Complexities of Genotype and Mendelian Phenotype in Population-Specific Studies
The relationship between genotype and phenotype, particularly in the context of Mendelian traits, has been a central focus in genetics for over a century. Recent advances in genetic research have allowed scientists to explore this relationship in greater depth, especially within specific populations. In this blog post, we delve into some of the latest findings from top scientific journals that shed light on the intricate interplay between genotype and Mendelian phenotype in population-specific studies.
1. Enhancing Understanding through Genotype-Based Recall Studies
In a 2018 review published in Circulation: Genomic and Precision Medicine, Franks and Timpson discuss the potential of genotype-based recall (GBR) studies in complex cardiometabolic traits. GBR studies selectively recall individuals from larger cohorts based on their genotypes of interest. This approach allows for more detailed investigations into genotype-phenotype associations, environmental exposures, and gene-treatment interactions within Mendelian randomization frameworks. The review emphasizes how GBR methods can augment randomized controlled trials and explore biological pathways relevant to cardiometabolic health outcomes. (Franks & Timpson, 2018)
2. Addressing Population Phenomena
Morris et al., in their 2019 paper published in Science Advances, discuss how population phenomena such as population stratification, dynastic effects, and assortative mating can inflate genotype-phenotype associations. The authors demonstrate that heritability and genetic correlation estimates obtained from samples of unrelated individuals may be biased. They advocate for the use of family-based designs to explore the mechanisms driving genotype-phenotype associations and identify factors underlying bias in estimates. (Morris et al., 2019)
3. Quantifying Genotyping Errors in Population Genetics
Broquet and Petit's 2004 paper in Molecular Ecology addresses the challenges of obtaining reliable genotypes from noninvasively collected samples in population genetics studies. The authors propose accurate codification for the frequencies of false alleles and allelic dropouts, emphasizing the importance of carefully computing and reporting genotyping error rates to ensure the reliability of genetic data. (Broquet & Petit, 2004)
4. Navigating Variant Prioritization in Mendelian Diseases
In a 2017 review in Nature Reviews Genetics, Eilbeck, Quinlan, and Yandell discuss the variant prioritization process in Mendelian diseases. They highlight the strengths and weaknesses of widely used computational approaches and explain their roles in the diagnostic and discovery process. The review also discusses how variant prioritization can inform (and misinform) expert reviewers and places it in the wider context of gene prioritization, burden testing, and genotype-phenotype association. (Eilbeck et al., 2017)
In conclusion, recent studies highlight the complexity of genotype-phenotype associations in population-specific contexts, particularly for Mendelian traits. Advances in genetic and phenotypic research are providing deeper insights into the genetic underpinnings of diseases and traits, paving the way for more precise and personalized medical interventions.
Reference:
Franks, P., & Timpson, N. (2018). Genotype-Based Recall Studies in Complex Cardiometabolic Traits. Circulation: Genomic and Precision Medicine, 11, e001947.
Morris, T., Davies, N., Hemani, G., & Smith, G. (2019). Population phenomena inflate genetic associations of complex social traits. Science Advances, 6.
Broquet, T., & Petit, E. (2004). Quantifying genotyping errors in noninvasive population genetics. Molecular Ecology, 13.
Eilbeck, K., Quinlan, A., & Yandell, M. (2017). Settling the score: variant prioritization and Mendelian disease. Nature Reviews Genetics, 18, 599-612.
