme variability in the recombination rate at a fine scale, and provide the first empirical evidence that such recombination 'hot spots' are a general feature of the human genome and have a principal role in shaping genetic variation in the human population.     

High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi

Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated whole-genome sequences for 19 Typhi isolates using 454 (Roche) and Solexa (Illumina) technologies. Isolates, including the previously sequenced CT18 and Ty2 isolates, were selected to represent major nodes in the phylogenetic tree. Comparative analysis showed little evidence of purifying selection, antigenic variation or recombination between isolates. Rather, evolution in the Typhi population seems to be characterized by ongoing loss of gene function, consistent with a small effective population size. The lack of evidence for antigenic variation driven by immune selection is in contrast to strong adaptive selection for mutations conferring antibiotic resistance in Typhi. The observed patterns of genetic isolation and drift are consistent with the proposed key role of asymptomatic carriers of Typhi as the main reservoir of this pathogen, highlighting the need for identification and treatment of carriers.     

Maize HapMap2 identifies extant variation from a genome in flux

Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize.