Understanding rare and common diseases in the context of human evolution

Quintana-Murci, Lluı́s

doi:10.1186/s13059-016-1093-y

Cited by 89 publications

(73 citation statements)

References 205 publications

(302 reference statements)

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“…Instead, we show that proteins enriched in rare variants are, based on the associated functional pathways, most similar to those enriched in common variants (Figure 8). Moreover, our results show that population variants implicate functions mainly associated with environmental response (Figure 3), in agreement with results from evolutionary studies reviewed in [84].…”

Section: Rare Variants Are Similar To Common Variantssupporting

confidence: 91%

Missense variants in health and disease affect distinct functional pathways and proteomics features

Laddach

Fraternali

2019

Preprint

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Missense variants are present amongst the healthy population, but some of them are causative of human diseases. Therefore, a classification of variants associated with "healthy" or "diseased" states is not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences, is essential to better distinguish pathogenic from population variants. Here we quantify variant enrichment across full-length proteins, their domains and 3D-structure defined regions. We integrate this with available transcriptomic and proteomic (protein half-life, thermal stability, abundance) data. Using this approach we have mined a rich set of molecular features which enable us to understand the differences underlying pathogenic and population variants: pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing, localise to protein cores and interaction interfaces, and are enriched in more abundant proteins. In terms of their molecular properties, we find that common population variants and pathogenic variants show the greatest contrast. Additionally, in contrary to other studies, we find that rare population variants display features closer to common than pathogenic variants. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants. Such details could be harnessed to predict variant deleteriousness, and prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at http://fraternalilab. kcl.ac.uk/ZoomVar. It allows users to programmatically annotate a large number of missense variants with protein structural information, and to calculate variant enrichment in different protein structural regions. Significance StatementOne of the greatest challenges in understanding the genetic basis of diseases is to discriminate between likely harmless and potentially disease-causing sequence variants. To better evaluate the pathogenic potential of missense variants, we developed a strategy to quantitatively measure the enrichment of both disease and non disease-related variants within a protein based on its structural and domain organisation. By integrating available transcriptomics and proteomics data, our approach distinguishes pathogenic from population variants far more clearly than previously possible, and reveals hitherto unknown details of how different proteins exhibit resilience and/or sensitivity towards genetic variants. Our results will help to prioritise variant-enriched proteins for therapeutic targeting; we have created the ZoomVar database, accessible at http://fraternalilab.kcl.ac.uk/ZoomVar, for programmatic mapping of user-defined variants to protein structural and domain information.

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Section: Rare Variants Are Similar To Common Variantssupporting

confidence: 91%

Missense variants in health and disease affect distinct functional pathways and proteomics features

Laddach

Fraternali

2019

Preprint

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“…A well-known example of this phenomenon is described above for the FUT2 gene. The maintenance of multiple ABO histo-blood groups, which most likely resulted from the selective pressure exerted by different pathogens, is also due to balancing selection (reviewed in (Quintana-Murci, 2016)). Several works have indicated that targets of balancing selection in primate genomes have often evolved in response to pathogen-driven selective pressures (Leffler et al, 2013;Ferrer-Admetlla et al, 2008;Azevedo et al, 2015;Fumagalli and Sironi, 2014), making overdominance an appealing model to test for resistance against infection.…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches

Mozzi

Pontremoli

Sironi

2018

Infection, Genetics and Evolution

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Genome-wide association studies (GWASs) have been widely applied to identify genetic factors that affect complex diseases or traits. Presently, the GWAS Catalog includes >2800 human studies. Of these, only a minority have investigated the susceptibility to infectious diseases or the response to therapies for the treatment or prevention of infections. Despite their limited application in the field, GWASs have provided valuable insights by pinpointing associations to both innate and adaptive immune response loci, as well as novel unexpected risk factors for infection susceptibility. Herein, we discuss some issues and caveats of GWASs for infectious diseases, we review the most recent findings ensuing from these studies, and we provide a brief summary of selected GWASs for infections in non-human mammals. We conclude that, although the general trend in the field of complex traits is to shift from GWAS to next-generation sequencing, important knowledge on infectious disease-related traits can be still gained by GWASs, especially for those conditions that have never been investigated using this approach. We suggest that future studies will benefit from the leveraging of information from the host's and pathogen's genomes, as well as from the exploration of models that incorporate heterogeneity across populations and phenotypes. Interactions within HLA genes or among HLA variants and polymorphisms located outside the major histocompatibility complex may also play an important role in shaping the susceptibility and response to invading pathogens.

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“…Curiously, these genetic variants are associated with a decreased risk of the disease and with clinicopathological parameters related to good prognosis. In general, it is expected that due to a natural selection effect the protective genetic variant becomes predominant over the time in a population . In this vein, it is conceivable that these SNPs may constitute recent events, which have not yet reached equilibrium among descendants.…”

Section: Discussionmentioning

confidence: 99%

Influence of E‐cadherin genetic variation in canine mammary tumour risk, clinicopathological features and prognosis

Canadas

Santos

Medeiros

et al. 2019

Vet Comparative Oncology

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E-cadherin is a cell adhesion molecule that participates in several cellular processes that guarantee the maintenance of structural and functional integrity of epithelial tissues. E-cadherin plays an important role in mammary carcinogenesis, and various studies have demonstrated the effect of CDH1 genetic variation in risk, progression and biological behaviour of human breast cancer. Although there are some recognized genetic variations in canine CDH1 gene, their influence in canine mammary tumour development and progression has not been previously evaluated. In this study, we aim to assess the influence of CDH1 SNPs rs850805755, rs852280880 and rs852639930 in the risk, clinicopathological features and clinical outcome of canine mammary tumours. A case-control study was conducted involving 206 bitches with mammary tumours and 161 bitches free of mammary neoplasia. CDH1 SNPs rs850805755 and rs852280880 were associated with a decreased risk and a later onset of mammary tumour development. Furthermore, these SNPs were related to the development of small size carcinomas, of low histological grade and low nuclear pleomorphism. SNP rs852639930 was associated with the development of small size tumours with a non-infiltrative, noninvasive growth pattern. Data from the present investigation demonstrate that these CDH1 genetic variants could have a protective role in canine mammary tumours, by being associated with low risk of tumour development, delayed onset of the disease and less aggressive clinicopathological features. K E Y W O R D S canine mammary tumour, CDH1 gene, E-cadherin, risk, SNP

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Understanding rare and common diseases in the context of human evolution

Cited by 89 publications

References 205 publications

Missense variants in health and disease affect distinct functional pathways and proteomics features

Missense variants in health and disease affect distinct functional pathways and proteomics features

Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches

Influence of E‐cadherin genetic variation in canine mammary tumour risk, clinicopathological features and prognosis

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