title: Multiple haplotype-resolved genomes reveal population patterns of gene and protein diplotypes.
abstract: To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known. Here we present a comprehensive analysis of haplotype-resolved genomes to assess the nature and variation of haplotypes and their pairs, diplotypes, in European population samples. We use a set of 14 haplotype-resolved genomes generated by fosmid clone-based sequencing, complemented and expanded by up to 372 statistically resolved genomes from the 1000 Genomes Project. We find immense diversity of both haploid and diploid gene forms, up to 4.1 and 3.9 million corresponding to 249 and 235 per gene on average. Less than 15% of autosomal genes have a predominant form. We describe a 'common diplotypic proteome', a set of 4,269 genes encoding two different proteins in over 30% of genomes. We show moreover an abundance of cis configurations of mutations in the 386 genomes with an average cis/trans ratio of 60:40, and distinguishable classes of cis- versus trans-abundant genes. This work identifies key features characterizing the diplotypic nature of human genomes and provides a conceptual and analytical framework, rich resources and novel hypotheses on the functional importance of diploidy.
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Margret R
authors.initials: MR
authors.lastname: Hoehe
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kroslak
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Palczewski
authors.affiliation: Department of Computer Science, University of Leipzig, Leipzig D-04107, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Nowick
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schulz
authors.affiliation: 1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany [2].
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Suk
authors.affiliation: 1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin D-14195, Germany [2].
authors.forename: Thomas
authors.initials: T
authors.lastname: Huebsch
mesh_terms: D015331:Cohort Studies; D004171:Diploidy; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D005858:Germany; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D011506:Proteins