Human activities, such as agriculture, hunting, and habitat modification, exert a significant effect on native species. Although many species have suffered population declines, increased population fragmentation, or even extinction in connection with these human impacts, others seem to have benefitted from human modification of their habitat. Here we examine whether population growth in an insectivorous bat (Tadarida brasiliensis mexicana) can be attributed to the widespread expansion of agriculture in North America following European settlement. Colonies of T. b. mexicana are extremely large (~10(6) individuals) and, in the modern era, major agricultural insect pests form an important component of their food resource. It is thus hypothesized that the growth of these insectivorous bat populations was coupled to the expansion of agricultural land use in North America over the last few centuries.

Although population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole-genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor approximately 261 ka, and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage approximately 68 ka. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of 1.4-fold around 970 ka and a recent 5.6-fold contraction in population size 23 ka. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection.

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ∼5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

The islands of North Maluku, Indonesia occupy a central position in the major prehistoric dispersal streams that shaped the peoples of Island Southeast Asia and the Pacific. Within this region a linguistic contact zone exists where speakers of Papuan and Austronesian languages reside in close proximity. Here we use population genetic data to assess the extent to which North Maluku populations experienced admixture of Asian genetic material, and whether linguistic boundaries reflect genetic differentiation today.

The penitremane and janthitremane families of indole-diterpenes are abundant natural products synthesized by Penicillium crustosum and P. janthinellum. Using a combination of PCR, cosmid library screening, and Illumina sequencing we have identified gene clusters encoding enzymes for the synthesis of these compounds. Targeted deletion of penP in P. crustosum abolished the synthesis of penitrems A, B, D, E, and F, and led to accumulation of paspaline, a key intermediate for paxilline biosynthesis in P. paxilli. Similarly, deletion of janP and janD in P. janthinellum abolished the synthesis of prenyl-elaborated indole-diterpenes, and led to accumulation in the latter of 13-desoxypaxilline, a key intermediate for the synthesis of the structurally related aflatremanes synthesized by Aspergillus flavus. This study helps resolve the genetic basis for the complexity of indole-diterpene natural products found within the Penicillium and Aspergillus species. All indole-diterpene gene clusters identified to date have a core set of genes for the synthesis of paspaline and a suite of genes encoding multi-functional cytochrome P450 monooxygenases, FAD dependent monooxygenases, and prenyl transferases that catalyse various regio- and stereo- specific oxidations that give rise to the diversity of indole-diterpene products synthesized by this group of fungi.

African Pygmies practicing a mobile hunter-gatherer lifestyle are phenotypically and genetically diverged from other anatomically modern humans, and they likely experienced strong selective pressures due to their unique lifestyle in the Central African rainforest. To identify genomic targets of adaptation, we sequenced the genomes of four Biaka Pygmies from the Central African Republic and jointly analyzed these data with the genome sequences of three Baka Pygmies from Cameroon and nine Yoruba famers. To account for the complex demographic history of these populations that includes both isolation and gene flow, we fit models using the joint allele frequency spectrum and validated them using independent approaches. Our two best-fit models both suggest ancient divergence between the ancestors of the farmers and Pygmies, 90,000 or 150,000 yr ago. We also find that bidirectional asymmetric gene flow is statistically better supported than a single pulse of unidirectional gene flow from farmers to Pygmies, as previously suggested. We then applied complementary statistics to scan the genome for evidence of selective sweeps and polygenic selection. We found that conventional statistical outlier approaches were biased toward identifying candidates in regions of high mutation or low recombination rate. To avoid this bias, we assigned P-values for candidates using whole-genome simulations incorporating demography and variation in both recombination and mutation rates. We found that genes and gene sets involved in muscle development, bone synthesis, immunity, reproduction, cell signaling and development, and energy metabolism are likely to be targets of positive natural selection in Western African Pygmies or their recent ancestors.

Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

At the dawn of the second millennium, the expansion of the Indian Ocean trading network aligned with the emergence of an outward-oriented community along the East African coast to create a cosmopolitan cultural and trading zone known as the Swahili Corridor. On the basis of analyses of new genome-wide genotyping data and uniparental data in 276 individuals from coastal Kenya and the Comoros islands, along with large-scale genetic datasets from the Indian Ocean rim, we reconstruct historical population dynamics to show that the Swahili Corridor is largely an eastern Bantu genetic continuum. Limited gene flows from the Middle East can be seen in Swahili and Comorian populations at dates corresponding to historically documented contacts. However, the main admixture event in southern insular populations, particularly Comorian and Malagasy groups, occurred with individuals from Island Southeast Asia as early as the 8th century, reflecting an earlier dispersal from this region. Remarkably, our results support recent archaeological and linguistic evidence-based suggestions that the Comoros archipelago was the earliest location of contact between Austronesian and African populations in the Swahili Corridor.

The debate concerning the origin of the Polynesian speaking peoples has been recently reinvigorated by genetic evidence for secondary migrations to western Polynesia from the New Guinea region during the 2nd millennium BP. Using genome-wide autosomal data from the Leeward Society Islands, the ancient cultural hub of eastern Polynesia, we find that the inhabitants' genomes also demonstrate evidence of this episode of admixture, dating to 1,700-1,200 BP. This supports a late settlement chronology for eastern Polynesia, commencing ~1,000 BP, after the internal differentiation of Polynesian society. More than 70% of the autosomal ancestry of Leeward Society Islanders derives from Island Southeast Asia with the lowland populations of the Philippines as the single largest potential source. These long-distance migrants into Polynesia experienced additional admixture with northern Melanesians prior to the secondary migrations of the 2nd millennium BP. Moreover, the genetic diversity of mtDNA and Y chromosome lineages in the Leeward Society Islands is consistent with linguistic evidence for settlement of eastern Polynesia proceeding from the central northern Polynesian outliers in the Solomon Islands. These results stress the complex demographic history of the Leeward Society Islands and challenge phylogenetic models of cultural evolution predicated on eastern Polynesia being settled from Samoa.

Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.

Pathogen incursions are a major impediment for global forest health. How pathogens and forest trees coexist over time, without pathogens simply killing their long-lived hosts, is a critical but unanswered question. The Dothistroma Needle Blight pathogen Dothistroma septosporum was introduced into New Zealand in the 1960s and remains a low-diversity, asexual population, providing a unique opportunity to analyze the evolution of a forest pathogen. Isolates of D. septosporum collected from commercial pine forests over 50 years were compared at whole-genome and phenotype levels. Limited genome diversity and increased diversification among recent isolates support the premise of a single introduction event. Isolates from the 1960s show significantly elevated virulence against Pinus radiata seedlings and produce higher levels of the virulence factor dothistromin compared to isolates collected in the 1990s and 2000s. However, later isolates have no increased tolerance to copper, used in fungicide treatments of infested forests and traditionally assumed to be a strong selection pressure. The isolated New Zealand population of this forest pathogen therefore appears to have become less virulent over time, likely in part to maintain the viability of its long-lived host. This finding has broad implications for forest health and highlights the benefits of long-term pathogen surveys.

Traces of interbreeding of Neanderthals and Denisovans with modern humans in the form of archaic DNA have been detected in the genomes of present-day human populations outside sub-Saharan Africa. Up to now, only nuclear archaic DNA has been detected in modern humans; we therefore attempted to identify archaic mitochondrial DNA (mtDNA) residing in modern human nuclear genomes as nuclear inserts of mitochondrial DNA (NUMTs).

New Guineans represent one of the oldest locally continuous populations outside Africa, harboring among the greatest linguistic and genetic diversity on the planet. Archeological and genetic evidence suggest that their ancestors reached Sahul (present day New Guinea and Australia) by at least 55,000 years ago (kya). However, little is known about this early settlement phase or subsequent dispersal and population structuring over the subsequent period of time. Here we report 379 complete Papuan mitochondrial genomes from across Papua New Guinea, which allow us to reconstruct the phylogenetic and phylogeographic history of northern Sahul. Our results support the arrival of two groups of settlers in Sahul within the same broad time window (50-65 kya), each carrying a different set of maternal lineages and settling Northern and Southern Sahul separately. Strong geographic structure in northern Sahul remains visible today, indicating limited dispersal over time despite major climatic, cultural, and historical changes. However, following a period of isolation lasting nearly 20 ky after initial settlement, environmental changes postdating the Last Glacial Maximum stimulated diversification of mtDNA lineages and greater interactions within and beyond Northern Sahul, to Southern Sahul, Wallacea and beyond. Later, in the Holocene, populations from New Guinea, in contrast to those of Australia, participated in early interactions with incoming Asian populations from Island Southeast Asia and continuing into Oceania.

Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder. There are four known types of OCA: OCA1-OCA4. The clinical manifestations of all types of OCA include skin and hair hypopigmentation and visual impairment. Although there are a few documented observations of high frequency of albinism among Native Americans, including the Hopi, Zuni, Kuna, Jemez, Laguna, San Juan, and Navajo, no causative molecular defect has been previously reported. In the present study, we show that albinism in one Native American population, the Navajo, is caused by a LINE-mediated 122.5-kilobase deletion of the P gene, thus demonstrating that albinism in this population is OCA2. This deletion appears to be Navajo specific, because this allele was not detected in 34 other individuals with albinism who listed other Native American origins, nor has it been reported in any other ethnic group. The molecular characterization of this deletion allele allowed us to design a three-primer polymerase chain reaction system to estimate the carrier frequency in the Navajo population by screening 134 unrelated normally pigmented Navajos. The carrier frequency was found to be approximately 4.5%. The estimated prevalence of OCA2 in Navajos is between approximately 1 per 1,500 and 1 per 2,000. We further estimate that this mutation originated 400-1,000 years ago from a single founder.

The Austronesian expansion, one of the last major human migrations, influenced regions as distant as tropical Asia, Remote Oceania and Madagascar, off the east coast of Africa. The identity of the Asian groups that settled Madagascar is particularly mysterious. While language connects Madagascar to the Ma'anyan of southern Borneo, haploid genetic data are more ambiguous. Here, we screened genome-wide diversity in 211 individuals from the Ma'anyan and surrounding groups in southern Borneo. Surprisingly, the Ma'anyan are characterized by a distinct, high frequency genomic component that is not found in Malagasy. This novel genetic layer occurs at low levels across Island Southeast Asia and hints at a more complex model for the Austronesian expansion in this region. In contrast, Malagasy show genomic links to a range of Island Southeast Asian groups, particularly from southern Borneo, but do not have a clear genetic connection with the Ma'anyan despite the obvious linguistic association.

Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans. Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations. However, no definitive case of adaptive introgression has yet been described. Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians (but not sub-Saharan Africans) has a sequence that closely matches that of the Neanderthal STAT2. This haplotype, referred to as N, was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals. Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence (~80 thousand years ago) and is found throughout Eurasia at an average frequency of ~5%. Interestingly, N is found in Melanesian populations at ~10-fold higher frequency (~54%) than in Eurasian populations. A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone. Although we are not able to pinpoint the precise target of positive selection, we identify nonsynonymous mutations in ERBB3, ESYT1, and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates.

Among patients with intractable epilepsy, the most commonly performed surgical procedure is craniotomy for amygdalohippocampectomy (AH). Stereotactic laser amygdalohippocampotomy (SLAH) has also been recently employed as a minimally invasive treatment for intractable temporal lobe epilepsy (TLE). Among patients treated with AH and SLAH approximately 65% and 54% of patients become seizure-free, respectively. Therefore, selection criteria for surgical candidates with improved prognostic value for post-operative seizure-free outcome are greatly needed. In this study, we perform RNA sequencing (RNA-Seq) on whole blood leukocyte samples taken from 16 patients with intractable TLE prior to SLAH to test the hypothesis that pre-operative leukocyte RNA expression profiles are prognostic for post-operative seizure outcome. Multidimensional scaling analysis of the RNA expression data indicated separate clustering of patients with seizure free (SF) and non-seizure-free (NSF) outcomes. Differential expression (DE) analysis performed on SF versus NSF groups revealed 24 significantly differentially expressed genes (≥2.0-fold change, p-value < 0.05, FDR <0.05). Network and pathway analyses identified differential activation of pathways involved in lipid metabolism, morphology of oligodendrocytes, inflammatory response, and development of astrocytes. These results suggest that pre-operative leukocyte expression profiles have prognostic value for seizure outcome following SLAH.

The Indian Ocean has long been a hub of interacting human populations. Following land- and sea-based routes, trade drove cultural contacts between far-distant ethnic groups in Asia, India, the Middle East and Africa, creating one of the world's first proto-globalized environments. However, the extent to which population mixing was mediated by trade is poorly understood. Reconstructing admixture times from genomic data in 3,006 individuals from 187 regional populations reveals a close association between bouts of human migration and trade volumes during the last 2,000 years across the Indian Ocean trading system. Temporal oscillations in trading activity match phases of contraction and expansion in migration, with high water marks following the expansion of the Silk Roads in the 5th century AD, the rise of maritime routes in the 11th century and a drastic restructuring of the trade network following the arrival of Europeans in the 16th century. The economic fluxes of the Indian Ocean trade network therefore directly shaped exchanges of genes, in addition to goods and concepts.

Structural features of genomes, including the three-dimensional arrangement of DNA in the nucleus, are increasingly seen as key contributors to the regulation of gene expression. However, studies on how genome structure and nuclear organisation influence transcription have so far been limited to a handful of model species. This narrow focus limits our ability to draw general conclusions about the ways in which three-dimensional structures are encoded, and to integrate information from three-dimensional data to address a broader gamut of biological questions. Here, we generate a complete and gapless genome sequence for the filamentous fungus, Epichloë festucae. We use Hi-C data to examine the three-dimensional organisation of the genome, and RNA-seq data to investigate how Epichloë genome structure contributes to the suite of transcriptional changes needed to maintain symbiotic relationships with the grass host. Our results reveal a genome in which very repeat-rich blocks of DNA with discrete boundaries are interspersed by gene-rich sequences that are almost repeat-free. In contrast to other species reported to date, the three-dimensional structure of the genome is anchored by these repeat blocks, which act to isolate transcription in neighbouring gene-rich regions. Genes that are differentially expressed in planta are enriched near the boundaries of these repeat-rich blocks, suggesting that their three-dimensional orientation partly encodes and regulates the symbiotic relationship formed by this organism.