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1.
Nat Genet ; 51(11): 1660, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31591513

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Nat Genet ; 51(9): 1330-1338, 2019 09.
Article in English | MEDLINE | ID: mdl-31477934

ABSTRACT

Inferring the full genealogical history of a set of DNA sequences is a core problem in evolutionary biology, because this history encodes information about the events and forces that have influenced a species. However, current methods are limited, and the most accurate techniques are able to process no more than a hundred samples. As datasets that consist of millions of genomes are now being collected, there is a need for scalable and efficient inference methods to fully utilize these resources. Here we introduce an algorithm that is able to not only infer whole-genome histories with comparable accuracy to the state-of-the-art but also process four orders of magnitude more sequences. The approach also provides an 'evolutionary encoding' of the data, enabling efficient calculation of relevant statistics. We apply the method to human data from the 1000 Genomes Project, Simons Genome Diversity Project and UK Biobank, showing that the inferred genealogies are rich in biological signal and efficient to process.


Subject(s)
Algorithms , Evolution, Molecular , Genetics, Population , Genome, Human , Pedigree , Selection, Genetic , Computer Simulation , Datasets as Topic , Haplotypes , Humans , Models, Genetic , Mutation , Polymorphism, Single Nucleotide , Population Density
3.
Cell ; 174(3): 622-635.e13, 2018 07 26.
Article in English | MEDLINE | ID: mdl-29909983

ABSTRACT

Transcription factors regulate the molecular, morphological, and physiological characteristics of neurons and generate their impressive cell-type diversity. To gain insight into the general principles that govern how transcription factors regulate cell-type diversity, we used large-scale single-cell RNA sequencing to characterize the extensive cellular diversity in the Drosophila optic lobes. We sequenced 55,000 single cells and assigned them to 52 clusters. We validated and annotated many clusters using RNA sequencing of FACS-sorted single-cell types and cluster-specific genes. To identify transcription factors responsible for inducing specific terminal differentiation features, we generated a "random forest" model, and we showed that the transcription factors Apterous and Traffic-jam are required in many but not all cholinergic and glutamatergic neurons, respectively. In fact, the same terminal characters often can be regulated by different transcription factors in different cell types, arguing for extensive phenotypic convergence. Our data provide a deep understanding of the developmental and functional specification of a complex brain structure.


Subject(s)
Drosophila melanogaster/embryology , Gene Expression Regulation, Developmental/physiology , Neurogenesis/physiology , Animals , Cell Differentiation , Cholinergic Neurons/physiology , Cluster Analysis , Computer Simulation , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Gene Expression Profiling/methods , Homeodomain Proteins , LIM-Homeodomain Proteins/metabolism , Maf Transcription Factors, Large/metabolism , Neuroglia/physiology , Neurons/physiology , Neurotransmitter Agents/genetics , Neurotransmitter Agents/physiology , Optic Lobe, Nonmammalian/physiology , Phenotype , Proto-Oncogene Proteins/metabolism , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription Factors/physiology
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