Limits...
Network Modules of the Cross-Species Genotype-Phenotype Map Reflect the Clinical Severity of Human Diseases.

Han SK, Kim I, Hwang J, Kim S - PLoS ONE (2015)

Bottom Line: Recent advances in genome sequencing techniques have improved our understanding of the genotype-phenotype relationship between genetic variants and human diseases.In a large patient population study, we found that disease classes enriched with essential genes tended to show a higher mortality rate than disease classes enriched with nonessential genes.Moreover, high disease mortality rates are explained by the multiple comorbid relationships and the high pleiotropy of disease genes found in the essential gene-enriched diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea.

ABSTRACT
Recent advances in genome sequencing techniques have improved our understanding of the genotype-phenotype relationship between genetic variants and human diseases. However, genetic variations uncovered from patient populations do not provide enough information to understand the mechanisms underlying the progression and clinical severity of human diseases. Moreover, building a high-resolution genotype-phenotype map is difficult due to the diverse genetic backgrounds of the human population. We built a cross-species genotype-phenotype map to explain the clinical severity of human genetic diseases. We developed a data-integrative framework to investigate network modules composed of human diseases mapped with gene essentiality measured from a model organism. Essential and nonessential genes connect diseases of different types which form clusters in the human disease network. In a large patient population study, we found that disease classes enriched with essential genes tended to show a higher mortality rate than disease classes enriched with nonessential genes. Moreover, high disease mortality rates are explained by the multiple comorbid relationships and the high pleiotropy of disease genes found in the essential gene-enriched diseases. Our results reveal that the genotype-phenotype map of a model organism can facilitate the identification of human disease-gene associations and predict human disease progression.

No MeSH data available.


Related in: MedlinePlus

Mapping essential and nonessential disease genes to the Human Disease Network (HDN).(a) The modular architecture of human diseases and their gene essentiality in the HDN. (b) The HDN with the gene essentiality of shared genes is highlighted. Essential/nonessential/other links are colored in red, blue and gray, respectively. Panels I and II show examples of essential and nonessential disease clusters, respectively. (c) The fraction of triangular network motifs connected by essential or nonessential genes. Others are triangular network motifs, where both essential and nonessential disease genes connect minimum two diseases in the network motifs.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4547739&req=5

pone.0136300.g002: Mapping essential and nonessential disease genes to the Human Disease Network (HDN).(a) The modular architecture of human diseases and their gene essentiality in the HDN. (b) The HDN with the gene essentiality of shared genes is highlighted. Essential/nonessential/other links are colored in red, blue and gray, respectively. Panels I and II show examples of essential and nonessential disease clusters, respectively. (c) The fraction of triangular network motifs connected by essential or nonessential genes. Others are triangular network motifs, where both essential and nonessential disease genes connect minimum two diseases in the network motifs.

Mentions: We found that essential/nonessential disease genes organize human diseases into a modular structure (Fig 2A). To investigate how the genotype-phenotype relationship organizes disease phenotypes based on gene essentiality, we constructed a human disease network (HDN) linked by essential or nonessential disease genes. HDN nodes represent diseases and links connect them if two diseases have any shared genetic origin [12]. HDN links were classified into essential or nonessential links when the shared genes of disease pair are exclusively essential or nonessential disease genes. HDN links were classified ‘others’ when the shared genes of disease pair include both essential and nonessential disease genes. We supplied the list of essential/nonessential links and shared genes in the HDN (S2 Table).


Network Modules of the Cross-Species Genotype-Phenotype Map Reflect the Clinical Severity of Human Diseases.

Han SK, Kim I, Hwang J, Kim S - PLoS ONE (2015)

Mapping essential and nonessential disease genes to the Human Disease Network (HDN).(a) The modular architecture of human diseases and their gene essentiality in the HDN. (b) The HDN with the gene essentiality of shared genes is highlighted. Essential/nonessential/other links are colored in red, blue and gray, respectively. Panels I and II show examples of essential and nonessential disease clusters, respectively. (c) The fraction of triangular network motifs connected by essential or nonessential genes. Others are triangular network motifs, where both essential and nonessential disease genes connect minimum two diseases in the network motifs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4547739&req=5

pone.0136300.g002: Mapping essential and nonessential disease genes to the Human Disease Network (HDN).(a) The modular architecture of human diseases and their gene essentiality in the HDN. (b) The HDN with the gene essentiality of shared genes is highlighted. Essential/nonessential/other links are colored in red, blue and gray, respectively. Panels I and II show examples of essential and nonessential disease clusters, respectively. (c) The fraction of triangular network motifs connected by essential or nonessential genes. Others are triangular network motifs, where both essential and nonessential disease genes connect minimum two diseases in the network motifs.
Mentions: We found that essential/nonessential disease genes organize human diseases into a modular structure (Fig 2A). To investigate how the genotype-phenotype relationship organizes disease phenotypes based on gene essentiality, we constructed a human disease network (HDN) linked by essential or nonessential disease genes. HDN nodes represent diseases and links connect them if two diseases have any shared genetic origin [12]. HDN links were classified into essential or nonessential links when the shared genes of disease pair are exclusively essential or nonessential disease genes. HDN links were classified ‘others’ when the shared genes of disease pair include both essential and nonessential disease genes. We supplied the list of essential/nonessential links and shared genes in the HDN (S2 Table).

Bottom Line: Recent advances in genome sequencing techniques have improved our understanding of the genotype-phenotype relationship between genetic variants and human diseases.In a large patient population study, we found that disease classes enriched with essential genes tended to show a higher mortality rate than disease classes enriched with nonessential genes.Moreover, high disease mortality rates are explained by the multiple comorbid relationships and the high pleiotropy of disease genes found in the essential gene-enriched diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea.

ABSTRACT
Recent advances in genome sequencing techniques have improved our understanding of the genotype-phenotype relationship between genetic variants and human diseases. However, genetic variations uncovered from patient populations do not provide enough information to understand the mechanisms underlying the progression and clinical severity of human diseases. Moreover, building a high-resolution genotype-phenotype map is difficult due to the diverse genetic backgrounds of the human population. We built a cross-species genotype-phenotype map to explain the clinical severity of human genetic diseases. We developed a data-integrative framework to investigate network modules composed of human diseases mapped with gene essentiality measured from a model organism. Essential and nonessential genes connect diseases of different types which form clusters in the human disease network. In a large patient population study, we found that disease classes enriched with essential genes tended to show a higher mortality rate than disease classes enriched with nonessential genes. Moreover, high disease mortality rates are explained by the multiple comorbid relationships and the high pleiotropy of disease genes found in the essential gene-enriched diseases. Our results reveal that the genotype-phenotype map of a model organism can facilitate the identification of human disease-gene associations and predict human disease progression.

No MeSH data available.


Related in: MedlinePlus