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1.
Methods Mol Biol ; 1910: 533-553, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278676

RESUMO

In this chapter, we give a short introduction to the genetics of complex diseases emphasizing evolutionary models for disease genes and the effect of different models on the genetic architecture, and we give a survey of the state-of-the-art of genome-wide association studies (GWASs).

2.
Plant Cell ; 31(7): 1466-1487, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31023841

RESUMO

The merging of distinct genomes, allopolyploidization, is a widespread phenomenon in plants. It generates adaptive potential through increased genetic diversity, but examples demonstrating its exploitation remain scarce. White clover (Trifolium repens) is a ubiquitous temperate allotetraploid forage crop derived from two European diploid progenitors confined to extreme coastal or alpine habitats. We sequenced and assembled the genomes and transcriptomes of this species complex to gain insight into the genesis of white clover and the consequences of allopolyploidization. Based on these data, we estimate that white clover originated ∼15,000 to 28,000 years ago during the last glaciation when alpine and coastal progenitors were likely colocated in glacial refugia. We found evidence of progenitor diversity carryover through multiple hybridization events and show that the progenitor subgenomes have retained integrity and gene expression activity as they traveled within white clover from their original confined habitats to a global presence. At the transcriptional level, we observed remarkably stable subgenome expression ratios across tissues. Among the few genes that show tissue-specific switching between homeologous gene copies, we found flavonoid biosynthesis genes strongly overrepresented, suggesting an adaptive role of some allopolyploidy-associated transcriptional changes. Our results highlight white clover as an example of allopolyploidy-facilitated niche expansion, where two progenitor genomes, adapted and confined to disparate and highly specialized habitats, expanded to a ubiquitous global presence after glaciation-associated allopolyploidization.

3.
Genetics ; 209(3): 907-920, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29769284

RESUMO

Ampliconic genes are multicopy, with the majority found on sex chromosomes and enriched for testis-expressed genes. While ampliconic genes have been associated with the emergence of hybrid incompatibilities, we know little about their copy number distribution and their turnover in human populations. Here, we explore the evolution of human X- and Y-linked ampliconic genes by investigating copy number variation (CNV) and coding variation between populations using the Simons Genome Diversity Project. We develop a method to assess CNVs using the read depth on modified X and Y chromosome targets containing only one repetition of each ampliconic gene. Our results reveal extensive standing variation in copy number both within and between human populations for several ampliconic genes. For the Y chromosome, we can infer multiple independent amplifications and losses of these gene copies even within closely related Y haplogroups, that diversified < 50,000 years ago. Moreover, X- and Y-linked ampliconic genes seem to have a faster amplification dynamic than autosomal multicopy genes. Looking at expression data from another study, we also find that X- and Y-linked ampliconic genes with extensive CNV are significantly more expressed than genes with no CNV during meiotic sex chromosome inactivation (for both X and Y) and postmeiotic sex chromosome repression (for the Y chromosome only). While we cannot rule out that the XY-linked ampliconic genes are evolving neutrally, this study gives insights into the distribution of copy number within human populations and demonstrates an extremely fast turnover in copy number of these regions.


Assuntos
Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Dosagem de Genes , Genes Ligados ao Cromossomo X , Genes Ligados ao Cromossomo Y , Biologia Computacional/métodos , Evolução Molecular , Feminino , Genética Populacional , Humanos , Masculino , Meiose , Família Multigênica
4.
Hum Mol Genet ; 27(3): 430-439, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186436

RESUMO

In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. KS patients display a varying adult phenotype but usually present with azoospermia due to testicular degeneration, which accelerates at puberty. The timing of the germ cell loss and whether it is caused by dysgenetic fetal development of the testes is not known. We investigated eight fetal KS testes and found a marked reduction in MAGE-A4-positive pre-spermatogonia compared with testes from 15 age-matched controls, indicating a failure of the gonocytes to differentiate into pre-spermatogonia. Transcriptome analysis by RNA-sequencing of formalin-fixed, paraffin-embedded testes originating from four fetal KS and five age-matched controls revealed 211 differentially expressed transcripts in the fetal KS testis. We found a significant enrichment of upregulated X-chromosomal transcripts and validated the expression of the pseudoautosomal region 1 (PAR1) gene, AKAP17A. Moreover, we found enrichment of long non-coding RNAs in the KS testes (e.g. LINC01569 and RP11-485F13.1). In conclusion, our data indicate that the testicular phenotype observed among adult men with KS is initiated already in fetal life by failure of the gonocyte differentiation into pre-spermatogonia, which could be due to aberrant expression of long non-coding RNAs.

5.
Science ; 358(6363): 655-658, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-28982794

RESUMO

To date, the only Neandertal genome that has been sequenced to high quality is from an individual found in Southern Siberia. We sequenced the genome of a female Neandertal from ~50,000 years ago from Vindija Cave, Croatia, to ~30-fold genomic coverage. She carried 1.6 differences per 10,000 base pairs between the two copies of her genome, fewer than present-day humans, suggesting that Neandertal populations were of small size. Our analyses indicate that she was more closely related to the Neandertals that mixed with the ancestors of present-day humans living outside of sub-Saharan Africa than the previously sequenced Neandertal from Siberia, allowing 10 to 20% more Neandertal DNA to be identified in present-day humans, including variants involved in low-density lipoprotein cholesterol concentrations, schizophrenia, and other diseases.


Assuntos
Evolução Biológica , Homem de Neandertal/genética , Alelos , Animais , Cavernas , Croácia , DNA Antigo , Genoma , Humanos
6.
Genome Res ; 27(9): 1597-1607, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28774965

RESUMO

Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.


Assuntos
Variação Genética/genética , Genética Populacional , Desequilíbrio de Ligação/genética , Complexo Principal de Histocompatibilidade/genética , Alelos , Mapeamento Cromossômico , Dinamarca , Haplótipos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética
7.
PLoS One ; 11(8): e0161822, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27571202

RESUMO

Scientific outreach delivers science to the people. But it can also deliver people to the science. In this work, we report our experience from a large-scale public engagement project promoting genomic literacy among Danish high school students with the additional benefit of collecting data for studying the genetic makeup of the Danish population. Not only did we confirm that students have a great interest in their genetic past, but we were also gratified to see that, with the right motivation, adolescents can provide high-quality data for genetic studies.


Assuntos
Genômica/economia , Ciência/educação , Adolescente , Adulto , Dinamarca , Feminino , Humanos , Masculino , Autorrelato , Estudantes/estatística & dados numéricos , Adulto Jovem
8.
Genetics ; 204(2): 711-722, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27535931

RESUMO

Denmark has played a substantial role in the history of Northern Europe. Through a nationwide scientific outreach initiative, we collected genetic and anthropometrical data from ∼800 high school students and used them to elucidate the genetic makeup of the Danish population, as well as to assess polygenic predictions of phenotypic traits in adolescents. We observed remarkable homogeneity across different geographic regions, although we could still detect weak signals of genetic structure reflecting the history of the country. Denmark presented genomic affinity with primarily neighboring countries with overall resemblance of decreasing weight from Britain, Sweden, Norway, Germany, and France. A Polish admixture signal was detected in Zealand and Funen, and our date estimates coincided with historical evidence of Wend settlements in the south of Denmark. We also observed considerably diverse demographic histories among Scandinavian countries, with Denmark having the smallest current effective population size compared to Norway and Sweden. Finally, we found that polygenic prediction of self-reported adolescent height in the population was remarkably accurate (R2 = 0.639 ± 0.015). The high homogeneity of the Danish population could render population structure a lesser concern for the upcoming large-scale gene-mapping studies in the country.


Assuntos
Demografia , Genética Populacional , Genômica , Adolescente , Antropometria , Dinamarca , Feminino , Genoma Humano , Humanos , Masculino , Densidade Demográfica
9.
Genome Biol Evol ; 8(6): 2020-30, 2016 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-27345955

RESUMO

The genus Pan is the closest genus to our own and it includes two species, Pan paniscus (bonobos) and Pan troglodytes (chimpanzees). The later is constituted by four subspecies, all highly endangered. The study of the Pan genera has been incessantly complicated by the intricate relationship among subspecies and the statistical limitations imposed by the reduced number of samples or genomic markers analyzed. Here, we present a new method to reconstruct complete mitochondrial genomes (mitogenomes) from whole genome shotgun (WGS) datasets, mtArchitect, showing that its reconstructions are highly accurate and consistent with long-range PCR mitogenomes. We used this approach to build the mitochondrial genomes of 20 newly sequenced samples which, together with available genomes, allowed us to analyze the hitherto most complete Pan mitochondrial genome dataset including 156 chimpanzee and 44 bonobo individuals, with a proportional contribution from all chimpanzee subspecies. We estimated the separation time between chimpanzees and bonobos around 1.15 million years ago (Mya) [0.81-1.49]. Further, we found that under the most probable genealogical model the two clades of chimpanzees, Western + Nigeria-Cameroon and Central + Eastern, separated at 0.59 Mya [0.41-0.78] with further internal separations at 0.32 Mya [0.22-0.43] and 0.16 Mya [0.17-0.34], respectively. Finally, for a subset of our samples, we compared nuclear versus mitochondrial genomes and we found that chimpanzee subspecies have different patterns of nuclear and mitochondrial diversity, which could be a result of either processes affecting the mitochondrial genome, such as hitchhiking or background selection, or a result of population dynamics.


Assuntos
Evolução Molecular , Genoma Mitocondrial/genética , Pan paniscus/genética , Pan troglodytes/genética , Animais , Variação Genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Filogenia
10.
Am J Hum Genet ; 97(4): 576-92, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26430803

RESUMO

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.


Assuntos
Desequilíbrio de Ligação/genética , Modelos Teóricos , Herança Multifatorial/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Prognóstico , Locos de Características Quantitativas
11.
PLoS Genet ; 11(8): e1005451, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26274919

RESUMO

The human and chimpanzee X chromosomes are less divergent than expected based on autosomal divergence. We study incomplete lineage sorting patterns between humans, chimpanzees and gorillas to show that this low divergence can be entirely explained by megabase-sized regions comprising one-third of the X chromosome, where polymorphism in the human-chimpanzee ancestral species was severely reduced. We show that background selection can explain at most 10% of this reduction of diversity in the ancestor. Instead, we show that several strong selective sweeps in the ancestral species can explain it. We also report evidence of population specific sweeps in extant humans that overlap the regions of low diversity in the ancestral species. These regions further correspond to chromosomal sections shown to be devoid of Neanderthal introgression into modern humans. This suggests that the same X-linked regions that undergo selective sweeps are among the first to form reproductive barriers between diverging species. We hypothesize that meiotic drive is the underlying mechanism causing these two observations.


Assuntos
Cromossomos Humanos X/genética , Animais , Feminino , Deriva Genética , Especiação Genética , Variação Genética , Humanos , Masculino , Homem de Neandertal , Recombinação Genética , Seleção Genética , Especificidade da Espécie
12.
Genome Biol Evol ; 7(4): 1122-32, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25829516

RESUMO

We study genome-wide nucleotide diversity in three subspecies of extant chimpanzees using exome capture. After strict filtering, Single Nucleotide Polymorphisms and indels were called and genotyped for greater than 50% of exons at a mean coverage of 35× per individual. Central chimpanzees (Pan troglodytes troglodytes) are the most polymorphic (nucleotide diversity, θw = 0.0023 per site) followed by Eastern (P. t. schweinfurthii) chimpanzees (θw = 0.0016) and Western (P. t. verus) chimpanzees (θw = 0.0008). A demographic scenario of divergence without gene flow fits the patterns of autosomal synonymous nucleotide diversity well except for a signal of recent gene flow from Western into Eastern chimpanzees. The striking contrast in X-linked versus autosomal polymorphism and divergence previously reported in Central chimpanzees is also found in Eastern and Western chimpanzees. We show that the direction of selection statistic exhibits a strong nonmonotonic relationship with the strength of purifying selection S, making it inappropriate for estimating S. We instead use counts in synonymous versus nonsynonymous frequency classes to infer the distribution of S coefficients acting on nonsynonymous mutations in each subspecies. The strength of purifying selection we infer is congruent with the differences in effective sizes of each subspecies: Central chimpanzees are undergoing the strongest purifying selection followed by Eastern and Western chimpanzees. Coding indels show stronger selection against indels changing the reading frame than observed in human populations.


Assuntos
Pan troglodytes/genética , Seleção Genética , Animais , Demografia , Exoma , Éxons , Aptidão Genética , Genômica , Humanos , Mutação INDEL , Pan troglodytes/classificação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
13.
Nat Commun ; 6: 5969, 2015 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-25597990

RESUMO

Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e-8 and 1.5e-9 per nucleotide per generation for SNVs and indels, respectively.


Assuntos
Genoma Humano/genética , Algoritmos , Humanos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/métodos
14.
Bioessays ; 36(9): 892-900, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25043668

RESUMO

Recombination maps of ancestral species can be constructed from comparative analyses of genomes from closely related species, exemplified by a recently published map of the human-chimpanzee ancestor. Such maps resolve differences in recombination rate between species into changes along individual branches in the speciation tree, and allow identification of associated changes in the genomic sequences. We describe how coalescent hidden Markov models are able to call individual recombination events in ancestral species through inference of incomplete lineage sorting along a genomic alignment. In the great apes, speciation events are sufficiently close in time that a map can be inferred for the ancestral species at each internal branch - allowing evolution of recombination rate to be tracked over evolutionary time scales from speciation event to speciation event. We see this approach as a way of characterizing the evolution of recombination rate and the genomic properties that influence it.


Assuntos
Evolução Molecular , Recombinação Genética , Animais , Cromossomos Humanos/genética , Genoma Humano , Humanos , Cadeias de Markov , Modelos Genéticos
15.
Nat Commun ; 5: 3765, 2014 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-24801114

RESUMO

Spiders are ecologically important predators with complex venom and extraordinarily tough silk that enables capture of large prey. Here we present the assembled genome of the social velvet spider and a draft assembly of the tarantula genome that represent two major taxonomic groups of spiders. The spider genomes are large with short exons and long introns, reminiscent of mammalian genomes. Phylogenetic analyses place spiders and ticks as sister groups supporting polyphyly of the Acari. Complex sets of venom and silk genes/proteins are identified. We find that venom genes evolved by sequential duplication, and that the toxic effect of venom is most likely activated by proteases present in the venom. The set of silk genes reveals a highly dynamic gene evolution, new types of silk genes and proteins, and a novel use of aciniform silk. These insights create new opportunities for pharmacological applications of venom and biomaterial applications of silk.


Assuntos
Genoma/genética , Proteínas de Insetos/genética , Seda/genética , Venenos de Aranha/genética , Aranhas/genética , Animais , Sequência de Bases , Evolução Molecular , Peptídeo Hidrolases/genética , Filogenia , Análise de Sequência de DNA
16.
Eur J Hum Genet ; 22(8): 1040-5, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24448545

RESUMO

In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise the variation found in the mtDNA sequence in Danes and relate the variation to diabetes risk as well as to several blood phenotypes of the controls but find no significant associations. We report 2025 polymorphisms, of which 393 have not been reported previously. These 393 mutations are both very rare and estimated to be caused by very recent mutations but individuals with type 2 diabetes do not possess more of these variants. Population genetics analysis using Bayesian skyline plot shows a recent history of rapid population growth in the Danish population in accordance with the fact that >40% of variable sites are observed as singletons.


Assuntos
DNA Mitocondrial , Diabetes Mellitus/genética , Estudos de Associação Genética , Variação Genética , Estudos de Casos e Controles , Dinamarca , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Frequência do Gene , Genética Populacional , Genótipo , Humanos , Filogenia , Polimorfismo Genético , Característica Quantitativa Herdável
17.
Genome Res ; 23(1): 195-200, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22972939

RESUMO

We present a new approach to indel calling that explicitly exploits that indel differences between a reference and a sequenced sample make the mapping of reads less efficient. We assign all unmapped reads with a mapped partner to their expected genomic positions and then perform extensive de novo assembly on the regions with many unmapped reads to resolve homozygous, heterozygous, and complex indels by exhaustive traversal of the de Bruijn graph. The method is implemented in the software SOAPindel and provides a list of candidate indels with quality scores. We compare SOAPindel to Dindel, Pindel, and GATK on simulated data and find similar or better performance for short indels (<10 bp) and higher sensitivity and specificity for long indels. A validation experiment suggests that SOAPindel has a false-positive rate of ∼10% for long indels (>5 bp), while still providing many more candidate indels than other approaches.


Assuntos
Mutação INDEL , Mapeamento Físico do Cromossomo/métodos , Análise de Sequência de DNA/métodos , Software , Reações Falso-Positivas , Genoma Humano , Técnicas de Genotipagem/métodos , Heterozigoto , Homozigoto , Humanos
18.
PLoS One ; 7(7): e40637, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848389

RESUMO

Non-human primates have emerged as an important resource for the study of human disease and evolution. The characterization of genomic variation between and within non-human primate species could advance the development of genetically defined non-human primate disease models. However, non-human primate specific reagents that would expedite such research, such as exon-capture tools, are lacking. We evaluated the efficiency of using a human exome capture design for the selective enrichment of exonic regions of non-human primates. We compared the exon sequence recovery in nine chimpanzees, two crab-eating macaques and eight Japanese macaques. Over 91% of the target regions were captured in the non-human primate samples, although the specificity of the capture decreased as evolutionary divergence from humans increased. Both intra-specific and inter-specific DNA variants were identified; Sanger-based resequencing validated 85.4% of 41 randomly selected SNPs. Among the short indels identified, a majority (54.6%-77.3%) of the variants resulted in a change of 3 base pairs, consistent with expectations for a selection against frame shift mutations. Taken together, these findings indicate that use of a human design exon-capture array can provide efficient enrichment of non-human primate gene regions. Accordingly, use of the human exon-capture methods provides an attractive, cost-effective approach for the comparative analysis of non-human primate genomes, including gene-based DNA variant discovery.


Assuntos
Exoma , Macaca fascicularis/genética , Pan troglodytes/genética , Polimorfismo de Nucleotídeo Único , Animais , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
19.
Nature ; 486(7404): 527-31, 2012 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-22722832

RESUMO

Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other.


Assuntos
Evolução Molecular , Variação Genética/genética , Genoma Humano/genética , Genoma/genética , Pan paniscus/genética , Pan troglodytes/genética , Animais , Elementos de DNA Transponíveis/genética , Duplicação Gênica/genética , Genótipo , Humanos , Dados de Sequência Molecular , Fenótipo , Filogenia , Especificidade da Espécie
20.
Methods Mol Biol ; 856: 275-91, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22399463

RESUMO

In this chapter, we give a short introduction to the genetics of complex disease with special emphasis on evolutionary models for disease genes and the effect of different models on the genetic architecture, and finally give a survey of the state-of-the-art of genome-wide association studies.


Assuntos
Doença/genética , Evolução Molecular , Estudo de Associação Genômica Ampla/métodos , Interpretação Estatística de Dados , Frequência do Gene , Humanos
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