Multiple haplotype-resolved genomes reveal population patterns of gene and protein diplotypes

Hoehe, Margret R.; Church, George M.; Lehrach, Hans; Kroslak, Thomas; Palczewski, Stefanie; Nowick, Katja; Schulz, Simon; Suk, Eun-Kyung; Huebsch, Thomas

doi:10.1038/ncomms6569

Cited by 29 publications

(45 citation statements)

References 42 publications

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“…Cis configurations of protein-altering mutations, leaving one form of the gene intact, would be expected to occur more frequently in human genomes to preserve organismal function (Hoehe et al 2014). To test this hypothesis at large scale in 1,092 genomes (Abecasis et al 2012) (Methods), we determined the ratio of cis to trans configurations of protein-altering mutations across all autosomal protein-coding genes for each of the genomes and derived the median of these ratios (Methods; see also Box 1).…”

Section: Global Abundance Of Cis Configurations Of Mutationsmentioning

confidence: 99%

“…Thus, to fully understand the biology of genes and genomes, the phase of mutations must be known. In a first population level analysis of haplotype-resolved genomes (Hoehe et al 2014), we have shown nonrandom distribution of mutations between homologous gene forms, as indicated by significant abundance of cis configurations with an average cis/trans ratio of approximately 60:40. This raises the question: Could cis-abundance of mutations, the preferential location of mutations on the same chromosomal homologue of an autosomal gene, represent a key characteristic of diploid human genomes?…”

Section: Introductionmentioning

confidence: 99%

“…We assessed the cis/trans ratios of mutations in 1,092 statistically haplotype-resolved genomes from the 1000 Genomes database (Abecasis et al 2012) and each of the different populations contained therein separately. Because the analysis of molecularly and statistically haplotype-resolved genomes had yielded nearly identical results earlier (Hoehe et al 2014), the use of this large resource appeared suitable. The key results obtained from this resource were then cross-validated in an independent sample of 184 experimentally phased genomes from the Personal Genome Project (PGP) (Mao et al 2016;Ball et al 2012), a huge advance over the recent population-level analysis of 14 molecularly haplotype-resolved genomes (Hoehe et al 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Because the analysis of molecularly and statistically haplotype-resolved genomes had yielded nearly identical results earlier (Hoehe et al 2014), the use of this large resource appeared suitable. The key results obtained from this resource were then cross-validated in an independent sample of 184 experimentally phased genomes from the Personal Genome Project (PGP) (Mao et al 2016;Ball et al 2012), a huge advance over the recent population-level analysis of 14 molecularly haplotype-resolved genomes (Hoehe et al 2014). Cis/trans ratios were assessed for population samples as a whole as well as for each individual genome separately as described in more detail in Box 1, which also provides further information on the concepts underlying our approach.…”

Section: Introductionmentioning

confidence: 99%

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Significant abundance ofcisconfigurations of mutations in diploid human genomes

Hoehe

Herwig

Mao

et al. 2017

Preprint

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To fully understand human genetic variation, one must assess the specific distribution of variants between the two chromosomal homologues of genes, and any functional units of interest, as the phase of variants can significantly impact gene function and phenotype. To this end, we have systematically analyzed 18,121 autosomal protein-coding genes in 1,092 statistically phased genomes from the 1000 Genomes Project, and an unprecedented number of 184 experimentally phased genomes from the Personal Genome Project. Here we show that mutations predicted to functionally alter the protein, and coding variants as a whole, are not randomly distributed between the two homologues of a gene, but do occur significantly more frequently in cis-than transconfigurations, with cis/trans ratios of ~60:40. Significant cis-abundance was observed in virtually all individual genomes in all populations. Nearly all variable genes exhibited either cis, or trans configurations of protein-altering mutations in significant excess, allowing distinction of cis-and trans-abundant genes. These common patterns of phase were largely constituted by a shared, global set of phase-sensitive genes. We show significant enrichment of this global set with gene sets indicating its involvement in adaptation and evolution. Moreover, cis-and trans-abundant genes were found functionally distinguishable, and exhibited strikingly different distributional patterns of protein-altering mutations. This work establishes common patterns of phase as key characteristics of diploid human exomes and provides evidence for their potential functional significance. Thus, it highlights the importance of phase for the interpretation of protein-coding genetic variation, challenging the current conceptual and functional interpretation of autosomal genes.

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Section: Global Abundance Of Cis Configurations Of Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Significant abundance ofcisconfigurations of mutations in diploid human genomes

Hoehe

Herwig

Mao

et al. 2017

Preprint

Self Cite

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“…Pure and intact genomic DNA fragments of about 35 Kb are separated in pools for haplotype analysis. For the relatively simple clone pipeline in comparison with BAC clone, fosmid clone was used to operate dilution pools strategy by several groups [33][34][35][36][37][38]. Kitzman et al [33] constructed a single, complex fosmid library in 2011.…”

Section: Fosmid Clone Poolsmentioning

confidence: 99%

Comparison of the experimental methods in haplotype sequencing via next generation sequencing

Lü

Duan

et al. 2016

Quant. Biol.

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Although the diploid nature has been observed for over 50 years, phasing the diploid is still a laborious task. The speed and throughput of next generation sequencing have largely increased in the past decades. However, the short read-length remains one of the biggest challenges of haplotype analysis. For instance, reads as short as 150 bp span no more than one variant in most cases. Numerous experimental technologies have been developed to overcome this challenge. Distance, complexity and accuracy of the linkages obtained are the main factors to evaluate the efficiency of whole genome haplotyping methods. Here, we review these experimental technologies, evaluating their efficiency in linkages obtaining and system complexity. The technologies are organized into four categories based on its strategy: (i) chromosomes separation, (ii) dilution pools, (iii) crosslinking and proximity ligation, (ix) long-read technologies. Within each category, several subsections are listed to classify each technology. Innovative experimental strategies are expected to have high-quality performance, low cost and be labor-saving, which will be largely desired in the future.

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