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Functional Genetics of Human Appearance

Our activities, and that of others, to unveil the genetic basis of human appearance traits via candidate gene and genome-wide association studies provide numerous DNA variants from various genes that demonstrate statistically significant trait associations. However, because of the use of microarrays for establishing genome-wide datasets of single nucleotide polymorphism (SNP), which in their design are biased towards SNPs outside genes, the functional relevance of the identified associated SNP typically is unclear. We are using up-to-date functional genetic and functional genomic methods and technologies to unveil the functional basis of appearance-associated SNPs, as next step in understanding the molecular basis of human appearance. For instance, we recently demonstrated that several pigmentation associated SNPs from different genes are functionally responsible for pigmentation variation because they are located in enhancer regions that depending on the SNP-allele interact with promotor regions of the same or nearby genes, and thus regulate pigmentation gene expression with consequent phenotypic differences in human pigmentation traits.

Selected relevant publications:

Liu, F., Visser, M., Duffy, D. L., Hysi, P. G., Jacobs, L. C., Lao, O., Zhong, K., Walsh, S., Chaitanya, L., Wollstein, A., Zhu, G., Montgomery, G. W., Henders, A. K., Mangino, M., Glass, D., Bataille, V., Sturm, R. A., Rivadeneira, F., Hofman, A., van, IJcken W. F., Uitterlinden, A. G., Palstra, R. J., Spector, T. D., Martin, N. G., Nijsten, T. E., Kayser, M. Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up. Hum Genet. 2015 134: 823-35.
PubMed: 25963972

Visser, M., Palstra, R. J., Kayser, M. Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter. Hum Mol Genet. 2015 24: 2649-61.
PubMed: 25631878

Visser, M., Palstra, R. J., Kayser, M. Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene. Hum Mol Genet. 2014 23: 5750-62.
PubMed: 24916375

Visser, M., Kayser, M., Grosveld, F., Palstra, R. J. Genetic variation in regulatory DNA elements: the case of OCA2 transcriptional regulation. Pigment Cell Melanoma Res. 2014 27: 169-77.
PubMed: 24387780

Visser, M., Kayser, M., Palstra, R. J. HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res. 2012 22: 446-55.
PubMed: 22234890