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.
Highlights
To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known
We addressed the following specific objectives: (i) to determine the entirety of different gene and protein haplotypes and diplotypes in the European population, and evaluate their frequencies of occurrence (FoO); (ii) to examine whether certain classes of genes preferentially encode two different forms of the protein to gain insight into the potential functional importance of diploidy and (iii) to evaluate the distribution of cis versus trans configurations of mutations at the gene and whole-genome level to uncover common patterns of phase
We identify key features characterizing the diploid landscape in human genomes, and contribute novel insights into the ‘true nature of genetic variation’, which cannot be understood without knowing the distribution of variants on each of the two parental sets of chromosomes
Summary
To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known. We addressed the following specific objectives: (i) to determine the entirety of different gene and protein haplotypes and diplotypes in the European population, and evaluate their frequencies of occurrence (FoO); (ii) to examine whether certain classes of genes preferentially encode two different forms of the protein to gain insight into the potential functional importance of diploidy and (iii) to evaluate the distribution of cis versus trans configurations of mutations at the gene and whole-genome level to uncover common patterns of phase. We observe different classes of cis- and trans-abundant genes With these results, we identify key features characterizing the diploid landscape in human genomes (for overview see Fig. 1), and contribute novel insights into the ‘true nature of genetic variation’, which cannot be understood without knowing the distribution of variants on each of the two parental sets of chromosomes
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