Project description:We investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level.SNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively.Six of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes.There is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.
Project description:By using the 1.6 million single-nucleotide polymorphism (SNP) genotype data set from Perlegen Sciences [Hinds, D. A., Stuve, L. L., Nilsen, G. B., Halperin, E., Eskin, E., Ballinger, D. G., Frazer, K. A. & Cox, D. R. (2005) Science 307, 1072-1079], a probabilistic search for the landscape exhibited by positive Darwinian selection was conducted. By sorting each high-frequency allele by homozygosity, we search for the expected decay of adjacent SNP linkage disequilibrium (LD) at recently selected alleles, eliminating the need for inferring haplotype. We designate this approach the LD decay (LDD) test. By these criteria, 1.6% of Perlegen SNPs were found to exhibit the genetic architecture of selection. These results were confirmed on an independently generated data set of 1.0 million SNP genotypes (International Human Haplotype Map Phase I freeze). Simulation studies indicate that the LDD test, at the megabase scale used, effectively distinguishes selection from other causes of extensive LD, such as inversions, population bottlenecks, and admixture. The approximately 1,800 genes identified by the LDD test were clustered according to Gene Ontology (GO) categories. Based on overrepresentation analysis, several predominant biological themes are common in these selected alleles, including host-pathogen interactions, reproduction, DNA metabolism/cell cycle, protein metabolism, and neuronal function.
Project description:Understanding the timing and character of the expansion of Homo sapiens out of Africa is critical for inferring the colonization and admixture processes that underpin global population history. It has been argued that dispersal out of Africa had an early phase, particularly ~130-90 thousand years ago (ka), that reached only the East Mediterranean Levant, and a later phase, ~60-50?ka, that extended across the diverse environments of Eurasia to Sahul. However, recent findings from East Asia and Sahul challenge this model. Here we show that H. sapiens was in the Arabian Peninsula before 85?ka. We describe the Al Wusta-1 (AW-1) intermediate phalanx from the site of Al Wusta in the Nefud desert, Saudi Arabia. AW-1 is the oldest directly dated fossil of our species outside Africa and the Levant. The palaeoenvironmental context of Al Wusta demonstrates that H. sapiens using Middle Palaeolithic stone tools dispersed into Arabia during a phase of increased precipitation driven by orbital forcing, in association with a primarily African fauna. A Bayesian model incorporating independent chronometric age estimates indicates a chronology for Al Wusta of ~95-86?ka, which we correlate with a humid episode in the later part of Marine Isotope Stage 5 known from various regional records. Al Wusta shows that early dispersals were more spatially and temporally extensive than previously thought. Early H. sapiens dispersals out of Africa were not limited to winter rainfall-fed Levantine Mediterranean woodlands immediately adjacent to Africa, but extended deep into the semi-arid grasslands of Arabia, facilitated by periods of enhanced monsoonal rainfall.
Project description:We searched the primary sequence of influenza A H5N1 polyprotein for hexamer amino acid sequences shared with human proteins using the Protein International Resource database and the exact peptide matching analysis program. We find that the viral polyprotein shares numerous hexapeptides with the human proteome. The human proteins involved in the viral overlap are represented by antigens associated with basic cell functions such as proliferation, development, and differentiation. Of special importance, many human proteins that share peptide sequences with influenza A polyprotein are antigens such as reelin, neurexin I-?, myosin-IXa, Bardet-Biedl syndrome 10 protein, Williams syndrome transcription factor, disrupted in schizophrenia 1 protein, amyotrophic lateral sclerosis 2 chromosomal region candidate gene 17 protein, fragile X mental retardation 2 protein, and jouberin. That is, the viral-vs-human overlap involves human proteins that, when altered, have been reported to be potentially associated with multiple neurological disorders that can include autism, epilepsy, obesity, dystonia, ataxia-telangiectasia, amyotrophic lateral sclerosis, sensorineural deafness, sudden infant death syndrome, Charcot-Marie-Tooth disease, and myelination. The present data are discussed as a possible molecular basis for understanding influenza A viral escape from immunosurveillance and for defining anti-influenza immune-therapeutic approaches devoid of collateral adverse events.
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
Project description:The geometric morphometric analysis of shape variation in complex biological structures such as the human skull poses a number of specific challenges: the registration of homologous morphologies, the treatment of bilateral symmetry, the graphical representation of form variability in three dimensions and the interpretation of the results in terms of differential growth processes. To visualize complex patterns of shape change, we propose an alternative to classical Cartesian deformation grids in the style of D'Arcy W. Thompson. Reference to the surface structures of the organism under investigation permits a comprehensive visual grasp of shape change and its tentative interpretation in terms of differential growth. The application of this method to the analysis of human craniofacial shape variation reveals distinct modes of growth and development of the neurocranial and viscerocranial regions of the skull. Our data further indicate that variations in the orientation of the viscerocranium relative to the neurocranium impinge on the shapes of the face and the cranial vault.
Project description:The genealogies of different genetic loci vary in depth. The deeper the genealogy, the greater the chance that it will include a rare event, such as the insertion of a mobile element. Therefore, the genealogy of a region that contains a mobile element is on average older than that of the rest of the genome. In a simple demographic model, the expected time to most recent common ancestor (TMRCA) is doubled if a rare insertion is present. We test this expectation by examining single nucleotide polymorphisms around polymorphic Alu insertions from two completely sequenced human genomes. The estimated TMRCA for regions containing a polymorphic insertion is two times larger than the genomic average (P < <10(-30)), as predicted. Because genealogies that contain polymorphic mobile elements are old, they are shaped largely by the forces of ancient population history and are insensitive to recent demographic events, such as bottlenecks and expansions. Remarkably, the information in just two human DNA sequences provides substantial information about ancient human population size. By comparing the likelihood of various demographic models, we estimate that the effective population size of human ancestors living before 1.2 million years ago was 18,500, and we can reject all models where the ancient effective population size was larger than 26,000. This result implies an unusually small population for a species spread across the entire Old World, particularly in light of the effective population sizes of chimpanzees (21,000) and gorillas (25,000), which each inhabit only one part of a single continent.
Project description:This study identifies and analyzes statistically significant overlaps between selective sweep screens in anatomically modern humans and several domesticated species. The results obtained suggest that (paleo-)genomic data can be exploited to complement the fossil record and support the idea of self-domestication in Homo sapiens, a process that likely intensified as our species populated its niche. Our analysis lends support to attempts to capture the "domestication syndrome" in terms of alterations to certain signaling pathways and cell lineages, such as the neural crest.
Project description:Protein-coding regions in a genome evolve by sequence divergence and gene gain and loss, altering the gene content of the organism. However, it is not well understood how this has given rise to the enormous diversity of metazoa present today.To obtain a global view of human genomic evolution, we quantify the divergence of proteins by functional category at different evolutionary distances from human.This analysis highlights some general systems-level characteristics of human evolution: regulatory processes, such as signal transducers, transcription factors and receptors, have a high degree of plasticity, while core processes, such as metabolism, transport and protein synthesis, are largely conserved. Additionally, this study reveals a dynamic picture of selective forces at short, medium and long evolutionary timescales. Certain functional categories, such as 'development' and 'organogenesis', exhibit temporal patterns of sequence divergence in eukaryotes relative to human. This framework for a grammar of human evolution supports previously postulated theories of robustness and evolvability.