Guenther et al. publish in this week's Nature Genetics on their research demonstrating that a single nucleotide substitution in a transcription factor binding site upstream of the KITLG gene decreases the binding of the LEF1 transcription factor, thereby decreasing expression of the gene by ~20% and contributing to lightened pigmentation of the hair. Many genome wide association studies reveal associations between SNPs and phenotype, but discovering the exact genetic basis of these correlations remains challenging. This study provides a great example of painstaking effort by the research team to identify the causal SNP in a blond-associated haplotype and the necessary experimental validation of its functional impact in human cell lines and transgenic mice. Although this is an impressive achievement, as Hopi Hoekstra writes in a comment piece, it also demonstrates the challenges facing researchers in identifying and characterizing the impact of cis-reulgatory changes.
Also particularly notable about this paper is its citation of the work of YMAL lab member, Susan Walsh!