Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture

Burbano, Hernán A.; Hodges, Emily; Green, Edward; Briggs, Adrian W.; Krause, Johannes; Meyer, Matthias; Good, Jeffrey M.; Maričić, Tomislav; Johnson, Philipp L.F.; Xuan, Zhenyu; Rooks, Michelle; Bhattacharjee, Arindam; Brizuela, Leonardo; Albert, Frank W.; Vives, Marco de la Rasilla; Fortea, Javier; Rosas, Antonio; Lachmann, Michael; Hannon, Gregory J.; Pääbo, Svante

doi:10.1126/science.1188046

Cited by 250 publications

(208 citation statements)

References 26 publications

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“…The use of sequence-capture arrays (e.g. Burbano et al 2010) even allows targeted sequencing of specific genomic regions, which means that these technologies can also be used as genotyping platforms for CNVs.…”

Section: Cnv Detection Methodsmentioning

confidence: 99%

Gene copy-number polymorphism in nature

2010

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Differences between individuals in the copy-number of whole genes have been found in every multicellular species examined thus far. Such differences result in unique complements of protein-coding genes in all individuals, and have been shown to underlie adaptive phenotypic differences. Here, we review the evidence for copy-number variants (CNVs), focusing on the methods used to detect them and the molecular mechanisms responsible for generating this type of variation. Although there are multiple technical and computational challenges inherent to these experimental methods, next-generation sequencing technologies are making such experiments accessible in any system with a sequenced genome. We further discuss the connection between copy-number variation within species and copynumber divergence between species, showing that these values are exactly what one would expect from similar comparisons of nucleotide polymorphism and divergence. We conclude by reviewing the growing body of evidence for natural selection on copy-number variants. While it appears that most genic CNVsespecially deletions-are quickly eliminated by selection, there are now multiple studies demonstrating a strong link between copy-number differences at specific genes and phenotypic differences in adaptive traits. We argue that a complete understanding of the molecular basis for adaptive natural selection necessarily includes the study of copy-number variation.

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Section: Cnv Detection Methodsmentioning

confidence: 99%

Gene copy-number polymorphism in nature

2010

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“…R. Soc. B 370: 20130374 been retrieved with high-coverage using this approach [32,55,67]. Recently, a whole genome capture method that uses home-made biotinylated RNA probes as bait (which significantly reduces the cost of probe design) has been developed [68].…”

Section: Future Developmentsmentioning

confidence: 99%

Almost 20 years of Neanderthal palaeogenetics: adaptation, admixture, diversity, demography and extinction

Sánchez-Quinto

Lalueza-Fox

2015

Phil. Trans. R. Soc. B

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Nearly two decades since the first retrieval of Neanderthal DNA, recent advances in next-generation sequencing technologies have allowed the generation of high-coverage genomes from two archaic hominins, a Neanderthal and a Denisovan, as well as a complete mitochondrial genome from remains which probably represent early members of the Neanderthal lineage. This genomic information, coupled with diversity exome data from several Neanderthal specimens is shedding new light on evolutionary processes such as the genetic basis of Neanderthal and modern human-specific adaptations-including morphological and behavioural traits-as well as the extent and nature of the admixture events between them. An emerging picture is that Neanderthals had a long-term small population size, lived in small and isolated groups and probably practised inbreeding at times. Deleterious genetic effects associated with these demographic factors could have played a role in their extinction. The analysis of DNA from further remains making use of new large-scale hybridization-capture-based methods as well as of new approaches to discriminate contaminant DNA sequences will provide genetic information in spatial and temporal scales that could help clarify the Neanderthal's-and our very own-evolutionary history.

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“…In contrast, little is known about the coding variation in Neandertals, an extinct hominin group closely related to presentday humans. The main reasons for this are the rarity of Neandertal remains and the fact that >99% of the DNA extracted from typical Neandertal bones is derived from microbes (8,9), making shotgun sequencing of the endogenous DNA impractical.…”

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confidence: 99%

Patterns of coding variation in the complete exomes of three Neandertals

Castellano

Parra

Sánchez-Quinto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage.ancient DNA | exome capture | site frequency spectra | paleogenetics A nalyses of the coding regions of multiple present-day human individuals have uncovered many amino acid-changing SNPs segregating at low frequency in present-day human populations (1-7). It also has been shown that Europeans carry a larger proportion than Africans of amino acid-changing SNPs inferred to alter the structure or function of proteins and thus to be potentially deleterious (4), a fact attributed to the bottleneck and subsequent expansion of human populations during and after the migration out of Africa (4). In contrast, little is known about the coding variation in Neandertals, an extinct hominin group closely related to presentday humans. The main reasons for this are the rarity of Neandertal remains and the fact that >99% of the DNA extracted from typical Neandertal bones is derived from microbes (8, 9), making shotgun sequencing of the endogenous DNA impractical.Here, we use a hybridization approach to enrich and sequence the protein-coding fractions of the genomes of two Neandertals from Spain and Croatia. We analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia (10) and show that the genetic diversity, pattern of coding variation, and genes that may underlie phenotypic changes in Neandertals are remarkably different from those in present-day humans. Results and DiscussionWe used densely tiled oligonucleotide probes (9) and a recently described protocol (11) to capture the protein-coding exons from 17,367 genes in a ∼49,000-y-old (12) (uncalibrated radiocarbon date) Neandertal from Spain (SD1253, El Sidrón Cave) and a ∼44,000-y-old (uncalibrated radiocarbon date) Neandertal from Croatia (Vi33.15, Vindija Cave). The DNA libraries from these two Neandertals contain 0.2% and 0.5% endogenous DNA, respectively, and the capture approach enriched the endogenous DNA 325-fold and 153-fold, resulting in an average coverage of 12.5-fold and 42.0-fold for the El Sidrón and Vindi...

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Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture

Cited by 250 publications

References 26 publications

Gene copy-number polymorphism in nature

Gene copy-number polymorphism in nature

Almost 20 years of Neanderthal palaeogenetics: adaptation, admixture, diversity, demography and extinction

Patterns of coding variation in the complete exomes of three Neandertals

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