Publications by authors named "Joshua M Akey"

107 Publications

Implications of localized charge for human influenza A H1N1 hemagglutinin evolution: Insights from deep mutational scans.

PLoS Comput Biol 2020 06 25;16(6):e1007892. Epub 2020 Jun 25.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.

Seasonal influenza A viruses of humans evolve rapidly due to strong selection pressures from host immune responses, principally on the hemagglutinin (HA) viral surface protein. Based on mouse transmission experiments, a proposed mechanism for immune evasion consists of increased avidity to host cellular receptors, mediated by electrostatic charge interactions with negatively charged cell surfaces. In support of this, the HA charge of the globally circulating H3N2 has increased over time since its pandemic. However, the same trend was not seen in H1N1 HA sequences. This is counter-intuitive, since immune escape due to increased avidity (due itself to an increase in charge) was determined experimentally. Here, we explore whether patterns of local charge of H1N1 HA can explain this discrepancy and thus further associate electrostatic charge with immune escape and viral evolutionary dynamics. Measures of site-wise functional selection and expected charge computed from deep mutational scan data on an early H1N1 HA yield a striking division of residues into three groups, separated by charge. We then explored evolutionary dynamics of these groups from 1918 to 2008. In particular, one group increases in net charge over time and consists of sites that are evolving the fastest, that are closest to the receptor binding site (RBS), and that are exposed to solvent (i.e., on the surface). By contrast, another group decreases in net charge and consists of sites that are further away from the RBS and evolving slower, but also exposed to solvent. The last group consists of those sites in the HA core, with no change in net charge and that evolve very slowly. Thus, there is a group of residues that follows the same trend as seen for the entire H3N2 HA. It is possible that the H1N1 HA is under other biophysical constraints that result in compensatory decreases in charge elsewhere on the protein. Our results implicate localized charge in HA interactions with host cells, and highlight how deep mutational scan data can inform evolutionary hypotheses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1007892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316228PMC
June 2020

Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals.

Cell 2020 02 30;180(4):677-687.e16. Epub 2020 Jan 30.

The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA. Electronic address:

Admixture has played a prominent role in shaping patterns of human genomic variation, including gene flow with now-extinct hominins like Neanderthals and Denisovans. Here, we describe a novel probabilistic method called IBDmix to identify introgressed hominin sequences, which, unlike existing approaches, does not use a modern reference population. We applied IBDmix to 2,504 individuals from geographically diverse populations to identify and analyze Neanderthal sequences segregating in modern humans. Strikingly, we find that African individuals carry a stronger signal of Neanderthal ancestry than previously thought. We show that this can be explained by genuine Neanderthal ancestry due to migrations back to Africa, predominately from ancestral Europeans, and gene flow into Neanderthals from an early dispersing group of humans out of Africa. Our results refine our understanding of Neanderthal ancestry in African and non-African populations and demonstrate that remnants of Neanderthal genomes survive in every modern human population studied to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.01.012DOI Listing
February 2020

The long walk to African genomics.

Genome Biol 2019 06 27;20(1):130. Epub 2019 Jun 27.

Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, South Drive, Princeton, NJ, 08544, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-019-1740-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598360PMC
June 2019

Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia.

Science 2018 08;361(6401):511-516

Department of Biomolecular Engineering, University of California, Santa Cruz, CA, USA.

Flores Island, Indonesia, was inhabited by the small-bodied hominin species , which has an unknown evolutionary relationship to modern humans. This island is also home to an extant human pygmy population. Here we describe genome-scale single-nucleotide polymorphism data and whole-genome sequences from a contemporary human pygmy population living on Flores near the cave where was found. The genomes of Flores pygmies reveal a complex history of admixture with Denisovans and Neanderthals but no evidence for gene flow with other archaic hominins. Modern individuals bear the signatures of recent positive selection encompassing the FADS (fatty acid desaturase) gene cluster, likely related to diet, and polygenic selection acting on standing variation that contributed to their short-stature phenotype. Thus, multiple independent instances of hominin insular dwarfism occurred on Flores.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aar8486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709593PMC
August 2018

Massive variation of short tandem repeats with functional consequences across strains of .

Genome Res 2018 08 3;28(8):1169-1178. Epub 2018 Jul 3.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

Short tandem repeat (STR) mutations may comprise more than half of the mutations in eukaryotic coding DNA, yet STR variation is rarely examined as a contributor to complex traits. We assessed this contribution across a collection of 96 strains of , genotyping 2046 STR loci each, using highly parallel STR sequencing with molecular inversion probes. We found that 95% of examined STRs are polymorphic, with a median of six alleles per STR across these strains. STR expansions (large copy number increases) are found in most strains, several of which have evident functional effects. These include three of six intronic STR expansions we found to be associated with intron retention. Coding STRs were depleted of variation relative to noncoding STRs, and we detected a total of 56 coding STRs (11%) showing low variation consistent with the action of purifying selection. In contrast, some STRs show hypervariable patterns consistent with diversifying selection. Finally, we detected 133 novel STR-phenotype associations under stringent criteria, most of which could not be detected with SNPs alone, and validated some with follow-up experiments. Our results support the conclusion that STRs constitute a large, unascertained reservoir of functionally relevant genomic variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.231753.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071631PMC
August 2018

Outstanding questions in the study of archaic hominin admixture.

PLoS Genet 2018 05 31;14(5):e1007349. Epub 2018 May 31.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.

The complete sequencing of archaic and modern human genomes has revolutionized the study of human history and evolution. The application of paleogenomics has answered questions that were beyond the scope of archaeology alone-definitively proving admixture between archaic and modern humans. Despite the remarkable progress made in the study of archaic-modern human admixture, many outstanding questions remain. Here, we review some of these questions, which include how frequent archaic-modern human admixture was in history, to what degree drift and selection are responsible for the loss and retention of introgressed sequences in modern human genomes, and how surviving archaic sequences affect human phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1007349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978786PMC
May 2018

Evolution of DNAase I Hypersensitive Sites in MHC Regulatory Regions of Primates.

Genetics 2018 06 18;209(2):579-589. Epub 2018 Apr 18.

Department of Genome Sciences, University of Washington, Seattle, Washington 98125

It has been challenging to determine the disease-causing variant(s) for most major histocompatibility complex (MHC)-associated diseases. However, it is becoming increasingly clear that regulatory variation is pervasive and a fundamentally important mechanism governing phenotypic diversity and disease susceptibility. We gathered DNase I data from 136 human cells to characterize the regulatory landscape of the MHC region, including 4867 DNase I hypersensitive sites (DHSs). We identified thousands of regulatory elements that have been gained or lost in the human or chimpanzee genomes since their evolutionary divergence. We compared alignments of the DHS across six primates and found 149 DHSs with convincing evidence of positive and/or purifying selection. Of these DHSs, compared to neutral sequences, 24 evolved rapidly in the human lineage. We identified 15 instances of transcription-factor-binding motif gains, such as , , , , , , , and observed 16 GWAS (genome-wide association study) SNPs associated with diseases within these 24 DHSs using FIMO (Find Individual Motif Occurrences) and UCSC (University of California, Santa Cruz) ChIP-seq data. Combining eQTL and Hi-C data, our results indicated that there were five SNPs located in human gains motifs affecting the corresponding gene's expression, two of which closely matched DHS target genes. In addition, a significant SNP, rs7756521, at genome-wide significant level likely affects DDR expression and represents a causal genetic variant for HIV-1 control. These results indicated that species-specific motif gains or losses of rapidly evolving DHSs in the primate genomes might play a role during adaptation evolution and provided some new evidence for a potentially causal role for these GWAS SNPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1534/genetics.118.301028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972428PMC
June 2018

Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture.

Cell 2018 03 15;173(1):53-61.e9. Epub 2018 Mar 15.

Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA; The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.

Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. VIDEO ABSTRACT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866234PMC
March 2018

Selection plays the hand it was dealt: evidence that human adaptation commonly targets standing genetic variation.

Genome Biol 2017 08 1;18(1):139. Epub 2017 Aug 1.

Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.

Using a powerful machine learning approach, a recent study of human genomes has revealed widespread footprints of recent positive selection on standing genetic variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-017-1280-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537971PMC
August 2017

Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression.

Cell 2017 02;168(5):916-927.e12

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address:

Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2017.01.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219754PMC
February 2017

Tracing the peopling of the world through genomics.

Nature 2017 01;541(7637):302-310

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark.

Advances in the sequencing and the analysis of the genomes of both modern and ancient peoples have facilitated a number of breakthroughs in our understanding of human evolutionary history. These include the discovery of interbreeding between anatomically modern humans and extinct hominins; the development of an increasingly detailed description of the complex dispersal of modern humans out of Africa and their population expansion worldwide; and the characterization of many of the genetic adaptions of humans to local environmental conditions. Our interpretation of the evolutionary history and adaptation of humans is being transformed by analyses of these new genomic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature21347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772775PMC
January 2017

Editorial overview: Genetics of human origin: New horizons in human population genetics.

Curr Opin Genet Dev 2016 12 23;41:v-vi. Epub 2016 Nov 23.

Department of Human Genetics, University of Chicago, Chicago, IL, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gde.2016.11.002DOI Listing
December 2016

Human RECQ Helicase Pathogenic Variants, Population Variation and "Missing" Diseases.

Hum Mutat 2017 02 9;38(2):193-203. Epub 2016 Dec 9.

Department of Genome Sciences, University of Washington, Seattle, Washington.

Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes-RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases-may remain missing, as they likely incompatible with life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518694PMC
February 2017

Archaic Hominin Admixture Facilitated Adaptation to Out-of-Africa Environments.

Curr Biol 2016 12 10;26(24):3375-3382. Epub 2016 Nov 10.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address:

As modern humans dispersed from Africa throughout the world, they encountered and interbred with archaic hominins, including Neanderthals and Denisovans [1, 2]. Although genome-scale maps of introgressed sequences have been constructed [3-6], considerable gaps in knowledge remain about the functional, phenotypic, and evolutionary significance of archaic hominin DNA that persists in present-day individuals. Here, we describe a comprehensive set of analyses that identified 126 high-frequency archaic haplotypes as putative targets of adaptive introgression in geographically diverse populations. These loci are enriched for immune-related genes (such as OAS1/2/3, TLR1/6/10, and TNFAIP3) and also encompass genes (including OCA2 and BNC2) that influence skin pigmentation phenotypes. Furthermore, we leveraged existing and novel large-scale gene expression datasets to show many positively selected archaic haplotypes act as expression quantitative trait loci (eQTLs), suggesting that modulation of transcript abundance was a common mechanism facilitating adaptive introgression. Our results demonstrate that hybridization between modern and archaic hominins provided an important reservoir of advantageous alleles that enabled adaptation to out-of-Africa environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2016.10.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764441PMC
December 2016

Robust Inference of Identity by Descent from Exome-Sequencing Data.

Am J Hum Genet 2016 Nov 13;99(5):1106-1116. Epub 2016 Oct 13.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address:

Identifying and characterizing genomic regions that are shared identical by descent (IBD) among individuals can yield insight into population history, facilitate the identification of adaptively evolving loci, and be an important tool in disease gene mapping. Although increasingly large collections of exome sequences have been generated, it is challenging to detect IBD segments in exomes, precluding many potentially informative downstream analyses. Here, we describe an approach, ExIBD, to robustly detect IBD segments in exome-sequencing data, rigorously evaluate its performance, and apply this method to high-coverage exomes from 6,515 European and African Americans. Furthermore, we show how IBD networks, constructed from patterns of pairwise IBD between individuals, and principles from graph theory provide insight into recent population history and reveal cryptic population structure in European Americans. Our results enable IBD analyses to be performed on exome data, which will expand the scope of inferences that can be made from existing massively large exome-sequencing datasets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097937PMC
November 2016

Detecting Sources of Transcriptional Heterogeneity in Large-Scale RNA-Seq Data Sets.

Genetics 2016 Dec 11;204(4):1391-1396. Epub 2016 Oct 11.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195

Gene expression levels are dynamic molecular phenotypes that respond to biological, environmental, and technical perturbations. Here we use a novel replicate-classifier approach for discovering transcriptional signatures and apply it to the Genotype-Tissue Expression data set. We identified many factors contributing to expression heterogeneity, such as collection center and ischemia time, and our approach of scoring replicate classifiers allows us to statistically stratify these factors by effect strength. Strikingly, from transcriptional expression in blood alone we detect markers that help predict heart disease and stroke in some patients. Our results illustrate the challenges and opportunities of interpreting patterns of transcriptional variation in large-scale data sets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1534/genetics.116.193714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161273PMC
December 2016

Population genetics: A map of human wanderlust.

Nature 2016 10 21;538(7624):179-180. Epub 2016 Sep 21.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature19472DOI Listing
October 2016

Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.

Nature 2016 08 3;536(7615):205-9. Epub 2016 Aug 3.

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11. rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature19075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988886PMC
August 2016

Human Diversity in a Cell Surface Receptor that Inhibits Autophagy.

Curr Biol 2016 07 23;26(14):1791-801. Epub 2016 Jun 23.

Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Department of Immunology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address:

Mutations in genes encoding autophagy proteins have been associated with human autoimmune diseases, suggesting that diversity in autophagy responses could be associated with disease susceptibility or severity. A cellular genome-wide association study (GWAS) screen was performed to explore normal human diversity in responses to rapamycin, a microbial product that induces autophagy. Cells from several human populations demonstrated variability in expression of a cell surface receptor, CD244 (SlamF4, 2B4), that correlated with changes in rapamycin-induced autophagy. High expression of CD244 and receptor activation with its endogenous ligand CD48 inhibited starvation- and rapamycin-induced autophagy by promoting association of CD244 with the autophagy complex proteins Vps34 and Beclin-1. The association of CD244 with this complex reduced Vps34 lipid kinase activity. Lack of CD244 is associated with auto-antibody production in mice, and lower expression of human CD244 has previously been implicated in severity of human rheumatoid arthritis and systemic lupus erythematosus, indicating that increased autophagy as a result of low levels of CD244 may alter disease outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2016.05.003DOI Listing
July 2016

A flexible method for estimating the fraction of fitness influencing mutations from large sequencing data sets.

Genome Res 2016 06 14;26(6):834-43. Epub 2016 Apr 14.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195-5065, USA.

A continuing challenge in the analysis of massively large sequencing data sets is quantifying and interpreting non-neutrally evolving mutations. Here, we describe a flexible and robust approach based on the site frequency spectrum to estimate the fraction of deleterious and adaptive variants from large-scale sequencing data sets. We applied our method to approximately 1 million single nucleotide variants (SNVs) identified in high-coverage exome sequences of 6515 individuals. We estimate that the fraction of deleterious nonsynonymous SNVs is higher than previously reported; quantify the effects of genomic context, codon bias, chromatin accessibility, and number of protein-protein interactions on deleterious protein-coding SNVs; and identify pathways and networks that have likely been influenced by positive selection. Furthermore, we show that the fraction of deleterious nonsynonymous SNVs is significantly higher for Mendelian versus complex disease loci and in exons harboring dominant versus recessive Mendelian mutations. In summary, as genome-scale sequencing data accumulate in progressively larger sample sizes, our method will enable increasingly high-resolution inferences into the characteristics and determinants of non-neutral variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.203059.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889975PMC
June 2016

Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.

Science 2016 Apr 17;352(6282):235-9. Epub 2016 Mar 17.

Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aad9416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743480PMC
April 2016

The phenotypic legacy of admixture between modern humans and Neandertals.

Science 2016 Feb;351(6274):737-41

Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA. Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA.

Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neandertals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neandertal variants to over 1000 electronic health record (EHR)-derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neandertal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neandertal alleles together explained a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neandertal alleles were significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neandertal haplotypes, and demonstrate the utility of EHR data in evolutionary analyses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aad2149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849557PMC
February 2016

Patterns of deleterious variation between human populations reveal an unbalanced load.

Proc Natl Acad Sci U S A 2016 Jan 19;113(4):809-11. Epub 2016 Jan 19.

Department of Genome Sciences, University of Washington, Seattle, WA 98195

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1524016113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743776PMC
January 2016

Methods and models for unravelling human evolutionary history.

Nat Rev Genet 2015 Dec 10;16(12):727-40. Epub 2015 Nov 10.

Department of Genome Sciences, University of Washington, 3720 15th Avenue NE, box 355065, Seattle, Washington 98195-5065, USA.

The genomes of contemporary humans contain considerable information about the history of our species. Although the general contours of human evolutionary history have been defined with increasing resolution throughout the past several decades, the continuing deluge of massively large sequencing data sets presents new opportunities and challenges for understanding human evolutionary history. Here, we review the signatures that demographic history imparts on patterns of DNA sequence variation, statistical methods that have been developed to leverage information contained in genome-scale data sets and insights gleaned from these studies. We also discuss the importance of using exploratory analyses to assess data quality, the strengths and limitations of commonly used population genomics methods, and factors that confound population genomics inferences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrg4005DOI Listing
December 2015

Small Amounts of Archaic Admixture Provide Big Insights into Human History.

Cell 2015 Oct;163(2):281-4

Department of Genome Sciences, University of Washington, 3720 15th Avenue Northeast, Box 355065, Seattle, WA 98195-5065, USA. Electronic address:

Modern humans overlapped in time and space with other hominins, such as Neanderthals and Denisovans, and limited amounts of hybridization occurred. Here, we review recent work that has identified archaic hominin sequence that survives in modern human genomes and what these genomic excavations reveal about human evolutionary history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2015.09.042DOI Listing
October 2015

The origins, determinants, and consequences of human mutations.

Science 2015 Sep 24;349(6255):1478-83. Epub 2015 Sep 24.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

Germline mutations are the principal cause of heritable disease and the ultimate source of evolutionary change. Similarly, somatic mutations are the primary cause of cancer and may contribute to the burden of human disease more broadly than previously appreciated. Here, we review recent insights into the rates, spectrum, and determinants of genomic mutations and how these parameters inform our understanding of both Mendelian and complex human diseases. We also consider models for conceptualizing mutational consequences and outline several key areas for future research, including the development of new technologies to access and quantify the full spectrum of mutations, as well as to better interpret the consequences of mutations with respect to molecular functionality, evolutionary fitness, and disease pathogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aaa9119DOI Listing
September 2015

Comprehensive identification and analysis of human accelerated regulatory DNA.

Genome Res 2015 Sep 23;25(9):1245-55. Epub 2015 Jun 23.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;

It has long been hypothesized that changes in gene regulation have played an important role in human evolution, but regulatory DNA has been much more difficult to study compared with protein-coding regions. Recent large-scale studies have created genome-scale catalogs of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To better define regulatory DNA that has been subject to human-specific adaptive evolution, we performed comprehensive evolutionary and population genetics analyses on over 18 million DHSs discovered in 130 cell types. We identified 524 DHSs that are conserved in nonhuman primates but accelerated in the human lineage (haDHS), and estimate that 70% of substitutions in haDHSs are attributable to positive selection. Through extensive computational and experimental analyses, we demonstrate that haDHSs are often active in brain or neuronal cell types; play an important role in regulating the expression of developmentally important genes, including many transcription factors such as SOX6, POU3F2, and HOX genes; and identify striking examples of adaptive regulatory evolution that may have contributed to human-specific phenotypes. More generally, our results reveal new insights into conserved and adaptive regulatory DNA in humans and refine the set of genomic substrates that distinguish humans from their closest living primate relatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.192591.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561485PMC
September 2015

Complex history of admixture between modern humans and Neandertals.

Am J Hum Genet 2015 Mar 12;96(3):448-53. Epub 2015 Feb 12.

Department of Genome Sciences, University of Washington, 3720 15(th) Avenue NE, PO Box 355065, Seattle WA 98195-5065, USA. Electronic address:

Recent analyses have found that a substantial amount of the Neandertal genome persists in the genomes of contemporary non-African individuals. East Asians have, on average, higher levels of Neandertal ancestry than do Europeans, which might be due to differences in the efficiency of purifying selection, an additional pulse of introgression into East Asians, or other unexplored scenarios. To better define the scope of plausible models of archaic admixture between Neandertals and anatomically modern humans, we analyzed patterns of introgressed sequence in whole-genome data of 379 Europeans and 286 East Asians. We found that inferences of demographic history restricted to neutrally evolving genomic regions allowed a simple one-pulse model to be robustly rejected, suggesting that differences in selection cannot explain the differences in Neandertal ancestry. We show that two additional demographic models, involving either a second pulse of Neandertal gene flow into the ancestors of East Asians or a dilution of Neandertal lineages in Europeans by admixture with an unknown ancestral population, are consistent with the data. Thus, the history of admixture between modern humans and Neandertals is most likely more complex than previously thought.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2015.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375686PMC
March 2015

Estimates of continental ancestry vary widely among individuals with the same mtDNA haplogroup.

Am J Hum Genet 2015 Feb 22;96(2):183-93. Epub 2015 Jan 22.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address:

The association between a geographical region and an mtDNA haplogroup(s) has provided the basis for using mtDNA haplogroups to infer an individual's place of origin and genetic ancestry. Although it is well known that ancestry inferences using mtDNA haplogroups and those using genome-wide markers are frequently discrepant, little empirical information exists on the magnitude and scope of such discrepancies between multiple mtDNA haplogroups and worldwide populations. We compared genetic-ancestry inferences made by mtDNA-haplogroup membership to those made by autosomal SNPs in ∼940 samples of the Human Genome Diversity Panel and recently admixed populations from the 1000 Genomes Project. Continental-ancestry proportions often varied widely among individuals sharing the same mtDNA haplogroup. For only half of mtDNA haplogroups did the highest average continental-ancestry proportion match the highest continental-ancestry proportion of a majority of individuals with that haplogroup. Prediction of an individual's mtDNA haplogroup from his or her continental-ancestry proportions was often incorrect. Collectively, these results indicate that for most individuals in the worldwide populations sampled, mtDNA-haplogroup membership provides limited information about either continental ancestry or continental region of origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2014.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320259PMC
February 2015

Rare variation facilitates inferences of fine-scale population structure in humans.

Mol Biol Evol 2015 Mar 21;32(3):653-60. Epub 2014 Nov 21.

Department of Genome Sciences, University of Washington, Seattle.

Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European-American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molbev/msu326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327153PMC
March 2015